Jmcpsuppb Oct07

Renin-Angiotensin Aldosterone System and Hypertension:
Current Approaches and Future Directions

John M. Flack, MD, MPH
Steven A. Atlas, MD
James L. Pool, MD
William B. White, MD
Supplement
October 2007
Vol. 13, No. 8, S-b
AUTHORS
Editor-in-Chief
Frederic R. Curtiss, PhD, RPh, CEBS
(830) 935-4319, fcurtiss@amcp.org
Managing Editor
Jamie Kunkle, (703) 671-1358
jkunkle@amcp.org
Assistant Editor
Diane P. Britton
drbritton@verizon.net
Peer Review Administrator
Jennifer A. Booker, (703) 317-0725
jmcpreview@amcp.org
Graphic Designer
Leslie Goodwin
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Account Manager
Peter Palmer, (856) 795-5777, ext. 13
peter@promedgroup.net
Publisher
Judith A. Cahill, CEBS
Executive Director
Academy of Managed Care Pharmacy
This supplement to the Journal of Managed Care Pharmacy
(ISSN 10834087) is a publication of the Academy of Managed
Care Pharmacy, 100 North Pitt St., Suite 400, Alexandria, VA
22314; (703) 683-8416; (703) 683-8417 (fax).
Copyright 2007, Academy of Managed Care Pharmacy.
All rights reserved. No part of this publication may be
reproduced or transmitted in any form or by any means,
electronic or mechanical, without written permission from
the Academy of Managed Care Pharmacy.
POSTMASTER: Send address changes to JMCP,
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Standards for Supplements to the
Journal of Managed Care Pharmacy
Supplements to the Journal of Managed Care Pharmacy are

intended to support medical education and research in areas
of clinical practice, health care quality improvement, or
efficient administration and delivery of health benefits. The
following standards are applied to all JMCP supplements to
assure quality and assist readers in evaluating potential
bias and determining alternate explanations for findings
and results.
1. Disclose the principal sources of funding in a manner that
permits easy recognition by the reader.
2. Disclose the existence of all potential conflicts of interest among supplement contributors, including financial or
personal bias.
3. Describe all drugs by generic name unless the use of
the brand name is necessary to reduce the opportunity for
confusion among readers.
4. Strive to report subjects of current interest to managed
care pharmacists and other managed care professionals.
5. Seek and publish content that does not duplicate content
in the Journal of Managed Care Pharmacy.
6. Subject all supplements to expert peer review.
Steven A. Atlas, MD, is an associate professor of medicine, Mount Sinai School

of Medicine, New York, and chief of the Cardiology/Hypertension/Endocrinology
Practice, James J. Peters VA Medical Center, Bronx, NY, where he also directs the
Hypertension Research Laboratory.
Atlass research has focused on the renin-angiotensin system and the natriuretic
peptide hormone family. He was one of the first investigators to study the ACE inhibitors, participating in the earliest clinical trials of captopril and subsequent agents.
He has also published widely in the area of renin biochemistry. In recent years, he
has focused on the regulation of cardiac expression of angiotensin II and the natriuretic peptides and their interaction with cytokines and growth factors in the cardiac
response to pressure overload.
Atlas has been an invited lecturer at major medical and scientific meetings. He is
a reviewer for numerous medical journals and has been a member of several editorial boards and research review committees (e.g., National Institutes of Health, the
American Heart Association, and the Veterans Administration). He is a Fellow of the
Council for High Blood Pressure Research and the American Heart Association, and is
a member of several other medical societies, including the American Society of Clinical
Investigation, the American Society of Hypertension, and the Endocrine Society.
John M. Flack, MD, MPH, FAHA, is a specialist in clinical hypertension and is
principal investigator, Center for Urban and African American Health, Wayne State
University, Detroit, MI. Flack is also a professor, interim chair, and chief of the
Division of Translational Research and Clinical Epidemiology, Department of Internal
Medicine, Wayne State University School of Medicine, and specialist-in-chief for
internal medicine, Detroit Medical Center.
Flack has 145 peer-reviewed publications to his credit and has been repeatedly
named one of the Best Doctors in America. He received the Pillar of Excellence award
from the Michigan Peer Review Organization (MPRO) and the Health Care Hero award
from Crains Detroit Business (2005) for disparities-related research. He serves on the
boards of MPRO, the American Heart AssociationMetro Detroit, and the National
Kidney Foundation Scientific Advisory Group. Flack is also a member of the CardioRenal Advisory Panel for the Food and Drug Administration.
James L. Pool, MD, is a professor of medicine and pharmacology, Baylor College
of Medicine, Houston, TX, and holds the James L. Pool Endowed Chair in Clinical
Pharmacology. He is also the clinical director, Hypertension-Clinical Pharmacology
Research Clinic, at Baylor.
Pool has received numerous awards and honors, including being named a Fellow of
the American Heart Association and one of the Best Doctors in America in internal
medicine and clinical pharmacology from 1996 to 2006. He is a board-certified medical specialist in internal medicine, endocrinology, and clinical pharmacology.
Pool is an international lecturer and has published numerous abstracts, articles,
and book chapters. He has also written and hosted several films, videos, telelectures,
and television productions on medical subjects.
For the past 3 decades, his research interests have been in the fields of hypertension, clinical pharmacology, antihypertensive drug development, metabolic effects of
cardiovascular drugs, and cardiovascular disorders of the autonomic nervous system.
In addition, Pool has been a leader in the development of information technology for
health care.
William B. White, MD, is a professor, Department of Medicine, and chief, Division
of Hypertension and Clinical Pharmacology, Pat and Jim Calhoun Cardiology Center,
University of Connecticut Health Center, Farmington, where he has worked for 29 years.
In addition, he is lead physician, Hypertension and Vascular Diseases faculty practice,
Cardiology Center, John Dempsey Hospital, and medical director, Clinical Trials Unit,
Farmington.
White is the author or coauthor of more than 340 articles and book chapters in
the field of hypertension and clinical pharmacology and is the editor for the medical
textbook series Clinical Hypertension and Vascular Diseases, published by Humana
Press, Ltd. (Totowa, NJ) on the evaluation, management, and treatment of hypertension and related disorders. A Fellow of the American Heart Association and American
College of Physicians, White also has served on 12 editorial boards, including the
American Journal of Cardiology, American Journal of Medicine, Clinical Pharmacology
and Therapeutics, Journal of Human Hypertension, Journal of Clinical Hypertension, and
Hypertension.
Table of Contents
Renin-Angiotensin Aldosterone System and Hypertension:
Current Approaches and Future Directions
John M. Flack, MD, MPH, FAHA; Steven A. Atlas, MD; James L. Pool, MD; and William B. White, MD
S2 Epidemiology and Unmet Needs in Hypertension

John M. Flack, MD, MPH, FAHA
S9 The Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition

Steven A. Atlas, MD
S21 Direct Renin Inhibition: Focus on Aliskiren

James L. Pool, MD
S34 Importance of Blood Pressure Control Over a 24-Hour Period

The opinions expressed in the supplement are those of the faculty and do not necessarily represent the official policies or views
of the Academy of Managed Care Pharmacy or the authors institutions unless so specified. The authors have disclosed if any
unlabeled use of products is mentioned in their articles. Before prescribing any medicine, clinicians should consult primary
references of full prescribing information.
Epidemiology and Unmet Needs in Hypertension

John M. Flack, MD, MPH, FAHA
Abstract
Background: The persistent control of blood pressure (BP) to levels
below current recommended levels is an important but often elusive goal
for patients with hypertension.
Objective: To provide an overview of unmet needs in contemporary
hypertension treatment.
Summary: The rationale for BP normalization is very persuasive.
Incrementally higher BP levels predict higher rates of microvascular
(e.g., retinopathy, stroke, nephropathy) and macrovascular disease (e.g.,
myocardial infarction), as well as organ (e.g., heart) failure. Accordingly,
the pharmacologic reduction of BP levels with a broad range of mechanistically dissimilar agents reduces the risk of these BP-related complications.
The primary prevention of BP-related complications has been closely linked
to the magnitude of decreases in BP brought about pharmacologically,
but some modest disease-specific differences have been noted between
drug classes. However, pharmacologic blockade of the renin-angiotensin
aldosterone system in high-risk patients (e.g., patients with diabetic
nephropathy) reduces the risk of BP-related renal end points more than
treatment strategies that do not include these agents, even when BP levels
are lowered to similar degrees.
Conclusion: Despite the large number of antihypertensive agents
available, the majority of patients with hypertension who are treated
with drugs do not attain goal BP levels. Though the reasons for this are
complex and relate to various factors for patients, providers, and systems
of medical care delivery, new pharmacologic treatments hold the potential
to augment the reduction of BP levels while minimizing class-specific
side effects.
Keywords: Blood pressure, Vascular disease, Hypertensive agents,
Hypertension
J Manag Care Pharm. 2007;13(8)(suppl S-b):S2-S8
Copyright 2007, Academy of Managed Care Pharmacy. All rights reserved.
Author
John M. Flack, MD, MPH, FAHA, is a specialist in clinical

hypertension and is principal investigator, Center for Urban and
African American Health, Wayne State University, Detroit, MI.
He is also a professor, interim chair, and chief of the Division of
Translational Research and Clinical Epidemiology, Department
of Internal Medicine, Wayne State University School of Medicine,
and specialist-in-chief for internal medicine, Detroit Medical Center.
Author Correspondence: John M. Flack, MD, MPH, FAHA,
Harper Professional Building, Wayne State University, 4160 John R,
Suite 1002, Detroit, MI 48201. Tel: (313) 745-4525;
Fax: (313) 993-0085; E-mail: jflack@med.wayne.edu
S2 Supplement to Journal of Managed Care Pharmacy
JMCP
October 2007
pproximately 72 million people in the United States have

hypertension.1 The prevalence of hypertension is increasing in both men and women across the age span, but more
rapidly in women. Indeed, the age-adjusted prevalence of hypertension is higher in women than in men, and is also higher in
black people than in members of other racial groups. If elevated
blood pressure (BP) was only a number, then the monumental
attention it has received over the last several decades in the medical community would be unwarranted. Thus it is important to
understand that incrementally higher levels of BPespecially systolic BP (SBP)beginning at levels well within the normal range,
cause or promote microvascular and macrovascular diseases,
as well as target-organ injury or failure.2-4 The absolute risk for
BP-related cardiovascular disease (CVD) events is much higher
when elevated BP levels coexist with other CVD risk factors, such
as diabetes and dyslipidemia. Pharmacologic lowering of BP with
mechanistically dissimilar antihypertensive agents reduces the
risk of, but does not entirely prevent, BP-related CVD events, such
as stroke, heart failure, retinopathy, and nephropathy.
Pharmacologic reduction of BP levels in patients with hypertension does not reduce risk of CVD and renal events to an
incidence similar to that of normotensive individuals. Certainly,
some of the residual risk in drug-treated patients with hypertension is attributable to BP levels that remain significantly above
those in normotensive individuals. However, the risk of CVD
and renal events remains higher in treated patients with hypertension than in normotensive patients, even when they have the
same BP level.
This is an intuitively logical observation. Once BP is persistently elevated, which is undoubtedly both a consequence and
a cause of vascular/organ injury, it seems implausible that total
reversal of the underlying vascular/organ pathology will occur
without prolonged reduction of BP levels that are well below
currently recommended treatment targets. Accordingly, it is possible to argue that currently recommended BP target levels are
not truly normal in a physiologic sense because they have been
largely derived from clinical trial data that, until recently, did not
reflect an attempt in the study to reduce BP levels to normal or
near-normal levels. The Treatment of Mild Hypertension Study
(TOMHS),5 an often overlooked trial, reported fewer cardiovascular events in relatively low-risk patients with hypertension
when SBP was lowered to ~125 mm Hg compared with ~131 mm
Hg. Thus, the anticipated benefit of reducing BP levels could be
even greater among high-risk patients with hypertension, such
as those with diabetes mellitus, who attained a very low BP level
(e.g., <120/70 mm Hg), assuming that the reduction of BP to
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such a level was both feasible and harmless. Given the current
armamentarium of antihypertensive agents, this very low level
will undoubtedly require a carefully assembled multidrug treatment strategy that will almost assuredly include a diuretic.
The holy grail of antihypertensive treatment is to persistently
reduce BP to below goal levels with drug regimens that maximize
target-organ protection. Reducing cuff BP levels has typically
served as a reliable proxy for the primary prevention of BP-related
target-organ complications.6 Indeed, most of the risk reduction
for BP-related complications, especially in nonhigh-risk hypertensive patients, can be statistically linked very closely, though
not exclusively, to the magnitude of the reduction of the BP level
with mechanistically dissimilar antihypertensive agents.6,7
As White discusses in another article in this supplement,
lowering BP throughout the entire 24-hour time interval is highly
desirable.8 The most accurate way to determine that BP control
truly occurs throughout the day and night is to use ambulatory
BP monitoring. A less accurate way to assess 24-hour BP control
is to determine BP levels just before morning dosing when the
hypotensive effect of antihypertensive medication(s) is at its
nadir.
In patients with hypertension who are at higher risk, such as
those with diabetic nephropathy or at high cardiovascular risk,
the superiority of suppressing the renin-angiotensin aldosterone
system (RAAS) with angiotensin receptor blockers (ARBs) compared with other antihypertensive agents has been repeatedly
demonstrated, most often in renoprotection and reduction of
risk of hospitalization for new heart failure.9-11 The data on nonrenal target-organ protection using RAAS blockade in high-risk
patients, both normotensive and hypertensive, has been encouraging but not consistent.12-14 It should be noted, however, that the
reduction in the BP level occurs as a consequence of favorably
altering vascular hemodynamics, intravascular volume status,
and cardiac function in response to drug-induced changes in
basic organ and cellular metabolism and function. Accordingly,
the close statistical link between the reduction of BP level and
the reduction of the risk of CVD events does not mean that BP
reduction, occurring as a consequence of unmeasured changes
in cardiac, vascular, and kidney function, is the sole mediator of
CVD and renal risk reduction.
There are clinical end point data showing that different
antihypertensive drugs lead to significantly different CVD
outcomes, possibly on the basis of differential effects on intravascular hemodynamics.14-16 However, the largest hypertension
end point trial ever conducted, the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT)
study, found no difference in the primary, and prespecified
secondary pressure-related, clinical outcomes between 2 of
the 3 treatment strategies (amlodipine vs. chlorthalidone).
However, there was a greater incidence of the combined CVD
secondary end point with lisinopril than with chlorthalidone.13
Nevertheless, in nonhigh-risk patients with hypertension, even
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Vol. 13, No. 8, S-b
when differences in the primary prevention of clinical outcomes

between drug classes have been noted, differences in outcomes
tend to be organ specific, and the majority of CVD-renal
outcomes do not consistently favor 1 drug class. Interestingly,
a recently published comparison of hypertension guidelines in
the United States and Europe indicated that lower hypertension guideline treatment thresholds and more intensive anti
hypertensive treatment in the United States was associated with
better hypertension control compared with that seen in western
Europe.17
Adequacy of Recommendations for Control of BP Levels
Current BP reduction targets for high-risk patients with
hypertensionthose with diabetes, vascular disease, previous
CVD or coronary heart disease, and/or kidney diseasehave
received criticism for not being evidence-based. The likely reason
for such criticism is that the benefits and safety of these targets
have not been demonstrated explicitly in a randomized clinical
trial in which a treatment arm goal was specified to be a BP of
<130/80 mm Hg. However, though clinical trials provide a high
level of evidence-based information, data from any trial must be
both interpreted and considered in the context of all the available
information, including previous clinical trials, rigorous observational studies, and physiologic and basic science observations.
If BP levels are to be persistently maintained below
recommended goal levels, then practitioners must aim to drive
BP levels well below these target BP levels. Thus, goal BP levels
must be considered more like ceilings than floors. Even nonhighrisk hypertensive patients will likely manifest residual risk for
pressure-related CVD sequelae if BP levels are only lowered into
the range of slightly below 140/90 mm Hg.5 Epidemiologic data
document that the risk of CVD doubles for every 20/10 mm Hg
increment above ~115/75 mm Hg.18 Currently recommended
target-organ protection BP levels for nonhigh-risk patients with
hypertension remain well above the upward inflection point for
CVD risk (~115/75 mm Hg; Figure 1). Thus, given the extensive
clinical database regarding the risks and benefits of pharmacologic treatment and the fact that virtually no unconfounded
evidence exists that pharmacologic treatment is harmful in most
patients with hypertension, striving to maintain BP levels as close
to the upward inflection point (~115/75 mm Hg) for CVD risk
with a combination of lifestyle modifications and drug therapies
seems intuitively appealing. Nevertheless, attaining and maintaining such a BP level will be more difficult in high-risk patients
with hypertension than in their nonhigh-risk counterparts.
A qualified recommendation of this nature, however, does not
obviate the necessity to prove its validity in clinical end point
studies.
Control of BP Levels
Thirty-one percent of white, 27% of black, and 41% of Mexican
American people with hypertension are unaware of their
October 2007
JMCP
Supplement to Journal of Managed Care Pharmacy S3
condition.19 Seventy-five percent of people were unaware that

they had hypertension, even though their BP was measured by
a health professional within the previous year. Approximately
40% were taking a non-BP prescription medicine and the 75% of
patients who were unaware that they had hypertension averaged
at least 3 clinic visits to a physicians office a year.19 Accordingly,
better identification of hypertension in our clinical practices
seems warranted.
It is also important to identify all concurrent CVD risk factors
and to undertake adequate risk stratification of patients before
treatment. For example, application of the Seventh Report of the
Joint National Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure (JNC 7) guidelines would
require, at a minimum, that diabetes status be ascertained, that
a spot urine albumin to creatinine ratio be obtained, and that
serum creatinine be measured so that the glomerular filtration
rate can be estimated.
Therapeutic Inertia
Therapeutic inertia is lack of practitioner action to intensify antihypertensive drug therapy or initiate new antihypertensive drugs
for a patient with documented BP elevations. Therapeutic inertia
occurs in the majority of hypertension visits that occur in the
ambulatory outpatient setting among patients with documented
BP elevations.20-21 In a 2006 study by Okonofua and colleagues,
therapeutic inertia occurred at ~87% of clinic visits when BP was
uncontrolled (>140/90 mm Hg).21 It is important that higher
therapeutic inertia scores were linked to significantly less longitudinal BP lowering. Accordingly, patients in the lowest therapeutic
JMCP
October 2007
inertia quintile were ~33 times more likely than those in the
highest quintile to attain BP control. The investigators further
estimated that if therapeutic inertia could be avoided in ~30% of
visits, BP control rates would increase from 45.1% to 65.9% in
this hypertensive cohort.21
Therapeutic inertia is not solely the result of the practitioner,
but likely represents a complex interaction between the patient
and the practitioner. Patients are often reluctant to take either
higher doses or additional antihypertensive medications, in part
because they mistake BP-related side effects for drug-induced
side effects. In clinical practice, patients belief that the long-term
use of antihypertensive medication is potentially more harmful
than persistent BP elevations with less-intense pharmacologic
treatment is not uncommon. The practitioner often gets frustrated by seeing limited reductions in BP levels, which may be in
part because of the use of suboptimal drug combinations, patient
noncompliance, and patient reports of drug-induced side effects.
Thus, the practitioner is susceptible to the incessant bargaining
that occurs during office visits with patients promising to lose
weight, begin exercising, reduce their salt intake, and so onall
so that no increases in antihypertensive drug therapy are prescribed. My impression is that this bargaining and practitioners
susceptibility to such bargaining is particularly intense when the
patients goal BP level is almost achieved but still above target.
Patient Noncompliance
Patient noncompliance with prescribed antihypertensive drug
regimens is very common. High medication adherence (80%)
compared with intermediate (50%-79%) and low (<50%) medication adherence to a single-pill antihypertensive drug regimen
(as estimated by the medication possession ratio) was recently
linked to greater BP control43% for high, 34% for inter
mediate, and 33% for low medication adherence, respectively,
over a 4-year period in 13 U.S. health plans.22 Furthermore,
in this same study, there was a borderline significant inverse
relationship between adherence and the number of unique
nonantihypertensive drugs, and a strong direct relationship
between the mean days of drug supply per pharmacy claim and
adherence. The number of unique nonantihypertensive drugs
taken per patient was inversely and strongly related to a lower
BP control rate.
Patterns of antihypertensive medication nonadherence were
reported across 21 studies of once-daily antihypertensive drug
treatment using ambulatory electronic monitors.23 These authors
found one half of patients with hypertension discontinued
antihypertensive medications within one year, approximately
8% to 10% of scheduled drug doses were missed on any given
day, weekend doses were more likely to be missed than weekday doses, and evening doses were more likely to be missed
than morning doses. Intriguingly, the quality of execution of
the daily drug dosing regimen in the early phase of treatment
was a predictor of early discontinuation. There is a complex
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aggregate of reasons for patient noncompliance, which relate to

patient, physician, and health care system factors. Nevertheless,
these data provide some clues to potential strategies controlled
by the practitioner that should minimize noncompliance. One
easy-to-implement strategy that minimizes the loss of BP control
during intermittent noncompliance is to use antihypertensive
drugs with prolonged hypotensive effects (preferably effects that
extend well beyond the 24-hour dosing interval). This approach
should provide some coverage against loss of BP control during
the vulnerable period between the missed dose and the next dose
of medication taken (Figure 2).
Optimizing Available Strategies
Lifestyle Modifications
Practitioners should always emphasize appropriate lifestyle
changes that have shown benefit in lowering BP and/or increasing target-organ protection. The Table displays such lifestyle and
behavioral changes. Many, though not all, hypertensive patients
are overweight, and the implementation of the suggested lifestyle changes in many hypertensive patients will induce weight
loss. At least a few of the recommendations are probably less
familiar to the average patient. Calcium intake has been shown
to reduce BP levels in persons with low daily intakes of calcium
and/or hypovitaminosis D. Natural sources of calcium, such as
low-fat dairy products, have been proven more effective than
dietary supplements. Emerging data show that augmentation
of dietary calcium intake promotes weight loss and lower body
fat.24-25 A multifaceted approach such as that undertaken in
the TOMHS study5 weight loss, salt and alcohol restriction,
and increased physical activityshould be considered. A diet
similar or identical in composition to the Dietary Approaches
to Stop Hypertension (DASH) diet26 is an excellent approach
to making dietary changes that will reduce BP levels in many
patients with hypertension. Dietary salt restriction not only lowers BP in the majority of hypertensive individuals but augments
the BP-lowering effect of most antihypertensive drugs. Urinary
protein excretion is also diminished by both salt restriction and
weight loss.
Pharmacologic Strategies
A major step forward in pharmacologically treating hypertension is to minimize the reliance on monotherapy. In most
trials in patients with hypertension, the average BP levels typically remain well above 140/90 mm Hg, even with combination
therapy. It is a distinct minority of pharmacologically treated
patients with hypertension who will attain their goal BP without
the use of multiple antihypertensive drugs.
Combination drug therapy should be embraced with a
vengeance. The JNC 7 guidelines27 and the International Society
on Hypertension in Blacks (ISHIB) guidelines28 on hypertension both comment explicitly on the use of multidrug therapy.
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Vol. 13, No. 8, S-b
When BP levels are >20/10 mm Hg above normal (per JNC 7) or

>15-20/10 mm Hg above normal (per ISHIB), practitioners
should recommend the use of multiple antihypertensive drugs.
Multiple antihypertensive drugs will be needed to attain and
maintain goal BP levels in most hypertensive patients. Use of
suboptimal antihypertensive drug regimens has been identified
as a major cause of inadequate BP control in patients referred to
specialty antihypertensive care settings. Pharmacologic antagonism of the RAAS, which is reviewed in this supplement by
Atlas, has shown the most promise for conferring target-organ
TABLE
Changes
Physical
activity
Lifestyle and Behavioral Changes

to Lower Blood Pressure27
Intervention
Increase
Comment
Appropriate aerobic activity should
be encouraged.
Weight lifting (heavy) can raise blood
pressure.
Diet
Sodium
Decrease
Approximately 2 g (87 mmol) of

dietary sodium a day is a good target.
Approximately 80% of dietary sodium
comes from processed foods.
Potassium
Increase
Approximately 4.7 g (120 mmol) of

dietary potassium a day is recommended
by the Institute of Medicine.
Fresh fruits and green leafy vegetables are
good sources of dietary potassium.
Lifestyle
Alcohol
Limit
Fewer than 2 drinks (1 oz or 30 mL of

ethanol) a day is recommended.
Smoking
Avoid or quit
Smoking acutely raises blood pressure.
October 2007
JMCP
protection that can be statistically disentangled from reductions

of BP levels.29 However, in free-living patients with hypertension
who may consume ad libitum daily amounts of dietary sodium,
the BP-lowering efficacy of RAAS blockers is attenuated more so
than the BP-lowering efficacy of calcium antagonists (and probably diuretics), whereas RAAS blockers, during low dietary sodium intake, lower BP to a similar degree as calcium antagonists.
This BP lowering was seen in an examination of the relationship
of SBP and urinary sodium excretion, which confirmed that
isradipine, a calcium antagonist, decreased BP responsiveness to
sodium to a greater degree than either placebo or enalapril, an
angiotensin-converting enzyme inhibitor (ACEI).30 However, it is
fortuitous that diuretics and calcium antagonists both augment
the reduction of BP levels of RAAS antagonists in high-sodium
environments quite well.
Race should be avoided as a criterion on which to base
the selection of antihypertensive drug therapy. Diuretics and
calcium blockers have been promulgated as meriting favor in
blacks, while beta-blockers and RAAS antagonism have been
advocated in whites. These recommendations appear to contradict physiologic data that suggest that blacks have greater
activation of the RAAS than whites.31 Furthermore, increasing
dietary sodium intake (which undermines BP reduction with
RAAS antagonists) consequently suppresses renin but also turns
on the synthesis of vascular angiotensin II32 while suppressing
the production of nitric oxide.33 There is strong evidence that
despite the greater BP responses of whites compared with
those of blacks to monotherapy with a ACEI (for example,
the BP response distributions are widemuch wider than
the differences in the means of the race-specific response
distributionsand these distributions overlap to a very large
degree), the addition of either a calcium antagonist or a diuretic
to RAAS blockers enhances the BP response and also eliminates
racial differences in BP response.34-35 Thus, the vast majority of
the BP response distribution to RAAS monotherapy is shared
between races, rendering this factor a grossly inaccurate predictor of BP responses for individuals of either race targeted. Finally,
the use of self-identified race as a criterion for drug selection will
become increasingly inapplicable to an ever-enlarging sector of
the U.S. population, given that this sector is phenotypically not
black or white.
New Therapies
Because many patients still do not reach their target BP level,
there remains an unmet need to find new antihypertensive therapies that are safe, reduce BP effectively, and provide target-organ
protection. It appears unlikely that pharmacologic interruption
of any physiologic system in isolation is going to reduce BP to
a level that will allow most hypertensive patients to attain BP
normalization on a single agent. Therefore, newer therapies need
to combine well with older therapies, so that they may be effectively integrated into multidrug regimens.
JMCP
October 2007
Direct Renin Inhibitors
One pharmacologic approach has been targeted at the RAAS,

but unlike ACEIs and ARBs, it has a novel mechanism of action.
Direct renin inhibitors (DRIs) are the newest antihypertensive
drug class on the market in the United States. Aliskiren, the first
drug in this class to receive Food and Drug Administration (FDA)
approval, is indicated for treatment of hypertension in doses of
150 mg and 300 mg once daily.36 Aliskiren has a long terminal
half-life (24-40 hours) and, after abrupt withdrawal, BP rises very
slowly over several weeks back to pretreatment levels.37 Despite
providing blockade of the rate-limiting step in the synthesis of
angiotensin II, the addition of an ARB to aliskiren provides incremental BP lowering.38-39 The drug is partially metabolized via the
cytochrome 3A4 pathway, although approximately one quarter
of the absorbed dose is excreted in the urine as the parent drug.
There is no need, however, to alter aliskiren dosing in persons
with either chronic kidney or liver disease. As with other RAAS
blockers, combining aliskiren with diuretics produces a very
significant incremental BP response with attenuation of the risk
of diuretic-induced hypokalemia, and with a lower incidence of
cough and angioedema compared with ACEIs.40 In an article in
this supplement, Pool provides an in-depth review of aliskiren
and the clinical utility of this agent.41
Summary
Control of BP to levels persistently below target levels will require
multiple antihypertensive agents in the majority of patients with
hypertension. The use of thiazide diuretics and calcium antagonists with RAAS antagonists represents the logical combinations
that reduce BP very effectively. Pharmacologic antagonism of the
RAAS (ACEIs, ARBs, or DRIs) has shown the most promise for
preventing target-organ injury or failure to a degree not solely
explained by the reduction of BP levels. Practitioners should
attempt to implement multidimensional lifestyle and behavioral
changes that will also help reduce BP levels. Antihypertensive
agents do not lower risk for all BP-related end points equivalently,
even when cuff BP is lowered to a similar degree, but the need
for multiple antihypertensive agents to control BP affords the
practitioner the ability to use highly effective drug combinations
that both reduce BP and protect target organs.
Disclosures
Funding from the National Institute of Environmental Health Sciences supported this research.
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statistics2007 update: a report from the American Heart Association
Statistics Committee and Stroke Statistics Subcommittee. Circulation.
2007;115:e69-e171.
2. Flack JM, Gardin JM, Yunis C, Liu K, for the CARDIA Research Group.
Static and pulsatile blood pressure correlates of left ventricular structure
and function in black and white young adults: the CARDIA study.
Am Heart J. 1999;138(pt 1):856-64.
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3. Flack JM, Neaton J, Grimm R Jr, et al. Blood pressure and mortality
among men with prior myocardial infarction. Circulation. [serial online].
November 1, 1995;92(9):2437-45. http://circ.ahajournals.org/cgi/content/
full/92/9/2437. Accessed May 15, 2007.
4. Flack JM, Neaton JD, Daniels B, Esunge P. Ethnicity and renal disease:
lessons from the Multiple Risk Factor Intervention Trial and the Treatment
of Mild Hypertension Study. Am J Kidney Dis. 1993;21(suppl 1):S31-S40.
5. Neaton JD, Grimm RH Jr, Prineas RJ, et al. Treatment of Mild
Hypertension Study: final results. JAMA. 1993;270:713-24.
6. Blood Pressure Lowering Treatment Trialists Collaboration. Effects of
different blood-pressure-lowering regimens on major cardiovascular events:
results of prospectively-designed overviews of randomised trials. Lancet.
2003;362:1527-35.
7. Blood Pressure Lowering Treatment Trialists Collaboration. Effects of
ACE inhibitors, calcium antagonists, and other blood-pressure-lowering
drugs: results of prospectively designed overviews of randomised trials.
Lancet. 2000;356:1955-64.
8. White WB. Importance of blood pressure control over a 24-hour period.
J Manag Care Pharm. 2007;13(8)(suppl b):S34-S39.
9. Brenner BM, Cooper ME, De Zeeuw D, et al. Effects of losartan on
renal and cardiovascular outcomes in patients with type 2 diabetes and
nephropathy. N Engl J Med. 2001;345:861-69.
10. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the
angiotensin-receptor antagonist irbesartan in patients with nephropathy
due to type 2 diabetes. N Engl J Med. 2001;345:851-60.
20. Berlowitz DR, Ash AS, Hickey EC, et al. Inadequate management
of blood pressure in a hypertensive population. N Engl J Med.
1998;339:1957-63.
21. Okonofua EC, Simpson KN, Jesri A, Rehman SU, Durkalski VL, Egan
BM. Therapeutic inertia is an impediment to achieving the Healthy People
2010 blood pressure control goals. Hypertension. 2006;47:345-51.
22. Bramley TJ, Gerbino PP, Nightengale BS, Frech-Tamas F. Relationship
of blood pressure control to adherence with antihypertensive monotherapy
in 13 managed care organizations. J Manag Care Pharm. 2006;12:239-45.
Available at: http://www.amcp.org/data/jmcp/Research_239-245.pdf.
23. Burnier M, Vincze G, Kristanto P, Vrijens B. Adherence to prescribed
once daily anti-hypertensive drug treatments: analysis of 4783 patients
electronically compiled dosing histories. Abstract presented at: European
Society of Cardiology Congress Annual Meeting; September 1-5, 2007;
Vienna, Austria.
24. Zemel MB, Richards J, Milstead A, Campbell P. Effects of calcium and
dairy on body composition and weight loss in African-American adults.
Obes Res. 2005;13:1218-25.
25. Zemel MB, Richards J, Mathis S, Milstead A, Gebhardt L, Silva E. Dairy
augmentation of total and central fat loss in obese subjects. Int J Obes.
2005;29:391-97.
26. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of
reduced dietary sodium and the Dietary Approaches to Stop Hypertension
(DASH) diet. N Engl J Med. 2001;344:3-10.
11. Carr AA, Kowey PR, Devereux RB, et al. Hospitalizations for new heart
failure among subjects with diabetes mellitus in the RENAAL and LIFE
studies. Am J Cardiol. 2005;96:1530-36.
27. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report
of the Joint National Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure: the JNC 7 report. JAMA.
2003;289:2560-72.
12. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-convertingenzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.
The Heart Outcomes Prevention Evaluation Study Investigators.
N Engl J Med. 2000;342:145-53.
28. Douglas JG, Bakris GL, Epstein M, et al. Management of high blood
pressure in African Americans: consensus statement of the Hypertension
in African Americans Working Group of the International Society on
Hypertension in Blacks. Arch Intern Med. 2003;163:525-41.
13. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative
Research Group. Major outcomes in high-risk hypertensive patients
randomized to angiotensin-converting enzyme inhibitor or calcium channel
blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981-97.
29. Atlas SA. The renin-angiotensin aldesterone system: pathophsiologicalrole and pharmacologic inhibition. J Manag Care Pharm.
2007;13(8)(suppl b):S9-S20.
14. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity

and mortality in the Losartan Intervention For Endpoint reduction in
hypertension study (LIFE): a randomised trial against atenolol. Lancet.
2002;359:995-1003.
15. Dahlof B, Sever PS, Poulter NR, et al. Prevention of cardiovascular
events with an antihypertensive regimen of amlodipine adding perindopril
as required versus atenolol adding bendroflumethiazide as required, in
the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering
Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet.
2005;366:895-906.
16. Williams B, Lacy PS, Thom SM, et al. Differential impact of blood
pressure-lowering drugs on central aortic pressure and clinical outcomes:
principal results of the Conduit Artery Function Evaluation (CAFE) study.
Circulation. 2006;113:1213-25.
17. Wang YR, Alexander GC, Stafford RS. Outpatient hypertension
treatment, treatment intensification, and control in Western Europe and
the United States. Arch Intern Med. 2007;167:141-47.
18. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific
relevance of usual blood pressure to vascular mortality: a meta-analysis
of individual data for one million adults in 61 prospective studies. Lancet.
2002;360:1903-13.
19. Hyman DJ, Pavlik VN. Characteristics of patients with uncontrolled
hypertension in the United States. Lancet. 2002;360:1903-13.
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30. Chrysant SG, Weder AB, McCarron DA, et al. Effects of isradipine
or enalapril on blood pressure in salt-sensitive hypertensives during low
and high dietary salt intake. MIST II Trial Investigators. Am J Hypertens.
2000;13:1180-88.
31. Price DA, Fisher NDL, Osei SY, Lansang MC, Hollenberg NK. Renal
perfusion and function in healthy African Americans. Kidney Int.
2001;59:1037-43.
32. Boddi M, Poggesi L, Coppo M, et al. Human vascular renin-angiotensin
system and its functional changes in relation to different sodium intakes.
Hypertension. 1998;31:836-42.
33. Campese VM, Tawadrous M, Bigazzi R, et al. Salt intake and plasma
atrial natriuretic peptide and nitric oxide in hypertension. Hypertension.
[serial online]. September 1996;28(3):335-40. http://hyper.ahajournals.org/
cgi/content/full/28/3/335. Accessed May 15, 2007.
34. Sehgal AR. Overlap between whites and blacks in response to
antihypertensive drugs. Hypertension. 2004;43:566-72.
35. Mokwe E, Ohmit SE, Nasser SA, et al. Determinants of blood
pressure response to quinapril in black and white hypertensive patients:
the Quinapril Titration Interval Management Evaluation trial. Hypertension.
2004;43:1202-07.
36. Tekturna (aliskiren) [prescribing information]. East Hanover, NJ:
Novartis Pharmaceuticals Corporation; March 2007.
37. Oh B-H, Mitchell J, Herron JR, Chung J, Khan M, Keefe DL. Aliskiren,
an oral renin inhibitor, provides dose-dependent efficacy and sustained
24-hour blood pressure control in patients with hypertension. J Am Coll
Cardiol. 2007;49:1157-63.
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38. Pool JL, Schmieder RE, Azizi M, et al. Aliskiren, an orally effective renin
inhibitor, provides antihypertensive efficacy alone and in combination with
valsartan. Am J Hypertens. 2007;20:11-20.
40. Villamil A, Chrysant SG, Calhoun D, et al. Renin inhibition with

aliskiren provides additive antihypertensive efficacy when used in
combination with hydrochlorothiazide. J Hypertens. 2007;25:217-26.
39. Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A. Efficacy

and safety of combined use of aliskiren and valsartan in patients with
hypertension: a randomised, double-blind trial. Lancet. 2007;370:221-29.
41. Pool JL. Direct renin inhibition: focus on aliskiren. J Manag Care Pharm.
2007;13(8)(suppl b):S21-S33.
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The Renin-Angiotensin Aldosterone System:

Pathophysiological Role and Pharmacologic Inhibition
Steven A. Atlas, MD
Abstract
Background: The renin-angiotensin aldosterone system (RAAS) is a
hormonal cascade that functions in the homeostatic control of arterial
pressure, tissue perfusion, and extracellular volume. Dysregulation of the
RAAS plays an important role in the pathogenesis of cardiovascular and
renal disorders.
Objectives: To review the role of the RAAS in the development of
hypertensive cardiovascular disease and related conditions and provide an
overview of the classes of pharmacologic agents that inhibit this system.
Results: The RAAS is initiated by the regulated secretion of renin, the
rate-limiting enzyme that catalyzes the hydrolysis of angiotensin (Ang) I
from the N-terminus of angiotensinogen. Ang I is in turn hydrolyzed by
angiotensin-converting enzyme (ACE) to form Ang II, a potent vasocon
strictor and the primary active product of the RAAS. Recent evidence
has suggested that other metabolites of Ang I and II may have biological
activity, particularly in tissues. Development of agents that block the RAAS
(e.g., beta blockers, ACE inhibitors [ACEIs], and angiotensin receptor
blockers [ARBs]) began as a therapeutic strategy to treat hypertension.
Preclinical and clinical studies have indicated important additional
cardiovascular and renal therapeutic benefits of ACEIs and ARBs.
However, blockade of the RAAS with these agents is incomplete.
Conclusion: Therapeutic approaches that target more complete inhibition
of the RAAS may offer additional clinical benefits for patients with cardiovascular and renal disorders. These approaches may include dual blockade
using ACEIs and ARBs in combination, or new therapeutic modalities such
as direct renin inhibition with aliskiren, recently approved for the treatment
of hypertension.
Keywords: Renin-angiotensin aldosterone system; Hypertension;
Angiotensin II, renin; ACE inhibitors; Angiotensin receptor blockers
Author
Steven A. Atlas, MD, is an associate professor of medicine,

Mount Sinai School of Medicine, New York, and chief, Cardiology/
Hypertension/Endocrinology Practice, and director, Hypertension
Research Laboratory, James J. Peters VA Medical Center, Bronx, NY.
Author Correspondence: Steven A. Atlas, MD,
130 W. Kingsbridge Rd., Bronx, NY 10468. Tel: (718) 584-9000;
Fax: (718) 741-4295; E-mail: steven.atlas@med.va.gov
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Vol. 13, No. 8, S-b
he renin-angiotensin aldosterone system (RAAS) plays an

integral role in the homeostatic control of arterial pressure,
tissue perfusion, and extracellular volume. It functions
as an unusual endocrine axis in which the active hormone,
angiotensin (Ang) II, is formed in the extracellular space by
sequential proteolytic cleavage of its precursors. This pathway
is initiated by the regulated secretion of renin, the rate-limiting
processing enzyme. Although renin was discovered more than a
century ago,1 the significance of this system in the pathogenesis
of cardiovascular and renal disorders has gained wide acceptance only during the past 3 decades, in large part because of
the availability of specific pharmacologic agents that can block
the system.
In this article, I will review the evidence concerning the role
of the RAAS in the development of hypertensive cardiovascular
disease and related conditions and provide an overview of the
agents that inhibit this system.
Historical Perspective
In 1898, Tigerstedt and Bergmann published an account of their
research demonstrating the existence of a heat-labile substance
in crude extracts of rabbit renal cortex that caused a sustained
increase in arterial pressure.1 They proposed the term renin for
a presumed humoral pressor agent secreted by the kidney, a concept that was widely disputed or ignored until the classical studies of Goldblatt and colleagues, published in 1934, that showed
that renal ischemia induced by clamping of the renal artery
could induce hypertension.1 Shortly thereafter it was shown
that the ischemic kidney also released a heat-stable, short-lived
pressor substance, in addition to renin. This finding eventually
led to the recognition that renins pressor activity was indirect
and resulted from its proteolytic action on a plasma substrate
(eventually termed angiotensinogen) to liberate a direct-acting
pressor peptide. This peptide was initially termed angiotonin
or hypertensin by competing investigators in the United States
(Page and colleagues) and in Argentina (Braun-Menendez and
colleagues), who ultimately compromised on the term angiotensin.1 In the early 1950s, during attempts at purification, Skeggs
and colleagues discovered that this peptide existed in 2 forms,
eventually termed Ang I and II.2 In later work, they demonstrated
that Ang I was cleaved by a contaminating plasma enzyme,
termed angiotensin-converting enzyme, to generate the active
pressor peptide Ang II.3 Soon after, the work of several investigators, including Laragh, Genest, Davis, Ganong, and their colleagues, culminated in the discovery that Ang II also stimulated
the release of the adrenal cortical hormone aldosterone, a major
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The Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition
regulator of sodium and potassium balance.4 These landmark

discoveries established the concept that a single system, the
RAAS, was involved in the regulation of both blood pressure and
fluid and electrolyte balance.
Components of the RAAS
The renin-angiotensin aldosterone hormonal cascade begins
with the biosynthesis of renin by the juxtaglomerular cells (JG)
that line the afferent (and occasionally efferent) arteriole of the
renal glomerulus. Renin is synthesized as a preprohormone,
and mature (active) renin is formed by proteolytic removal of a
43-amino-acid prosegment peptide from the N-terminus of prorenin, the proenzyme or renin precursor. Mature renin is stored
in granules of the JG cells and is released by an exocytic process
involving stimulus-secretion coupling into the renal and then
the systemic circulation. In addition to this regulated pathway,
it appears that the kidney also releases unprocessed prorenin via
a constitutive pathway. In fact, prorenin accounts for about 70%
to 90% of the immunoreactive renin in the human circulation.
The potential biological significance of this finding is poorly
understood at present.
Active renin secretion is regulated principally by 4 interdependent factors: (1) a renal baroreceptor mechanism in the
afferent arteriole that senses changes in renal perfusion pressure,
(2) changes in delivery of NaCl (sensed as changes in Cl- concentration) to the macula densa cells of the distal tubule (which
lie close to the JG cells and, together, form the JG apparatus),
(3) sympathetic nerve stimulation via beta-1 adrenergic receptors, and (4) negative feedback by a direct action of Ang II on the
JG cells.5 Renin secretion is stimulated by a fall in perfusion
pressure or in NaCl delivery and by an increase in sympathetic
activity. Renin is also synthesized in other tissues, including
brain, adrenal gland, ovary, and visceral adipose tissue, and perhaps heart and vascular tissue. The factors regulating synthesis
and possible actions of renin in these other tissues are poorly
understood.
Control of renin secretion is a key determinant of the activity
of the RAAS. Renin regulates the initial, rate-limiting step of the
RAAS by cleaving the N-terminal portion of a large molecular
weight globulin, angiotensinogen, to form the biologically inert
decapeptide Ang I or Ang-(1-10), as shown in the Figure. The
primary source of systemic circulating angiotensinogen is the
liver, but angiotensinogen mRNA expression has also been
detected in many other tissues, including kidney, brain, heart,
vascular, adrenal gland, ovary, placenta, and adipose tissue.6
Angiotensinogen is secreted constitutively by the liver, so plasma
levels are generally stable and do not change acutely; however,
both hepatic and extrahepatic synthesis have been shown to rise
in response to glucocorticoids, estrogens and other sex steroids,
thyroid hormone, inflammatory cytokines (e.g., interleukin-1
and tumor necrosis factor), and Ang II.6 Adrenal insufficiency,
orchiectomy, hypothyroidism, and insulin deficiency have been
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associated with a decline in plasma concentration and/or tissue

mRNA expression of angiotensinogen.6 Long-term elevations in
angiotensinogen concentration, which occur with pregnancy,
Cushings syndrome, or glucocorticoid treatment, may be a risk
factor for hypertension, although there is evidence that chronic
stimulation of angiotensinogen may be partly compensated for by
a reduction in renin secretion.
The inactive decapeptide Ang I is hydrolyzed by angiotensin-converting enzyme (ACE), which removes the C-terminal
dipeptide to form the octapeptide Ang II [Ang-(1-8)], a biologically active, potent vasoconstrictor. ACE is a membrane-bound
exopeptidase and is localized on the plasma membranes of various cell types, including vascular endothelial cells, microvillar
brush border epithelial cells (e.g., renal proximal tubule cells),
and neuroepithelial cells. It is this membrane-bound ACE that
is thought to be physiologically important. ACE also exists in a
soluble form in plasma, but this form may simply reflect turnover
and clearance of membrane-bound ACE. ACE (also known as
kininase II) metabolizes a number of other peptides, including
the vasodilator peptides bradykinin and kallidin, to inactive
metabolites.7 Thus, functionally, the enzymatic actions of ACE
potentially result in increased vasoconstriction and decreased
vasodilation.
Although Ang II is the primary active product of the RAAS,
there is evidence that other metabolites of Ang I and II may have
significant biological activity, particularly in tissues. Ang III
and IV are formed by the sequential removal of amino acids
from the N-terminus of Ang II by the action of aminopeptidases
(Figure). They are most likely produced in tissue with high levels
of aminopeptidases A and N, such as brain and kidney tissue.8
Ang III [Ang-(2-8)], a heptapeptide formed by removal of the
first N-terminal amino acid, is present in the central nervous
system (CNS), where it is thought to play an important role in
tonic blood pressure maintenance and in hypertension.8 Ang IV
[Ang-(3-8)] is a hexapeptide formed by further enzymatic degradation of Ang III.8 Preclinical studies have suggested a cooperative
effect of Ang IV in Ang II signaling. For instance, it appears that in
the brain, Ang IV increases blood pressure by cooperating with
Ang II on angiotensin II type 1 (AT1)-receptor signaling (see
below), because its hemodynamic effects require the presence of
both Ang II and functional AT1 receptors.8
Peptides truncated at the C-terminus of Ang II may also have
biological activity. For example, Ang-(1-7), a heptapeptide fragment of Ang II, can be formed from Ang I or Ang II by the actions
of several endopeptidases or from Ang II by the action of carboxypeptidases, including one with significant structural homology to
ACE (which has been termed ACE 2). Unlike ACE, this enzyme
does not convert Ang I to Ang II and its activity is not affected
by ACE inhibitors (ACEIs).7 Ang-(1-7), which appears to act via a
unique receptor (see below), was first described to have vasodilatory effects and act as a natural ACEI. Cardioprotective effects
have also been proposed to result from a direct effect of Ang-(1-7)
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on heart cells or a generalized systemic effect,8 but evidence for

such actions in human studies is lacking. ACE 2 can also cleave a
single amino acid from the C-terminus of Ang I to form Ang-(1-9),
a peptide with no known function at this time.
As already noted, Ang II is the primary effector of a variety
of RAAS-induced physiological and pathophysiological actions.
At least 4 angiotensin receptor subtypes have been described.9
The type 1 (AT1) receptor mediates most of the established physiological and pathophysiological effects of Ang II (Figure). These
include actions on the cardiovascular system (vasoconstriction, increased blood pressure, increased cardiac contractility,
vascular and cardiac hypertrophy), kidney (renal tubular
sodium reabsorption, inhibition of renin release), sympathetic
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nervous system, and adrenal cortex (stimulation of aldosterone

synthesis).7
The AT1 receptor also mediates effects of Ang II on cell growth
and proliferation, inflammatory responses, and oxidative stress.2
This receptor, which is typical of the G protein-coupled receptor superfamily containing 7 membrane-spanning sequences,
is widely distributed on many cell types in Ang II target
organs.
The type 2 (AT2) receptor is abundant during fetal life in the
brain, kidney, and other sites, and its levels decrease markedly
in the postnatal period. There is some evidence that, despite
low levels of expression in the adult, the AT2 receptor might
mediate vasodilation and antiproliferative and apoptotic effects
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in vascular smooth muscle and inhibit growth and remodeling

in the heart.7,9 In the kidney, it has been proposed that activation
of AT2 receptors may influence proximal tubule sodium reabsorption and stimulate the conversion of renal prostaglandin E2
to prostaglandin F2.2,7 However, the importance of any of these
AT2-mediated actions remains uncertain.
The type 4 (AT4) receptors are thought to mediate the release
of plasminogen activator inhibitor 1 by Ang II and by the
N-terminal truncated peptides (Ang III and Ang IV), but the
function of the type 3 (AT3) receptors is unknown.9 Lastly, the
putative effects attributed to the C-terminal truncated peptide
Ang 1-7, including vasodilatation, natriuresis, antiproliferation,
and cardiac protection, are presumed to be mediated by a unique
receptor that does not bind Ang II, most likely a product of the
Mas proto-oncogene known as the Mas receptor.9
In addition to receptors for the angiotensin peptides, very
recent evidence suggests the existence of high-affinity cell
surface receptors that bind both renin and prorenin in
several tissues, including heart, brain, placenta, and kidney,
with localization to glomerular mesangium and subendothelial
vascular smooth muscle.10 One receptor that has been carefully
characterized has been reported to cause reversible activation
of bound prorenin and to enhance the catalytic activity of
bound renin, thus serving as a template for local Ang I generation. The receptor also has been reported to initiate intracellular
signaling, independent of Ang peptide synthesis, leading to
activation of mitogen-activated protein kinases ERK1 and ERK2
(Figure).10
These findings raise the possibility of Ang II-independent
effects on cellular growth responses by renin or prorenin.
An intriguing series of studies raises the possibility that such
putative receptor-mediated mechanisms may contribute to the
development of experimental diabetic nephropathy.11 Research
into this new aspect of RAAS biology is progressing at a rapid
pace, although there is as yet no evidence for human counterparts to these novel mechanisms.
As already noted, Ang II, via the AT1 receptor, also stimulates
the production of aldosterone by the zona glomerulosa, the
outermost zone of the adrenal cortex. Aldosterone is a major
regulator of sodium and potassium balance and thus plays a
major role in regulating extracellular volume. It enhances the
reabsorption of sodium and water in the distal tubules and
collecting ducts (as well as in the colon and salivary and sweat
glands) and thereby promotes potassium (and hydrogen ion)
excretion.12 Ang II, together with extracellular potassium levels,
are the major regulators of aldosterone, but Ang II synthesis
may also be stimulated by adrenocorticotrophic hormone
(ACTH; corticotropin), norepinephrine, endothelin, and serotonin and inhibited by atrial natriuretic peptide and nitric oxide
(NO). It is also important to note that Ang II is a major trophic
factor for the zona glomerulosa, which can atrophy (reversibly)
in its absence.
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Classical Endocrine Pathway of Angiotensin Biosynthesis

The classical enzymatic cascade of the RAAS is depicted in
the Figure. Reduction in renal perfusion pressure and afferent
arteriolar pressure induced, for instance, by a reduction in circulating blood volume triggers the release of renin from the stretchsensitive JG cells lining mainly the afferent renal arterioles. This
mechanism is reinforced by a reduction in the tubular fluid
sodium chloride concentration as sensed by the macula densa
cells of the distal tubules and at times by an increase in sympathetic discharge to the kidney. In the extracellular space, renin
cleaves the N-terminal 10 amino acids of circulating angiotensinogen to form the biologically inert decapeptide Ang I, which
in turn is converted to the active octapeptide Ang II by removal
of the C-terminal dipeptide by ACE. As mentioned earlier, this
last step in Ang II biosynthesis is mediated mainly by membranebound ACE, which is nearly ubiquitous on vascular endothelium. The concept of a circulating endocrine cascade has been
frequently misinterpreted to imply that Ang II is a circulating
hormone, but this is in fact unlikely. Instead, both Ang I and
Ang II, which have very short half-lives, are probably synthesized
very close to their site of action, with renin serving as the circulating hormonal signal that initiates the pathway at local sites.
The diverse actions of Ang II mediated by the AT1 receptor
play a key role in restoring or maintaining circulatory homeostasis. In addition to stimulating the production (and release)
of aldosterone from the adrenal cortex, Ang II promotes the
constriction of renal and systemic arterioles and the reabsorption
of sodium in proximal segments of the nephron. The increase
in blood pressure and volume, resulting from the effects of
Ang II and aldosterone on their target organs, serves to restore
renal perfusion and thereby inhibits further release of renin.
Although the RAAS thus plays an important role in normal
circulatory homeostasis, continued or inappropriate activation
of the system is thought to contribute to the pathophysiology of
diseases such as hypertension and heart failure.
Tissue RAAS and Alternative Pathways of Angiotensin
Biosynthesis
The evidence that angiotensin synthesis can occur in several
tissues as well as the circulation, together with the characterization of several subtypes of angiotensin receptors and signal
transduction pathways, the identification of truncated angiotensin peptides with possible unique actions, and most recently,
the identification of putative cell surface receptors for renin and
prorenin, has resulted in expansion of the traditional circulating RAAS paradigm to include the so-called tissue RAAS. The
prevailing concept is that the RAAS functions both as a circu
lating system and as a tissue paracrine/autocrine system.7,13
There is evidence that local or tissue Ang II biosyn
thesis may be initiated by renin and/or angiotensinogen taken
up from the circulation. In addition, independent Ang II
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generating systems have been postulated to exist in the

heart, peripheral blood vessels, kidney, brain, adrenal glands,
pituitary, adipose tissue, testes, ovaries, and skin.7,13 Serine
proteases, including several kallikrein-like enzymes (tonins),
cathepsin G, and chymase are thought to contribute to Ang II
formation in the tissue RAAS.14 Studies have suggested that
non-ACE pathways are, by inference, responsible for about
40% of Ang II generation in the intact human kidney15 and that
chymase is the dominant Ang II-generating pathway in the
human heart, coronary arteries, and atherosclerotic aorta in
vitro.14,16,17 It has thus been proposed that abnormal activation of the tissue RAAS may contribute to the pathogenesis of
cardiovascular disease even in the absence of derangements in
the circulating system.18 It must be considered, however, that
the bulk of the evidence favoring alternate enzymatic pathways
in the synthesis of angiotensin peptides comes from in vitro or
indirect observations, so that such concepts remain speculative
at present.
Under physiological conditions, the apparent function of the
cardiac RAAS is to maintain cellular balance of inhibiting and
inducing cell growth, and proliferation and mediation of adaptive responses to myocardial stretch.19 The majority of Ang II
in cardiac tissue appears to be produced by local synthesis of
Ang I and subsequent local conversion to Ang II, rather
than from uptake of peptides from the systemic circulation.7
Although it has been suggested that locally synthesized renin
and/or additional proteolytic enzymes may be involved in this
synthetic process, current evidence favors the concept that
circulating renin and angiotensinogen, which are able to pass
through the endothelial barrier, are taken up by cardiac tissue
where they act locally.20 Ang II exerts an inotropic effect (at least
in atrial preparations), mediates myocyte hypertrophy via the
AT1 receptor, and is involved in cardiac remodeling.19 Pathologic
activation of cardiac RAAS, perhaps through local upregulation
of ACE levels, has been proposed to contribute to the development and maintenance of left ventricular hypertrophy.18
Vascular smooth muscle, endothelial, and endocardial cells
generate Ang I and Ang II, again apparently via the uptake of
circulating renin.7 It has been suggested that the vascular RAAS
contributes to the maintenance of cardiovascular homeostasis
through its effects on both AT1 and AT2 receptors and mediates long-term effects on vascular remodeling by stimulating
proliferation of vascular smooth muscle cells and fibroblasts.19
Endothelial dysfunction is associated with upregulation of local
tissue ACE, which might contribute to disrupting the balance of
vasodilation and vasoconstriction. Activation of vascular ACE
may also alter other functions, including vascular smooth muscle
cell growth and the inflammatory and oxidative state of the
vessel wall.18 In addition, the production of reactive oxidative
species (superoxide and hydrogen peroxide), which is enhanced
by Ang II, has been associated with inflammation, athero
sclerosis, hypertrophy, remodeling, and angiogenesis.19
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The intrarenal RAAS may explain the primary role of Ang II

as a paracrine substance in the control of renal function. The
direct intrarenal actions of Ang II include renal vasoconstriction,
tubular sodium reabsorption, sensitivity of tubuloglomerular
feedback, modulation of pressure-natriuresis, and promotion of
renal tissue growth.7,13 Under normal conditions, Ang II constricts both the afferent and efferent arterioles and stimulates
mesangial cell contraction, which results in reduced renal blood
flow, glomerular filtration rate (GFR), and filtered sodium load.7
On the one hand, overactivation of the intrarenal RAAS may thus
contribute to the pathophysiology of sodium-retaining states,
such as hypertension and congestive heart failure (CHF).7 On the
other hand, in conditions characterized by severe impairment of
renal perfusion, such as renal artery stenosis, the afferent circulation, which is dilated as a result of autoregulation, is relatively
refractory to the constrictive actions of Ang II, and the predominant constriction of efferent arterioles by Ang II plays a major role
in maintaining glomerular perfusion pressure and, thus, GFR.
Although systemic Ang II may affect CNS function at selected
sites, the brain is largely isolated from the circulating RAAS
by the blood-brain barrier. Therefore, local Ang II synthesis
by a brain RAAS has been proposed to play a role in central
blood pressure regulation.19 Increases in brain renin activity,
renin and angiotensinogen mRNA, and detectable numbers of
AT1- and AT2-receptor subtypes have been reported in hypertensive rats.19 Selective inhibition of brain AT1- and AT2-receptors
has been shown to lower blood pressure in hypertensive rats.13
Furthermore, direct administration of Ang II into the brain has
been shown to increase blood pressure13,19 as a result of the
combined effects of vasopressin release, sympathetic nervous
system activation, and inhibition of baroreflexes.13 Studies in
transgenic rats with permanent inhibition of brain angiotensinogen synthesis have demonstrated significantly lower systolic
blood pressure compared with controls.19
All components of the RAAS are present in adrenal cortex
and comprise the adrenal RAAS. Renin and angiotensinogen
mRNA have been identified in the adrenal gland, and Ang II
formation has been demonstrated in zona glomerulosa cells.7
Most (90%) adrenal renin activity has been localized to the zona
glomerulosa,7 and more than 90% of adrenal Ang II originates
at local tissue sites.21 In transgenic animal models it has
been shown that sodium restriction can increase adrenal renin
and aldosterone independently of plasma or kidney renin
concentrations. Additionally, bilateral nephrectomy, which
decreases cardiac and vascular renin, does not decrease adrenal renin in experimental animals.7,21 These findings support
the concept of kidney-independent renin (and thus, Ang II)
production in the adrenal glands. It is not known if the adrenal
RAAS functions as a paracrine or autocrine system or if it has
a pathophysiologic role, and the relative importance of systemic
versus locally synthesized Ang II in the control of adrenal
function is uncertain.
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JMCP
Generally speaking, it is thought that the physiologic role

of tissue RAAS is complementary to the classical circulating
RAAS and serves as a mechanism for longer-term maintenance
of balance or homeostasis at the tissue level between opposing
effects mediated by the system (e.g., growth promotion and inhibition in the heart and vasculature).19 Pathophysiologic processes
might hypothetically occur when components of the RAAS
are overexpressed or inhibited, thus disturbing the intricate
balance of this regulatory system.
Dysregulation of the RAAS in Cardiovascular Disorders
Dysregulation of the RAAS is involved in the pathogenesis of
several hypertensive disorders (Table).22-24 It should be noted
that RAAS dysregulation in clinical hypertensive disorders
has been conceptualized at the level of the classical circulating
RAAS, and the potential contributions of tissue RAAS dysregu
lation remain poorly defined.
In addition to RAAS involvement in secondary forms of
hypertension, there is evidence that perturbations of the RAAS
are involved in essential hypertension as well as in the responses
of cardiovascular and renal tissue to hypertensive and nonhypertensive injury. It is established that plasma renin levels
vary widely in patients with essential hypertension (Table).22
Approximately 15% of patients with essential hypertension have
mild to moderate increases in plasma renin activity (PRA), with
several postulated mechanisms, including increased sympathetic
activity and mild volume depletion. Such high-renin essential
hypertension is particularly prevalent among younger males.
The majority (50% to 60%) of essential hypertensive patients
have PRA within the normal range, although it has been argued
that a normal renin level in the face of hypertension (which ought
to suppress renin secretion) may be inappropriate.
Therapeutic responses to RAAS blocking agents indicate that
maintenance of normal renin levels may indeed contribute
to blood pressure elevation, suggesting that renin-dependent
mechanisms may be involved in more than 70% of patients with
essential hypertension. On the other hand, about 25% to 30%
have evidence of low or suppressed renin levels, a finding that
may be an expected response or that may, in some cases, reflect,
by analogy to primary aldosteronism, sodium or volume excess
(so-called volume-dependent hypertension). Low-renin hypertension is more common among older people with hypertension,
women, African Americans, and patients with type 2 diabetes, as
well as among patients with chronic renal parenchymal disease.
Although such patients often have lesser blood pressurelowering benefit from RAAS blocking agents, there is evidence
that the circulating levels of PRA might not necessarily reflect
tissue activities of the system. This is particularly evident with
regard to the kidney, with several lines of evidence pointing
to substantial involvement of intrarenal Ang II in progression
of renal damage (and substantial benefit of RAAS blockade),
despite low circulating levels of renin and Ang II.
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October 2007
The RAAS also plays a pivotal role in several nonhypertensive

conditions, and in particular in CHF and the other edematous
disorders (cirrhosis with ascites and the nephrotic syndrome).
In these conditions, all characterized by underperfusion of
the kidneys due to reduced effective arterial volume, secondary hypersecretion of renin leads to secondary aldosteronism,
which makes an important contribution to progressive edema.
In addition, with regard to heart failure, the contribution of
Ang II to increased peripheral vascular resistance (cardiac
afterload) also plays a major role in progressive ventricular
dysfunction.
Beyond progression of renal disease, there is additional
clear evidence (again from responses to RAAS blockade) of
involvement of Ang II in development of both vascular and
cardiac hypertrophy and remodeling, as well as on mechanisms that contribute to vascular damage and atherosclerosis,
effects that appear to have major impact on morbidity and
mortality. Unlike the case for secondary hypertensive syndromes where the nature of RAAS dysregulation is well defined
(Table), the reasons for these pathologic effects of Ang II are
uncertain since they often occur in the absence of any perturbation of the circulating RAAS. It has been inferred that
there may be dysregulation of some component(s), such as of
ACE levels, the balance of AT-receptor subtypes, or even local
synthesis of renin or angiotensinogen, to account for such
phenomena, but clearcut evidence of such derangements are
mostly lacking. It also remains possible that the RAAS plays a
passive role in such eventsthat is, that tissue injury can be
accelerated even in the presence of normal Ang II levels.
RAAS Inhibition
Early Preclinical Findings
Because renin is the initial and rate-limiting step in the RAAS
cascade, it has long been considered the logical therapeutic
target for blocking the system. Preclinical studies with anti
renin antibodies and then with early synthetic renin inhibitors
established the potential utility of RAAS inhibition. In these
studies, renin inhibition induced decreases in plasma renin
levels (generally measured in these early studies as plasma
renin activity or PRA), Ang I, Ang II, and aldosterone, along
with decreases in blood pressure.25 These studies also provided
evidence that blood pressure-lowering activity was due to
inhibition of PRA.25 However, pharmacologic activity of the
early renin inhibitors could only be achieved with intravenous infusion, and the development of an orally active
direct renin inhibitor was fraught with numerous difficulties
arising from issues of potency, low bioavailability, duration
of action, and costs of synthesis. As a result, further development of these agents was halted in the mid-1990s. Concurrently,
other strategies for inhibiting the RAAS progressed to
clinical use.
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TABLE
Hypertensive Disorders Involving Dysregulation of the Renin-Angiotensin Aldosterone System22-24
Hypertensive Disorders
RAAS Dysregulation
Clinical Manifestations
Renin-secreting neoplasms
Primary hypersecretion of renin by renal

hemangiopericytomas (JG cell tumors),
some Wilms tumors and renal and
extrarenal carcinomas (ovary, pancreas, lung)
Secondary aldosteronism
Hypokalemia; sodium retention limited by pressure natriuresis
Renovascular hypertension
Hypersecretion of renin due to segmental,

unilateral, or bilateral renal ischemia
Hypertension (usually renin-dependent, accelerating hypertension

common); progressive renal dysfunction possible
Sodium retention (depending on extent of renal compromise);

hypokalemia may be masked by decreased distal delivery of sodium
Hypersecretion of renin due to generalized

renal ischemia
Severe renin-dependent hypertension

Renal dysfunction
Microangiopathic hemolytic anemia
Hypertensive encephalopathy
Sodium retention and hypokalemia variable (as above)
Hypersecretion of renin due to

catecholamine excess
Sustained or paroxysmal hypertension (accelerating hypertension

common)
Renal ischemia due to extrinsic renal

compression and/or neurofibromatosis
involving the renal artery (occasionally)
Other typical manifestations of catecholamine excess
Hypokalemia; sodium retention often limited by pressure

natriuresis
HR (~15%)PRA mildly elevated,

cause uncertain (sympathetic drive?,
hypovolemia?)
Hypertension usually responds well to RAAS blockade

Increased susceptibility to heart attack or stroke?
NR (~60%)PRA within normal range,

but may be inappropriate in setting of
hypertension
Hypertension often responds to RAAS blockade
LR (~25%)PRA low due to several possible

mechanisms (sodium/volume excess?,
nephrosclerosis?, appropriate response?)
Hypertension responds best to diuretics, calcium channel- or

alpha1-blockers
Tissue RAAS may not be similarly suppressed (e.g., kidney)
Primary hypersecretion of aldosterone or

other MC hormone (e.g., DOC) by adrenal
neoplasms; or very rare genetic syndromes
resulting in MC hormone dysregulation
Hypertension (may be severe at times)

Hypokalemia and hypomagnesemia
Sodium and volume expansion, without edema (limited by
mineralocorticoid escape)
Secondary suppression of renin and Ang II
Reversible atrophy of contralateral adrenal cortex (due to suppressed

Ang II)
Atheromatous (main)
Severe renin-dependent hypertension (accelerating hypertension

common)
Fibromuscular (main or branch)

Renal emboli/segmental infarcts
Renal artery aneurysms
Renal artery dissection/injury
Subcapsular hematoma
Malignant hypertension and other
renal small vessel disease (e.g.,
polyarteritis, scleroderma,
hemolytic uremic syndrome, lupus)
Pheochromocytoma and other

catecholamine-secreting tumors
Essential hypertension
Primary aldosteronism and other

MC excess
Ang=angiotensin aldosterone system; DOC=deoxycorticosterone; HR=high renin; JG=juxtaglomerular; LR=low renin; MC=mineralocorticoid; NR=normal renin;
PRA=plasma renin activity; RAAS=renin-angiotensin aldosterone system. A ? indicates that the true etiology is unknown.
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Beta Blockers
In the 1970s, Laragh and colleagues showed that, in patients
with various types of hypertension, beta-blocker therapy
(propranolol) reduced plasma renin levels by blocking sympathetically (beta1)-mediated renin release by the kidney.26 They
concluded that the reduction in plasma renin level (by about
75%) was closely correlated with reductions in blood pressure. They also showed that propranolol reduced aldosterone
secretion. Their results demonstrated the viability of pharmacologic blockade of the RAAS as a therapeutic strategy.
A more recent study demonstrated parallel suppression of
Ang II and PRA during beta-blocker therapy in hypertensive
subjects.27 In addition to suppression of renin release, there
is evidence that beta blockade may also inhibit intrarenal
conversion of prorenin to renin.27,28 The blood pressure-lowering activity of beta blockers occurs via both renin-dependent
and renin-independent mechanisms. Although many studies
suggest a preferential effect among patients with high-renin
forms of hypertension,25,26 there is evidence for benefit in
low-renin hypertension as well, particularly with high-dose
propranolol therapy (320 mg to 980 mg daily), independent
of changes in PRA.29
Angiotensin-Converting Enzyme Inhibitors
Early studies performed in the 1960s showed that peptides from
the venom of the Brazilian arrowhead viper (Bothrops jararaca)
inhibited kinase II, an enzyme that facilitates degradation of
bradykinin, and which was later shown to be identical to ACE.2
Synthetic analogues of the peptide fraction of snake venom,
such as the nonapeptide teprotide, were shown to lower blood
pressure in patients with hypertension and produce beneficial
hemodynamic effects in patients with heart failure.2 These
findings encouraged the search for orally active inhibitors of
ACE; the first of these, captopril, was designed based on known
inhibitors of another zinc-containing metalloprotease, carboxypeptidase A, and included a sulfhydryl-containing amino acid
to serve as ligand for the zinc moiety. Because many of the
unacceptable side effects of captopril, such as proteinuria, skin
rashes, and altered taste, were attributed to the sulfhydryl group,
subsequent work led to the development of ACEIs that replaced
this group with a carboxyl group (e.g., lisinopril, benazepril,
quinapril, ramipril, perindopril, cilazapril, trandolapril) or
phosphoryl group (fosinopril).30,31 The presence of the carboxyl
group conferred greater lipophilicity, which actually improved
binding to ACE, and improved tissue penetration.31
ACEIs competitively block the action of ACE and thus the
conversion of Ang I to Ang II, thereby reducing circulating
and local levels of Ang II. ACEIs also decrease aldosterone and
vasopressin secretion and sympathetic nerve activity, but there
is controversy regarding their efficacy in blocking other tissue
actions of the RAAS.32 Short-term ACEI therapy is associated
with a decrease in Ang II and aldosterone and an increase in
JMCP
renin release and Ang I. There is some evidence, however, that

over the long term ACE inhibition may be associated with a
return of Ang II and aldosterone toward baseline levels (ACE
escape)perhaps, it is proposed, through activation of the
so-called alternate pathways (Figure).32,33 Undoubtedly this
phenomenon has been greatly exaggerated, particularly from
early studies using faulty methodology that did not specifically
measure Ang II, and the relevance of alternate pathways of
Ang II synthesis in the intact human is unclear at present.
On the other hand, because ACEIs are all competitive inhibitors of the enzyme, it is possible that increased levels of Ang I
(provoked by the compensatory increase in PRA due to loss of
negative feedback inhibition) can tend to partially overcome
the blockade.34 This would be especially likely in high-renin
or volume-depleted patients with a particularly robust reactive
rise in PRA.
In general, short-term, pharmacodynamic responses to
decreases in Ang II through inhibition of ACE include dosedependent reductions in cardiac preload and afterload, with
lowering of systolic and diastolic blood pressure, but, in normotensive and hypertensive patients without cardiac dysfunction,
little or no change in cardiac output or capillary wedge pressure.
Of note, unlike direct-acting arterial vasodilators, ACEI-induced
reductions in total peripheral vascular resistance occur without
a significant change in heart rate.32 ACEIs also decrease renal
vascular resistance, increase renal blood flow, and promote
sodium and water excretion. Mainly through cellular effects
in the kidney and through alterations in glomerular hemo
dynamics, ACEIs also may prevent the progression of micro
albuminuria to proteinuria, reduce proteinuria in patients
with established glomerular disease, and prevent or delay the
progression of renal insufficiency to end-stage renal disease.
Efficacy in long-term trials has been demonstrated particularly
in patients with nondiabetic nephropathies or in patients with
insulin-dependent (type 1) diabetes.32,35,36
Because ACE is identical to kininase II, ACEIs may also lead
to elevation of bradykinin levels in some tissues (but unlikely
in the circulation); this effect is potentially associated with
increased bradykinin-dependent release of NO and vasoactive
prostaglandins, including prostacyclin and prostaglandin E2.32
These actions may potentially contribute to the vasodilatory,
antithrombotic, antiatherogenic, and antiproliferative effects of
ACEI, although the importance of this pathway is debated.32
In 40% to 60% of patients with mild-to-moderate hypertension, ACEI monotherapy produces a satisfactory reduction in
blood pressure.37 In this population, ACEIs contribute to reversal
of cardiac hypertrophy, and do so with significantly greater efficacy than beta blockers.38 In patients with CHF, ACEIs relieve
pulmonary congestion by a balanced reduction in cardiac preload
and afterload. They appear to induce venous vasodilation, which
increases peripheral venous capacitance and reduces right atrial
pressure, pulmonary arterial pressure, capillary wedge pressures,
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and left ventricular filling volumes and pressures. ACEIs also

induce arterial vasodilation, which reduces peripheral vascular
resistance (afterload) and increases cardiac output in this patient
population.32 ACEIs have also been shown to improve endothelial dysfunction in patients with heart failure, as well as in patients
with coronary artery disease and type 2 diabetes.32
In early landmark trials in patients with CHF (such as
CONSENSUS, SOLVD, and V-HeFT-II), ACEIs were shown not
only to markedly improve symptoms and functional status, but
also to dramatically reduce mortality. In subsequent studies in
patients who have suffered a myocardial infarction (MI), such
as SAVE, AIRE, and TRACE, ACEI therapy has been shown to
prevent or retard ventricular remodeling and progression to CHF,
and thereby to reduce overall mortality and prolong survival.39-46
Furthermore, results of the HOPE trial and other smaller
studies indicate broad cardiovascular benefits of ACEI therapy
in high-risk patients (including both hypertensive and normotensive individuals), and it is possible that these benefits occur in
part independently of their blood pressure-lowering effect.46
Several large-scale studies of various ACEIs have shown a
reduction in incidence of new-onset diabetes in association with
ACEI therapy. For example, this has been shown with captopril
in patients with hypertension (CAPP),47 with ramipril in
patients at high risk for cardiovascular disease (HOPE),46 with
enalapril in patients with left ventricular dysfunction (SOLVD),48
and with trandolapril in patients with stable coronary disease
(PEACE).49 The mechanism of this benefit has not been
determined.
ACEI therapy is generally well tolerated by most patients
but is nonetheless associated with some significant side effects.
Most frequent among these is a dry cough, which has been
attributed to accumulation of substance P (which is normally
degraded by kininase II). More serious side effects common to all
ACEIs include angioedema (which is potentiated by decreased
catabolism of kinins) and fetal abnormalities and mortality.
Other physiologic consequences of ACE inhibition may include
hypotension, deterioration of renal function, and hyperkalemia.
Lastly, toxic effects, associated mainly with captopril, include
abnormal (metallic or salty) taste, rash, neutropenia, hepatic
toxicity, and proteinuria (membranous nephropathy).30
Angiotensin Receptor Blockers (ARBs)
As mentioned earlier, the AT1 receptor mediates most of
the known actions of Ang II that contribute to hypertension
and volume dysregulation (vascular smooth muscle contraction, aldosterone secretion, dipsogenic responses, renal sodium
reabsorption, and pressor and tachycardiac responses) as well as
to cardiovascular damage (cellular hypertrophy or proliferation,
prothrombotic and proinflammatory effects, and superoxide
formation).7,9 Thus, with the discovery of different receptor
subtypes, specific antagonism of Ang II action at the AT1 receptor
became a logical therapeutic target, one considered likely to be
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Vol. 13, No. 8, S-b
more specific than ACE inhibition. Development of orally active,

nonpeptide, selective AT1 receptor blockers began in the 1990s
with the synthesis of losartan.2 Since that time, several
ARBs have been synthesized, including valsartan, irbesartan,
candesartan, eprosartan, telmisartan, and olmesartan.
Because ARBs act by blocking Ang II action at the receptor
level, rather than by inhibiting its synthesis, they ought to
antagonize AT1-mediated effects of Ang II no matter how it is
synthesized. In other words, if there were significant Ang II
synthesis in tissues by alternate pathways, such as chymase
in the heart, this would limit the efficacy of ACEIs (but not of
ARBs) through a mechanism postulated to contribute to the
escape phenomenon following long-term ACE inhibition.50
In contrast to the ACEIs, ARB therapy actually results in an
increase in Ang II levels.51 As with ACE inhibition, blockade
of the AT1 receptor inhibits the negative feedback loop, leading
to increased renin secretion and thus to increased synthesis
of Ang I. In the case of ARBs, the increase in Ang I leads to a
commensurate increase in Ang II, which is freely able to bind to
AT2 or other receptor subtypes. Earlier preclinical studies have
suggested that beyond AT1 receptor blockade, activation of the
AT2 receptor might mediate additional beneficial actions on the
vasculature, heart, and kidneys, in part via a bradykinin/NO/
cGMP pathway, an effect that would further distinguish ARBs
from ACEIs.7 But as attractive as this hypothesis is, there are no
clinical data to indicate that this pathway is a major mechanism
of ARB action in humans.
Like the ACEIs, ARBs reduce blood pressure by decreasing
systemic vascular resistance; they do not affect heart rate and
have minimal effect on cardiac output in the nonfailing heart.51
Reduced systemic vascular resistance results from a combination
of inhibition of Ang II-mediated vasoconstriction, reduced
sympathetic nervous system activity, and reduced extracellular
volume (i.e., by direct inhibition of proximal sodium reabsorption and by inhibition of aldosterone release).51 ARB monotherapy produces a satisfactory reduction in blood pressure in
40% to 60% of patients with mild-to-moderate hypertension.37
ARB therapy has also been shown to reduce markers of
inflammation in patients with atherosclerosis,52,53 suggesting
an anti-inflammatory effect, and to reverse endothelial dysfunction in patients with hypertension, indicating the possibility
of significant antiatherogenic effects.53 In patients with hypertension, ARB therapy has also been shown to improve arterial
compliance independent of the blood pressure-lowering effect.
This observation suggests that ARB therapy may contribute to
reversal of vascular wall damage.54
A number of recent large trials support the idea that the ARB
class may confer benefits on target organ protection beyond the
lowering of blood pressure per se. In patients with hypertension
and left ventricular hypertrophy, ARB-based therapy, compared
with beta-blocker (atenolol)-based therapy with identical blood
pressure control, has been shown to significantly reduce the
October 2007
JMCP
composite risk of cardiovascular death, stroke, and MI and to

decrease the rate of new-onset diabetes (LIFE study).55 Similarly,
ARB-based therapeutic regimens, compared with conventional
therapy, have been shown to reduce the progression of nephropathy in patients with diabetic nephropathy (IDNT, RENAAL studies).56,57 In nonhypertensive conditions, ARBs have shown benefits comparable with those of ACEIs. In patients with chronic
heart failure, addition of an ARB, compared with placebo, to conventional treatment has been shown to significantly reduce the
risk of cardiovascular mortality and hospitalization (CHARM,
Val-HeFT studies).58,59 In high-risk post-MI patients, ARB therapy has been shown to reduce the risks of all-cause mortality,
recurrent MI, sudden cardiac death, revascularization, coronary
artery bypass grafting, or all-cause hospital admission to a degree
similar to that of ACEI therapy (OPTIMAAL study).60
Like ACEIs, use of ARBs is contraindicated in pregnant women
because of the association of RAAS blockade with increased
fetal morbidity and mortality, particularly with exposure during
the second and third trimester. ARB therapy is otherwise
generally well tolerated, even in many patients who discontinue
ACEI therapy because of side effects. Although rare reports of
angioedema and cough have emerged from the early premarketing clinical trials with ARBs, it is currently debated whether
these are truly associated with the class as they are with ACEIs.
Most adverse events reported with ARB therapy are related to
expected potential effects of RAAS blockadefor example,
hypotension, hyperkalemia, and worsening renal functionand
are similar to those encountered in patients taking ACEIs.
Direct Renin Inhibitors
The most recent class of agents that block the RAAS to be
introduced are the direct renin inhibitors represented by
aliskiren, which was recently approved for treatment of hypertension. This compound differs from the ACEIs and ARBs in
that, by blocking the catalytic activity of renin at the point of
activation of the RAAS, it blocks the synthesis of all angiotensin peptides and prevents the compensatory increase in renin
activity. This topic is dealt with in detail in another article in
this series (see article titled Direct Renin Inhibition: Focus on
Aliskiren by Pool).61
Future Directions
ACEIs and ARBs are currently indicated for the treatment of
hypertension, diabetic nephropathy, post-MI left ventricular
dysfunction, and chronic heart failure, and their use has been
associated with improved survival and considerable cardiovascular and renal benefits in high-risk patients. These remarkable
benefits have been obtained even though blockade of the RAAS
with currently available agents may be incomplete, raising the
possibility that additional therapeutic modalities for RAAS
blockade might help to further slow progression of cardiovascular and renal disease.
JMCP
First, blockade of the RAAS by ACEIs and ARBs is incomplete

because their therapeutic response can be limited by the reactive rise in PRA. This is particularly so with the ACEIs, because
a marked rise in Ang I may compete with the relatively lowaffinity inhibition of ACE that they afford. Second, although the
notion that selective blockade of AT1 receptors may be a preferred
approach over ACE inhibition is based on attractive hypotheses
(i.e., the potential benefits of AT2 receptor agonism and/or the
ability to counteract the effects of ACE-independent pathways
of Ang II synthesis), these hypotheses are largely unproven in
humans. Moreover, there have been no large-scale clinical trials
over the past 15 years that demonstrate a clear superiority
of ARBs over ACEIs. Third, although our focus has been on
Ang II as the only villain of the RAAS, the possibility that other
angiotensin peptides might also contribute to cardiovascular
pathology has never been adequately tested. Fourth, questions of
mechanism aside, it is likely that differences in drug distribution
and/or tissue penetration between or within the classes may limit
the benefits of any single agent. Thus, it is reasonable at this point
to ask whether more-complete blockade of the system will offer
even more clinical benefits.
The clinical potential of simultaneous intervention at
multiple sites of the RAAS is compelling. As has already been
demonstrated in small clinical trials, dual RAAS blockade using
an ACEI and ARB in combination may have potential clinical value in symptomatic patients with CHF or left ventricular
systolic dysfunction and in patients with chronic proteinuric
renal disease.50 With the recent availability of aliskiren, the first
direct renin inhibitor approved for the treatment of hypertension,
the opportunity is at hand to test new therapeutic approaches
involving monotherapy with this agent or its use in combination
with an ACEI or ARB for more complete blockade of the RAAS.
Results obtained with this approach may direct investigators to
explore additional therapeutic targets in the future, such as other
angiotensin receptor subtypes, other relatively specific metabolic
pathways (e.g., ACE 2), or other angiotensin peptides (e.g.,
Ang III, Ang IV, and Ang-(1-7)). Lastly, the possibility of molecular approaches such as antisense gene therapy, targeting, for
instance, renin, angiotensinogen, the AT1 receptor, or ACE, will
also likely be explored in the not-too-distant future.
Disclosures
The author discloses no potential bias or conflict of interest relating to
this article.
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33. Pitt B. Escape of aldosterone production in patients with left

ventricular dysfunction treated with an angiotensin converting enzyme
inhibitor: implications for therapy. Cardiovasc Drugs Ther. 1995;9:145-49.
12. Funder JW. New biology of aldosterone, and experimental studies on

the selective aldosterone blocker eplerenone. Am Heart J. 2002;144:S8-11.
34. Atlas SA, Case DB, Yu ZY, Laragh JH. Hormonal and metabolic effects
of angiotensin converting enzyme inhibitors: possible differences between
enalapril and captopril. Am J Med. 1984;77:13-17.
13. Phillips MI. Tissue renin-angiotensin systems. In: Izzo JL, Black HR, ed.
Hypertension Primer: The Essentials of High Blood Pressure. 2nd ed. Baltimore,
MD: Lippincott William & Wilkins; 1999:23-24.
14. Ihara M, Urata H, Kinoshita A, et al. Increased chymase-dependent
angiotensin II formation in human atherosclerotic aorta. Hypertension.
1999;33:1399-405.
15. Hollenberg NK, Fisher NDL, Price DA. Pathways for angiotensin II
generation in intact human tissue: evidence from comparative
pharmacological interruption of the renin system. Hypertension.
1998;32:387-92.
16. Urata H, Healy B, Stewart RW, Bumpus FM, Husain A. Angiotensin
II-forming pathways in normal and failing human hearts. Circ Res.
1990;66:883-90.
17. Wolny A, Clozel JP, Rein J, et al. Functional and biochemical analysis
of angiotensin II-forming pathways in the human heart. Circ Res.
1997;80:219-27.
18. Pagliaro P, Penna C. Rethinking the renin-angiotensin system and its
role in cardiovascular regulation. Cardiovasc Drugs Ther. 2005;19:77-87.
19. Paul M, Poyan Mehr A, Kreutz R. Physiology of local renin-angiotensin
systems. Physiol Rev. 2006;86:747-803.
20. Danser AH, van Kats JP, Admiraal PJ, et al. Cardiac renin and
angiotensins. Uptake from plasma versus in situ synthesis. Hypertension.
1994;24:37-48.
21. van Kats JP, Chai W, Duncker DJ, Schalekamp MADH, Danser AHJ.
Adrenal angiotensin: origin and site of generation. Am J Hypertens.
2005;18:1104-10.
22. Laragh J. Laraghs lessons in pathophysiology and clinical pearls for
treating hypertension. Am J Hypertens. 2001;14:186-94.
23. Schmidt RJ, Soman SS. Renovascular Hypertension. Available at:
http://www.eMedicine.com. Accessed May 3, 2007.
35. Maschio G, Alberti D, Janin G, et al. Effect of the angiotensinconverting-enzyme inhibitor benazepril on the progression of chronic
renal insufficiency. N Engl J Med. 1996;334:939-45.
36. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, for the collaborative study
group. The effect of angiotensin-converting-enzyme inhibition on diabetic
37. Ibrahim MM. RAS inhibition in hypertension. J Hum Hypertens.
2006;20:101-08.
38. Klingbeil AU, Schneider M, Martus P, Messerli FH, Schmieder RE.
A meta-analysis of the effects of treatment on left ventricular mass in
essential hypertension. Am J Med. 2003;115:41-46.
39. The SOLVD Investigators. Effect of enalapril on mortality and the
development of heart failure in asymptomatic patients with reduced left
ventricular ejection fractions. N Engl J Med. 1992;327:685-91.
40. Effect of enalapril on survival in patients with reduced left ventricular
ejection fractions and congestive heart failure. The SOLVD Investigators.
N Engl J Med. 1991;325:293-302.
41. Gruppo Italiano per lo Studio della Sopravvivenza nellinfarto
Miocardico. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate
singly and together on 6-week mortality and ventricular function after acute
myocardial infarction. Lancet. 1994;343:1115-22.
42. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative
Group. ISIS-4: a randomised factorial trial assessing early oral captopril,
oral mononitrate, and intravenous magnesium sulphate in 58,050 patients
with suspected acute myocardial infarction. Lancet. 1995;345:669-85.
43. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality
and morbidity in patients with left ventricular dysfunction after myocardial
infarction. Results of the survival and ventricular enlargement trial.
The SAVE Investigators. N Engl J Med. 1992;327:669-77.
24. Corvol P, Pinet F, Plouin PF, Bruneval P, Menard J. Renin-secreting

tumors. Endocrinol Metab Clin North Am. 1994;23:255-70.
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44. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.

Effect of ramipril on mortality and morbidity of survivors of acute
myocardial infarction with clinical evidence of heart failure. Lancet.
1993;342:821-28.
45. The EURopean trial On reduction of cardiac events with Perindopril
in stable coronary Artery disease [EUROPA] Investigators. Efficacy of
perindopril in reduction of cardiovascular events among patients with stable
coronary artery disease: randomised, double-blind, placebo-controlled,
multicentre trial (the EUROPA study). Lancet. 2003;362:782-88.
46. Yusuf S, Sleight P, Pogue J, et al., for The Heart Outcomes Prevention
Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme
inhibitor, ramipril, on cardiovascular events in high-risk patients.
N Engl J Med. 2000;342:145-53.
47. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensinconverting-enzyme inhibition compared with conventional therapy on
cardiovascular morbidity and mortality in hypertension: the Captopril
Prevention Project (CAPPP) randomised trial. Lancet. 1999;353:611-16.
48. Vermes E, Ducharme A, Bourassa MG, Lessard M, White M, Tardif J-C.
Enalapril reduces the incidence of diabetes in patients with chronic heart
failure: insight from the Studies Of Left Ventricular Dysfunction (SOLVD).
Circulation. 2003;107:1291-96.
49. The PEACE Trial Investigators. Angiotensin-converting-enzyme
inhibition in stable coronary artery disease. N Engl J Med.
2004;351:2058-68.
50. Ruilope LM, Rosei EA, Bakris GL, et al. Angiotensin receptor blockers:
therapeutic targets and cardiovascular protection. Blood Press.
2005;14:196-209.
51. Hernandez-Hernandez R, Sosa-Canache B, Velasco M,
Armas-Hernandez MJ, Armas-Padilla MC, Cammarata R. Angiotensin II
receptor antagonists role in arterial hypertension. J Hum Hypertens.
2002;16(suppl 1):S93-S99.
53. Koh KK, Ahn JY, Han SH, et al. Pleiotropic effects of angiotensin II
receptor blocker in hypertensive patients. J Am Coll Cardiol. 2003;42:905-10.
54. Shargorodsky M, Leibovitz E, Lubimov L, Gavish D, Zimlichman R.
Prolonged treatment with the AT1 receptor blocker, valsartan, increases
small and large artery compliance in uncomplicated essential hypertension.
Am J Hypertens. 2002;15:1087-91.
55. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity
and mortality in the Losartan Intervention For Endpoint reduction in
hypertension study (LIFE): a randomised trial against atenolol. Lancet.
2002;359:995-1003.
56. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the
angiotensin-receptor antagonist irbesartan in patients with nephropathy
due to type 2 diabetes. N Engl J Med. 2001;345:851-60.
57. Brenner BM, Cooper ME, De Zeeuw D, et al. Effects of losartan on
renal and cardiovascular outcomes in patients with type 2 diabetes and
58. Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan
on mortality and morbidity in patients with chronic heart failure: the
CHARM-Overall programme. Lancet. 2003;362:759-66.
59. Maggioni AP, Anand I, Gottlieb SO, et al. Effects of valsartan on
morbidity and mortality in patients with heart failure not receiving
angiotensin-converting enzyme inhibitors. J Am Coll Cardiol.
2002;40:1414-21.
60. Dickstein K, Kjekshus J. Effects of losartan and captopril on mortality
and morbidity in high-risk patients after acute myocardial infarction: the
OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with
Angiotensin II Antagonist Losartan. Lancet. 2002;360:752-60.
61. Pool JL. Direct renin inhibition: focus on aliskiren. J Manag Care Pharm.
2007;13(8)(suppl b):S21-S33.
52. Navalkar S, Parthasarathy S, Santanam N, Khan BV. Irbesartan, an

angiotensin type 1 receptor inhibitor, regulates markers of inflammation in
patients with premature atherosclerosis. J Am Coll Cardiol. 2001;37:440-44.
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Direct Renin Inhibition: Focus on Aliskiren

James L. Pool, MD
Abstract
Background: Despite the availability of many effective, well-tolerated
drugs, a significant proportion of treated hypertensive patients still have
uncontrolled high blood pressure (BP) and thus face serious morbidity and
mortality. The renin-angiotensin aldosterone system (RAAS) is a key target
for BP control and for cardiovascular and renal protection. Renin controls
the rate-limiting step in the RAAS cascade and hence is the optimal target
for RAAS suppression. Aliskiren is the first direct renin inhibitor (DRI) to
be approved by the U.S. Food and Drug Administration and the European
Medicines Agency for treating hypertension.
Objective: To provide an overview of the pharmacology, pharmacokinetics, preclinical, and clinical efficacy and safety data on the DRI aliskiren.
Results: Approximately 70% of essential hypertension is associated
with elevated renin levels. Aliskiren is a potent and highly specific inhibitor
of renin, with oral bioavailability of 2.6% and an elimination half-life of
40 hours, making it suitable for once-daily oral administration. Aliskiren
dose-dependently reduced BP, inhibited plasma renin activity (PRA),
attenuated renal damage in animal models, and showed efficient and longer-lasting blockade of the RAAS in normotensive human subjects
compared with other RAAS inhibitors. The clinical efficacy and safety
of aliskiren have been evaluated both as monotherapy and in combination with other antihypertensive agents in phase II and phase III trials of
patients with mild to severe hypertension. When used as monotherapy,
aliskiren led to significant dose-dependent reductions in BP from baseline
that were greater than those obtained with placebo and comparable
with those achieved with an angiotensin II receptor blocker (ARB). The
combination of aliskiren with a diuretic, a calcium channel blocker (CCB),
an angiotensin-converting enzyme inhibitor (ACEI), or an ARB generally
had greater and longer-lasting BP-lowering efficacy than did single agents
alone. Aliskiren also countered the reactive increase in PRA caused by
diuretic, CCB, ACEI, and ARB therapy. Once-daily treatment with
aliskiren was well tolerated.
Conclusions: As a DRI, aliskiren blocks the RAAS more completely
than do other current downstream RAAS inhibitors. When used once daily,
aliskiren is a safe and effective antihypertensive agent that can be used
as monotherapy or in combination with other agents to provide additional
options to improve BP control.
Keywords: Aliskiren, Antihypertensives, Renin
Author
James L. Pool, MD, is a professor, medicine and pharmacology,

Baylor College of Medicine, Houston, TX, and holds the James L. Pool
Endowed Chair in Clinical Pharmacology. He is also the clinical director,
Hypertension-Clinical Pharmacology Research Clinic, at Baylor.
Author Correspondence: James L. Pool, MD, Baylor College
of Medicine, Houston, TX 77030; Tel: (713) 798-0180; E-mail:
jpool@bcm.edu
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Vol. 13, No. 8, S-b
he renin-angiotensin aldosterone system (RAAS) is

a coordinated hormonal cascade that governs cardio
vascular, renal, and adrenal functions by regulating
fluid and electrolyte balance as well as arterial pressure.1 The
RAAS regulates blood pressure (BP) via angiotensin release and
body electrolyte content via aldosterone release.2 Angiotensin
(Ang) II is the principal effector hormone of the RAAS and is
produced when renin acts on angiotensinogen to form Ang I,
which is subsequently converted to the biologically active Ang II
via the angiotensin-converting enzyme (ACE).3 The traditional
concept of the RAAS has expanded over the years to include
local tissue RAASs in the heart, brain, kidney, pancreas, and
peripheral vasculature, which act as paracrine or autocrine
systems that regulate vascular function and cell growth and
contribute to the pathogenesis of cardiovascular and renal
diseases.4,5
Inhibition of RAAS activity with ACE inhibitors (ACEIs) or
angiotensin receptor blockers (ARBs) has proven effective for
not only controlling hypertension but also delaying the onset
of diabetes mellitus, slowing renal damage in patients with
hypertension, and reversing left ventricular hypertrophy.6
However, these agents are no more effective than other antihypertensive agents in reducing major cardiovascular events,6
which suggests an incomplete blockade of the RAAS. Inhibition
of Ang II formation or action via ACEIs or ARBs does not provide
optimal suppression of RAAS activity, because a compensatory
increase in renin concentrations again increases Ang I and
Ang II levels. Ang II can also be formed using pathways that do
not involve ACE.4
Because it causes the conversion of angiotensinogen to
Ang I, which is the rate-limiting step in the RAAS cascade,
renin is the main determinant of RAAS activity and has been
considered for at least 50 years the optimal target for RAAS
suppression.7 Circulating renin can be taken up by cardiac
and coronary tissues, leading to the long-lasting generation
of Ang II via ACE and non-ACE activity that is only partially
suppressed by an ACEI.8 Inhibition of renin would favor more
complete blockade of the system. The successful production
of a highly potent, selective, clinically effective oral renin
inhibitor is a major development in the area of RAAS inhibition. This article provides an overview of direct renin inhibition
(DRI) and reviews the pharmacologic and clinical profile of
aliskiren, the first antihypertensive agent in a new class of drugs
approved by the U.S. Food and Drug Administration (FDA) in
more than 10 years. Aliskiren also received approval from the
European Medicines Agency (EMEA).
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Renin
Overactivity of the RAAS with high renin, Ang, and aldosterone
levels causes fatal malignant hypertension and renovascular
hypertension, whereas overactivity of the RAAS with milder
elevations of renin levels has been associated with up to 70%
of cases of essential hypertension.2 Patients with plasma renin
activity (PRA) levels exceeding 0.65 ng/mL/h have renin-mediated hypertension, and those with lower PRA levels have salt
hypertension, which accounts for the remaining 30% of essential
hypertension.2
Renin is an aspartyl protease that is synthesized as prorenin,
a proenzyme that is transformed into renin by cleavage of a
43-amino-acid segment from the N-terminal end (Figure 1).
This activation process, which occurs exclusively in the juxtaglo
merular cells of the kidney, is followed by the release of renin into
the circulation system.9 Although it is synthesized in only a few
tissues (eyes, adrenal glands, testes, ovaries, and brain), prorenin
represents between 70% and 90% of the total plasma renin in
individuals without diabetes and as much as 95% of the total
plasma renin in individuals with diabetes.10 The local actions of
renin are thus mediated by kidney-derived renin that is released
into the circulation system and taken up by tissues. For example,
cardiac Ang production depends on the conversion of angiotensinogen in extracellular fluid by plasma-derived renin.11
Renin receptors have been localized to glomerular mesangium
and vascular smooth muscle cells within the subendothelium
of glomerular and coronary arteries.9 The receptor colocalizes
with renin. Cells transfected with receptor cDNA result in the
expression of a membrane protein that specifically binds renin
and prorenin with high affinity.9 Labeling studies have demonstrated high-affinity binding (Kd=0.4 nM) of renin to receptors on
cultured human mesangial cells.12
The binding of renin to its receptor with a single transmembrane domain has multiple and far-reaching consequences.
Receptor binding induces a 4-fold increase in the catalytic
conversion of angiotensinogen to Ang I, suggesting that the cell
surface is an important site of Ang generation.9 Once bound,
renin triggers a series of intracellular events that culminate in
activation of the mitogen-activated protein kinases ERK1 (p44)
and ERK2 (p42), which are involved in cell hypertrophy and
proliferation.9 At physiologic levels, renin enhances the incorporation of 3H-thymidine into cells, with no increase in cell numbers;
increases transforming growth factor beta in mesangial cells
(suggesting upregulation through a receptor-mediated mechanism, independent of Ang II generation or action); and activates
the synthesis of plasminogen activator-1 and fibrotic extracellular
components such as fibronectin and collagen (suggesting that
renin may contribute to fibrotic disease).13,14 Overexpression of
the renin receptor in arterial smooth muscle cells of transgenic
rats resulted in high BP levels, increased heart rate, and significant elevation of plasma aldosterone levels, effects that were
attributed to local activation of the intraadrenal RAAS.15
JMCP
When bound to the renin receptor, the catalytic activity of

prorenin is comparable with that of renin and appears to be
of pathologic significance.9 Elevated prorenin levels have been
correlated with microvascular complications of diabetes, and
lesions mimicking diabetic nephrosclerosis are present in transgenic rats expressing prorenin.16 Rats with streptozocin-induced
diabetes have high levels of prorenin, Ang I, and Ang II, but not
of renin, ACE, or angiotensinogen.16 Nonproteolytic activation
of prorenin to its enzymatically active state occurs through the
binding of certain carbohydrate substances or the renin receptor.
When nonproteolytic conversion of prorenin was inhibited with
a blocking peptide, levels of renal Ang I and Ang II were reduced
and the development of nephropathy was attenuated, thus
substantiating that prorenin has a role in the progression of
diabetic renal damage.16 How prorenin contributes to the pathophysiology of these complications remains to be established.
Direct Renin Inhibition
The concept of blocking the RAAS at its origin by inhibiting
renin has existed for at least 50 years. The first synthetic renin
inhibitor was pepstatin, which was followed by first-generation
agents that were active but required parenteral administration.17
Oral agents that were subsequently developed, such as enalkiren, remikiren, and zankiren, had limited clinical use because
they demonstrated poor bioavailability (<2%), short half-lives,
and weak antihypertensive activity.17 Crystal structure analyses of renin-inhibitor complexes and computational molecular
modeling were later used to design selective nonpeptide DRIs that
lacked the extended peptide-like backbone of previous inhibitors
and had improved pharmacokinetic properties.18 Aliskiren is the
first of these new nonpeptide DRIs to be approved by the FDA
for the treatment of hypertension. It is administered once daily,
either as monotherapy or in combination with other antihypertensive agents. In Europe, aliskiren received approval from the
EMEA for the treatment of hypertension.
Aliskiren
Aliskiren is a transition-state mimetic agent with high hydrophilicity, which improves its oral bioavailability.18 It is a highly
potent inhibitor of renin (IC50=0.6 nM) with a high affinity for
renin and a high species specificity for primate renin. Aliskiren
inhibits human, marmoset, and rat plasma renin with IC50
values of 0.6 nmol per L, 2.0 nmol per L, and 80 nmol per L,
respectively.18 Therefore, preclinical testing has been performed
in sodium-depleted marmosets and in spontaneously hypertensive rats.
In sodium-depleted marmosets, doses of aliskiren ranging
from 0.3 mg per kg to 10 mg per kg caused a dose-dependent
reduction in mean arterial BP.19 All doses of aliskiren completely
inhibited PRA within 1.5 hours of administration, and this inhibition was sustained for more than 24 hours with the 3 mg per kg
and 10 mg per kg doses.19 When the 3 mg per kg dose was
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JMCP
administered, BP was reduced by a maximum of 30 mm Hg

without any effect on heart rate. The 10 mg per kg dose of aliskiren was more effective than similar doses of either benazepril or
valsartan in reducing mean arterial pressure.19
Pilz and colleagues compared the effects of subcutaneous
aliskiren 0.3 mg per kg per day, 3 mg per kg per day with valsartan 1 mg per kg per day, and 10 mg per kg per day with no treatment on the development of end-organ damage in hypertensive
double-transgenic rats with high levels of serum creatinine and
albuminuria.20 Both doses of aliskiren and the higher dose of valsartan reduced renal Ang I and II content, maintained creatinine
at normal levels, decreased albuminuria, prevented renal infiltration with inflammatory cells, reduced cardiac hypertrophy, and
prolonged survival.20 However, aliskiren 3 mg per kg per day
was significantly more effective than valsartan 10 mg per kg per
day in reducing systolic BP (SBP), cardiac hypertrophy, and left
ventricular wall thickness (P<0.05 for all endpoints).20 In this
model, renin inhibition compared favorably with AT1 receptor
blockade in reversing renal damage.
Subsequent studies in normotensive human subjects demonstrated efficient blockade of the RAAS with aliskiren. In
18 normotensive men with a sodium intake of 100 mmol/day,
treatment with aliskiren (40 mg per day to 640 mg per day) for
8 days significantly and in a dose-dependent manner suppressed
PRA and plasma concentrations of Ang I and Ang II.21 Maximal
reduction of Ang II occurred within 1 hour of the administration of aliskiren, compared with 6 hours with a 20 mg dose of
enalapril. The level of inhibition of Ang II by enalapril (57%) was
similar to that with a 160 mg dose of aliskiren (56%).21 A dose
of aliskiren 80 mg reduced plasma aldosterone levels within
3 hours of administration and, at the highest dose, these levels
remained suppressed for up to 24 hours.21 In response to the
reduction in Ang II level, plasma renin concentrations increased
similarly with aliskiren 160 mg and enalapril 20 mg.21
A double-blind, placebo-controlled, randomized, 4-period
crossover study in 12 normotensive men who were mildly sodium depleted compared a single high dose of aliskiren (300 mg),
a standard dose of valsartan (160 mg), and their combination at
half doses (aliskiren 150 mg plus valsartan 80 mg).22 In contrast
to valsartan, aliskiren decreased PRA and Ang I and Ang II levels
for 48 hours, inhibited urinary aldosterone secretion for a longer
period, and resulted in greater and longer-lasting increases in
plasma renin levels.22 In general, the effects of the low-dose combination were similar to those of aliskiren 300 mg than to those
of valsartan 160 mg. The combination blunted the valsartaninduced increase in PRA and Ang I and Ang II concentrations,
led to greater and longer suppression of urinary aldosterone
excretion compared with valsartan alone, and was as effective
as either monotherapy in reducing BP.22 The longer duration of
RAAS inhibition by aliskiren compared with valsartan suggested
that the effects of Ang II may be reduced more effectively by
direct renin inhibition than by Ang receptor blockade.
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Aliskiren Pharmacokinetics
The pharmacokinetics of aliskiren deviate from dose linearity, with an overproportional increase in area under the curve
(AUC) and Cmax with respect to the administered dose.22 The
mean terminal half-life is approximately 40 hours after multiple
administrations of a single dose, and repeated once-daily
administration leads to drug accumulation.23 The mean absolute
bioavailability is 2.6%24; administration with a high-fat meal
reduces AUC and Cmax values by 71% and 85%, respectively, of
those in the fasting state, so patients should be advised to take
aliskiren in the same manner each day with respect to meal
times.25 Peak plasma concentrations are reached 1 to 2 hours
after dosing,23,24 and steady state is reached after 5 to 8 days of
once-daily administration.21
The main pathway of elimination for aliskiren is via biliary
excretion as unmetabolized drug. Less than 1% of an orally
administered dose is excreted in urine.21 Aliskiren is not
metabolized by, and does not induce or inhibit, cytochrome
P450 enzymes and shows no clinically relevant pharmacokinetic interactions with warfarin,17 lovastatin,26 atenolol,26
celecoxib,26 cimetidine,26 amlodipine,27 valsartan,27 hydrochlorothiazide (HCTZ),27 or ramipril.27 Coadministration of aliskiren
with furosemide, a commonly used loop diuretic, reduced the
AUC of furosemide by 28% and Cmax by 49%, but the clinical
significance of this remains uncertain.28 The pharmacokinetics of
aliskiren remain unaffected by ethnicity,24 age,29 gender,23 hepatic
impairment,30 renal impairment,31 and diabetes.23
Studies in Patients With Hypertension
Phase II and III clinical trials have demonstrated the efficacy

of once-daily administration of aliskiren in the treatment of
patients with mild to moderate hypertension (diastolic blood
pressure [DBP] 95 mm Hg and <110 mm Hg, either as
monotherapy or in combination with diuretics, calcium
channel blockers [CCBs], ACEIs, or ARBs), or as monotherapy
in the treatment of severe hypertension (DBP 105 mm Hg
and <120 mm Hg). Two trials that evaluated both monotherapy
and combination therapy with aliskiren are discussed below in
Combination Therapy.32,33 Table 1 provides details of the study
design and the main findings of all the trials that are discussed.
Monotherapy
In a 4-week study, aliskiren 37.5 mg, 75 mg, 150 mg, or 300 mg

once daily was compared with losartan 100 mg once a day.34
Dose-dependent reductions from baseline in daytime ambulatory
SBP (ASBP) were obtained with all doses of aliskiren (P=0.0002
vs. baseline for all doses).34 The changes in daytime ASBP with
the 3 highest doses of aliskiren were similar to those obtained
with losartan 100 mg,34 and the heart rate remained unaltered.
All doses of aliskiren also led to significant dose-dependent
decreases of PRA between -55% and -83% (P=0.0008 vs. baseline), whereas PRA increased by 110% with losartan.34
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Phase II and III Double-Blind Clinical Trials of Once-Daily Aliskiren Treatment in Patients
With Mild to Moderate Hypertension32-41
TABLE 1
Study
Study Design (Number of

Patients Randomized; Mean Age)
Effects of Aliskiren on Primary Efficacy Variable

(Statistical Significance)
Treatments/ Duration*
Monotherapy
Stanton et al.34
(2003)
r, db, ac (226; 52 years)
Aliskiren 37.5 mg, 75 mg, 150 mg,

or 300 mg
Losartan 100 mg
4 weeks
Lowers daytime ASBP (P=0.0002 vs. baseline; all doses)

No significant difference between aliskiren 75 mg, 150 mg,
and 300 mg and losartan 100 mg in mean change in daytime
ASBP (all doses: P=NS)
Reductions from baseline in:

MSSBP/MSDBP (mm Hg)
A37.5 mg:
-4.3/-1.9
A75 mg:
-4.1/-0.2
A150 mg:
-10.0/-2.2
A300 mg:
-11.8/-5.7
L100 mg:
-11.4/-5.5
Gradman et
al.35 (2005)
r, db, pc, ac (652, 56 years)
Oh et al.36
(2007)
r, db, pc, (672; 53 years)
Strasser et al.37
(2007)
mc, r, db (183; 55.4 years)
Aliskiren 150 mg, 300 mg,

or 600 mg
Irbesartan 150 mg
Placebo
8 weeks
Lowers trough MSDBP (P<0.001 vs. placebo, all doses)

Aliskiren 150 mg=irbesartan 150 mg

MSSBP/MSDBP (mm Hg)
A150 mg:
-11.6/-9.8
A300 mg:
-15.8/-11.8
A600 mg:
-15.7/-11.5
Ir150 mg:
-12.5/-8.9
Placebo:
-5.3/-6.3
CR
38%
50%
46%
34%
21%

or 600 mg
Placebo
8 weeks
Lowers MSDBP and MSSBP (all doses; P<0.0001 vs. placebo)
Aliskiren 150 mg/300 mg

Lisinopril 20 mg/40 mg
(option to add HCTZ)
8 weeks
Mean reductions from baseline in:

MSSBP/MSDBP (mm Hg)
A300 mg:
-20.0/-18.5
L40 mg:
-22.3/-20.1
Reductions from baseline in MSSBP/MSDBP levels at 8 weeks,

and in RR and CR at 2 weeks postwithdrawal:

MSSBP/MSDBP (mm Hg)
RR
CR
A150 mg:
-13.0/-10.3
59%
36%
A300 mg:
-14.7/-11.1
63%
42%
A600 mg:
-15.8/-12.5
69%
46%
Placebo:
-3.8/-4.9
36%
20%
RR
81.5%
87.9%
continued on next page
In an 8-week placebo-controlled study, Gradman and

colleagues randomized patients to once-daily aliskiren 150 mg,
300 mg, or 600 mg; irbesartan 150 mg; or placebo.35 All doses
of aliskiren reduced mean sitting DBP (MSDBP) and mean
sitting SBP (MSSBP, P<0.001 vs. placebo for both variables).35
Antihypertensive efficacy and control rates were comparable in
the aliskiren 150 mg and irbesartan 150 mg arms but higher
in the aliskiren 300 mg and aliskiren 600 mg arms.35
In another placebo-controlled study, Oh and colleagues
evaluated the effects of treatment withdrawal after 8 weeks of
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monotherapy with aliskiren (150 mg, 300 mg, or 600 mg).36 All
doses of aliskiren produced greater reductions in MSDBP and
mean MSSBP than did placebo (P<0.0001, Figure 2),36 as well
as daytime and nighttime mean ambulatory DBP (ADBP) and
ASBP.36 The antihypertensive effect persisted for 2 weeks after
drug withdrawal, with BP levels lower in the aliskiren groups
than in the placebo group.36
In an 8-week, active-controlled, parallel-group study, Strasser
and colleagues compared the tolerability (primary endpoint) and
efficacy of aliskiren 150 mg once daily with lisinopril 20 mg once
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JMCP
Table 1 (continued)Phase II and III Double-Blind Clinical Trials of Once-Daily Aliskiren Treatment in Patients With
Mild to Moderate Hypertension
Study


Combination Therapy
Villamil et al.32
(2007)
r, db, pc (2,776; 55 years)

or 300 mg
Lowers MSDBP (P=0.0002 vs. placebo; overall Dunnetts test;

all doses)
HCTZ 6.25 mg, 12.5 mg, or 25 mg
Lowers MSDBP (all combinations, P<0.0001 vs. placebo; most

combinations, P<0.05 vs. monotherapy with either component)
Aliskiren 75 mg+HCTZ 6.25 mg,

12.5 mg, or 25 mg
Aliskiren 150 mg+
HCTZ 6.25 mg, 12.5 mg, or 25 mg
Aliskiren 300 mg+HCTZ 12.5 mg
or 25 mg
Placebo
8 weeks
Jordan et al.38
(2007)
r, db (560; 54.1 years)
HCTZ 25 mg
4 weeks
Then, for nonresponders to HCTZ:
Aliskiren 150 mg, irbesartan
150 mg, amlodipine 5 mg, or
placebo; each plus HCTZ 25 mg
4 weeks

MSSBP/MSDBP (mm Hg)
A75 mg:
-9.4/-8.7
A150 mg:
-12.2/-8.9
A300 mg:
-15.7/-10.3
HCTZ 6.25 mg:
-11.0/-9.1
HCTZ 12.5 mg:
-13.9/-10.1
HCTZ 25 mg:
-14.3/-9.4
A75 mg/HCTZ 6.25 mg:
-14.3/-10.8
-15.6/-11.1
A75 mg/HCTZ 25 mg:
-17.3/-11.5
-15.3/-10.4
-17.6/-11.9
A150 mg/HCTZ 25 mg:
-19.5/-12.7
-19.8/-13.9
A300 mg/HCTZ 25 mg:
-21.2/-14.3
Placebo:
-7.5/-6.9
RR
52%
52%
64%
54%
61%
59%
62%
64%
70%
58%
70%
71%
31%
77%
46%
Aliskiren/HCTZ: Lowers MSDBP in obese patients (P<0.0001

vs. placebo/HCTZ); treatment difference of -4.0 mm Hg for
MSDBP and -7.2 mm Hg for MSSBP
Aliskiren/HCTZ=irbesartan/HCTZ=amlodipine/HCTZ
(P=NS for group difference)
Aliskiren 300 mg, irbesartan

300 mg, amlodipine 10 mg, or
placebo; each plus HCTZ 25 mg
8 weeks
Drummond
et al.39 2007
r, sb then db, parallel-group
Amlodipine 5 mg
(sb, 4 weeks)
Amlodipine 5 mg,
amlodipine 10 mg, or aliskiren
150 mg plus amlodipine 5 mg
(db, 6 weeks)

A150 mg/amlodipine 5 mg:
Amlodipine 5 mg:
Amlodipine 10 mg:
MSSBP/MSDBP (mm Hg)

-11.0/-8.5
-5.0/-4.8
-9.6/-8.0
RR
Proportion of patients achieving MSDBP <90 mm Hg and/or
at least 10 mm Hg reduction from baseline
64.2%
Amlodipine 5 mg:
45.2%
Amlodipine 10 mg:
59.9%
CR
Proportion of patients achieving BP <140/90 mm Hg
42.8%
Amlodipine 5 mg:
22.6%
Amlodipine 10 mg:
37.9%
All outcome measures P<0.005 aliskiren 150 mg plus
amlodipine 5 mg or amlodipine 10 mg, compared with
amlodipine 5 mg
continued on next page
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Vol. 13, No. 8, S-b
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Table 1 (continued)Phase II and III Double-Blind Clinical Trials of Once-Daily Aliskiren Treatment in Patients With
Mild to Moderate Hypertension
Study


Combination Therapy (continued)

Uresin et al.40
(2006)
r, db (837; 59.8 years)
Pool et al.33
(2007)
r, db, pc (1,123; 56 years)
Oparil et al.41
(2007)
Patients with type 1 or type 2

diabetes
r, db, pc (1,797; 52.3 years)
Aliskiren 300 mg
Ramipril 10 mg
Aliskiren/ramipril 300/10 mg

MSSBP/MSDBP (mm Hg)
A300 mg:
-14.7/-11.3
R10 mg:
-12.0/-10.7
A300 mg/R10 mg:
-16.6/-12.8
Aliskiren 75 mg, 150 mg, 300 mg

Valsartan 80 mg, 160 mg, or
320 mg
Aliskiren (150 mg, 300 mg, or
600 mg)
Aliskiren/valsartan 75 mg/80 mg,
150 mg/160 mg, 300mg/320 mg
Valsartan/HCTZ 160 mg/12.5 mg
Placebo
8 weeks
Lowers MSDBP (aliskiren 300 mg; P<0.001 vs. placebo)

Aliskiren=valsartan
Aliskiren 300 mg
Valsartan 320 mg
Aliskiren/valsartan 300 mg/
320 mg
Placebo
8 weeks
Week 8 reductions from baseline in:

MSSBP/MSDBP MASBP/MADBP

(mm Hg)
(mm Hg)
CR
A300 mg:
-13.0/-9.0
-9.8/-7.1
37%
V320 mg:
-12.8/-9.7
-10.1/-7.1
34%
A300 mg/V320 mg: -17.2/-12.2
-14.4/-10.3 49%
Placebo:
4.6/-4.1
-1.3/-1.1
17%
Lowers MSDBP (P<0.05 vs. placebo),

aliskiren/valsartan=valsartan/HCTZ (P=NS for group difference)

MSSBP/
RR
CR

MSDBP (mm Hg)
A75 mg:
-12.1/-10.3
60%
36%
A150 mg:
-12.1/-10.3
59%
31%
A300 mg:
-15.0/-12.3
68%
42%
V80 mg:
-11.2/-10.5
55%
38%
V160 mg:
-15.5/-11.0
66%
47%
V320 mg:
-16.5/-11.3
63%
42%
A75 mg/V80 mg:
-14.5/-11.8
75%
43%
A150 mg/V160 mg:
-16.6/-12.1
67%
37%
A300 mg/V320 mg:
-18.0/-12.9
76%
50%
V160 mg/HCTZ12.5 mg: -18.9/-13.5
79%
55%
Placebo:
-10.0/-8.6
8%
28%
*All treatments were administered once daily.

This trial evaluated the efficacy of aliskiren as monotherapy and in combination with HCTZ. A total of 2,776 patients were randomized to placebo (n=195);
aliskiren 75 mg, 150 mg, 300 mg monotherapy (n=184, 185, 183); HCTZ 6.25 mg, 12.5 mg, 25 mg monotherapy (n=194, 188, 176); or combination
aliskiren/HCTZ therapy (75 mg/6.25 mg, n=188; 75 mg/12.5 mg, n=193; 75 mg/25 mg, n=186; 150 mg/6.25 mg, n=176; 150 mg/12.5 mg,
n=186; 150 mg/25 mg, n=188; 300 mg/12.5 mg, n=181; 300 mg/25 mg, n=173). The total number of patients given in the table includes the placebo group.
This trial evaluated the efficacy of aliskiren as monotherapy (primary objective) and in combination with valsartan (secondary objective). A total of 1,123
patients were randomized to placebo (n=177); aliskiren 75 mg, 150 mg, 300 mg monotherapy (n=179, 178, 175); valsartan 80 mg, 160 mg, 320 mg monotherapy
(n=58, 59, 60); combination aliskiren/valsartan (75 mg/80 mg, n=80; 150 mg/160 mg, n=60; 300 mg/320 mg, n=58); or combination valsartan/
HCTZ 160 mg/12.5 mg (active control; n=59). The total number of patients given in the table includes the placebo group.
A=aliskiren; ac=active controlled/active comparator; ASBP=ambulatory systolic blood pressure; CR=control rate; db=double blind; HCTZ=hydrochlorothiazide;
Ir=irbesartan; L=losartan; MADBP=mean ambulatory diastolic pressure; MASBP=mean ambulatory systolic pressure; MSDBP=mean sitting diastolic blood pressure;
MSSBP=mean sitting systolic blood pressure; NS=not significant; pc=placebo controlled; R=ramipril; r=randomized; RR=responder rate; sb=single blind;
SBP=systolic blood pressure; V=valsartan.
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October 2007
JMCP
daily in the treatment of uncomplicated severe hypertension

(MSDBP 105 mm Hg and <120 mm Hg).37 If additional BP
control was required, the dose of aliskiren or lisinopril could be
doubled, with the option of adding HCTZ 25 mg once daily to
the regimen. Titration to the higher dose of the antihypertensive
occurred in 74% and 66% of the aliskiren and lisinopril groups,
respectively. Rates of add-on therapy with HCTZ were similar
between groups (aliskiren 54%, lisinopril 45%). Similar reductions in MSDBP were observed in the aliskiren and lisinopril
groups.
Combination Therapy
Although BP may be controlled in some patients with aliskiren

monotherapy, there is greater likelihood that combination therapy
will be required to control BP in the majority of patients.
Two trials have evaluated the antihypertensive efficacy of
aliskiren in combination with HCTZ,32,38 and 4 trials have studied the efficacy of dual RAAS inhibition with aliskiren and a
CCB,39 an ACEI,40 or an ARB.33,41
Villamil and colleagues evaluated treatment with once-daily
aliskiren 75 mg, 150 mg, or 300 mg; HCTZ 6.25 mg, 12.5 mg, or
25 mg; or their combinations (aliskiren/HCTZ: 75 mg/6.25 mg,
75 mg/12.5 mg, 75 mg/25 mg, 150 mg/6.25 mg, 150 mg/
12.5 mg, 150 mg/25 mg, 300 mg/12.5 mg, and 300 mg/25 mg)
in an 8-week placebo-controlled study.32 Aliskiren 150 mg
and 300 mg, all doses of HCTZ, and all combinations were
superior to placebo in reducing MSDBP levels (P<0.0001).32
All combinations, with the exception of aliskiren/HCTZ 150 mg/
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6.25 mg and 75 mg/12.5 mg, were also more effective than

either monotherapy in reducing MSDBP and MSSBP levels
(P<0.05).32 Responder rates (the proportion of patients with
MSDBP <90 mm Hg or 10 mm Hg decrease from baseline)
were significantly higher with aliskiren 300 mg (P=0.0005),
HCTZ 12.5 mg and 25 mg (P<0.02), and with all combinations
(P<0.05) than with placebo.32 Responder rates for all combinations of aliskiren with HCTZ 25 mg and aliskiren/HCTZ
300 mg/12.5 mg were significantly higher than for their respective monotherapies (P<0.05). A higher proportion of subjects
achieved BP control (MSSBP/MSDBP <140/90 mm Hg) with
combination therapy than with aliskiren or HCTZ monotherapy.32 Combinations containing higher doses of 1 or both
drugs (aliskiren 150 mg or 300 mg or HCTZ 25 mg) yielded
significantly higher control rates compared with monotherapy.32
Treatment with aliskiren resulted in a reduction of PRA of up
to 65% from baseline. An increase in PRA of up to 72% with
HCTZ was averted with the aliskiren/HCTZ combination.32
Plasma renin concentrations increased with aliskiren, with
HCTZ 25 mg, and with all aliskiren/HCTZ combinations.32
An additional effect of combination therapy was a reduction
in the incidence of hypokalemia compared with the patients
receiving HCTZ monotherapy.32
The effects of adding aliskiren 150 mg once daily to amlodi
pine 5 mg once daily in patients whose hypertension was not fully
controlled with CCB monotherapy was compared with continuing treatment with amlodipine 5 mg or 10 mg once daily alone.39
At 6 weeks, patients who were treated with aliskiren 150 mg plus
amlodipine 5 mg had significant additional reductions in MSDBP
and MSSBP compared with patients who were treated with
amlodipine 5 mg alone (mean change, in mm Hg, -8.5 and -4.8
for MSDBP, respectively, and -11.0 and -5.0 for MSSBP, respectively; P<0.0001).39 The proportion of patients who achieved a
MSDBP of <90 mm Hg and/or at least a 10 mm Hg reduction
from baseline was significantly greater for those treated with
aliskiren 150 mg plus amlodipine 5 mg compared with amlodipine 5 mg alone (64.2% and 45.2%, respectively, P=0.0005). In
addition, a significantly greater proportion of patients who were
treated with aliskiren 150 mg plus amlodipine 5 mg achieved BP
levels of <140 mm Hg/90 mm Hg compared with amlodipine
5 mg alone (42.8% and 22.6%, respectively, P<0.0001).39 The
additional efficacy resulting from adding aliskiren to amlodipine
therapy was comparable with that achieved by doubling the dose
of amlodipine to 10 mg, but combination therapy was not associated with the increased incidence of edema that was reported
with high-dose amlodipine treatment.39
The effect of 12 weeks of add-on therapy with once-daily
aliskiren 300 mg, irbesartan 300 mg, or amlodipine 10 mg, or
placebo was studied in hypertensive obese patients who were
unresponsive to 4 weeks of initial treatment with HCTZ 25
mg.38 At 8 weeks, the aliskiren/HCTZ combination reduced
MSDBP and MSSBP significantly more than did HCTZ (mean
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treatment difference, -4.0 mm Hg and -7.2 mm Hg, respectively;

P<0.0001).38 Reductions in BP with the combination regimen of
aliskiren and HCTZ were comparable with reductions with irbesartan and HCTZ or with amlodipine and HCTZ.38 Responder
rates and BP control rates were higher in patients who were
switched to the aliskiren/HCTZ combination than in those continuing on HCTZ alone (week 12 responder rate of 76% vs. 58%
[P= 0.004] and control rate of 58% vs. 33% [P=0.0001]).38
A phase III study evaluated the use of aliskiren alone or in
combination with the ACEI ramipril for managing hypertension
in patients with type 1 or 2 diabetes mellitus.40 Patients were
randomized and forced-titrated to receive once-daily aliskiren
300 mg, ramipril 10 mg, or aliskiren/ramipril in combination
300 mg/10 mg for 8 weeks. Reductions in MSSBP and MSDBP
with aliskiren, ramipril, and aliskiren/ramipril were 14.7 mm
Hg/11.3 mm Hg, 12.0 mm Hg/10.7 mm Hg, and 16.6 mm
Hg/12.8 mm Hg, respectively (Figure 3a). A reactive increase in
PRA of 111% after ramipril treatment was countered by aliskiren
in patients receiving combination therapy, leading to an overall
44% reduction in PRA. These findings suggest that aliskiren, by
enhancing RAAS blockade when added to an ACEI, provides
additional antihypertensive efficacy in patients with diabetes and
hypertension.
Pool and colleagues33 studied the first-ever combination
of a DRI and an ARB. In a primary safety and tolerability
study, the once-daily antihypertensive efficacy of aliskiren alone
(75 mg, 150 mg, and 300 mg), valsartan alone (80 mg, 160 mg,
and 320 mg), aliskiren/valsartan combinations (75 mg/80 mg,
150 mg/160 mg, and 300 mg/320 mg), and valsartan/HCTZ
(160 mg/12.5 mg) was evaluated.33 Aliskiren 300 mg once daily
significantly reduced MSDBP and MSSBP levels compared with
placebo (P<0.0001). The magnitude of BP reduction was similar
for aliskiren and valsartan across all dose ranges.33 Reductions
in MSDBP and MSSBP levels were comparable for the aliskiren/
valsartan combinations and their respective component monotherapies.33 Responder rates with aliskiren monotherapy (P<0.05,
aliskiren 75 mg and 150 mg; P<0.001, aliskiren 300 mg) and for
all aliskiren/valsartan combinations (P<0.05, aliskiren 150 mg/
valsartan 160 mg; P<0.001, aliskiren 300 mg/valsartan 320 mg)
were significantly greater than with placebo. Responder rates for
most combinations did not differ from those for their respective
monotherapies.33 The reduction in BP and the responder rates
with the 2 highest dose combinations were similar to those with
the valsartan/HCTZ combination. Rates of BP control did not
differ between the aliskiren/valsartan combinations and their
component monotherapies.33
A phase III study was conducted in 1,797 patients with mild
to moderate hypertension who were randomized to once-daily
aliskiren 150 mg, valsartan 160 mg, aliskiren/valsartan 150 mg/
160 mg, or placebo for 4 weeks; followed by forced titration
to double the dose for another 4 weeks.41 At both 4 and 8 weeks,
reductions in MSDBP and MSSBP were significantly greater
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Vol. 13, No. 8, S-b
with all active treatments than with placebo (P<0.0001)

(Figure 3b). The aliskiren/valsartan combination was significantly more effective than either component alone in reducing
MSDBP and MSSBP (P<0.0001), 24-hour mean ADBP and
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JMCP
ASBP (P<0.0001), and daytime and nighttime mean ADBP.41

The aliskiren/valsartan combination provided significantly
smoother BP control for a 24-hour period (smoothness index
1.2 vs. 0.9 with either aliskiren or valsartan alone; P<0.05), with
a trough to peak ratio of 0.79. The combination thus provided
additional BP reductions that were maintained for 24 hours.
Safety and Tolerability
A pooled safety analysis has been conducted on data from

7 randomized double-blind multicenter studies in 4,704 patients
with mild to moderate hypertension (monotherapy, 2,598;
combination therapy, 2,106) treated with aliskiren (75 mg to
600 mg) for 6 to 8 weeks.25 In 5 placebo-controlled trials, the
overall incidence of adverse events after 52 to 55 days of treatment was similar for aliskiren monotherapy and placebo (39.8%
vs. 40.2%, respectively).25 Rates of discontinuation due to adverse
events were low and were reported as between 1.7% and 2.6%
with aliskiren 75 mg to 600 mg, respectively, and 3.5% with
placebo.25 Overall, the most frequently reported adverse events
with aliskiren and placebo were headache (5.7% vs. 8.7%; P<0.01
vs. placebo), nasopharyngitis (4.4% vs. 5.8%; P= NS), diarrhea
(2.6% vs. 1.2%; P<0.05 vs. placebo), dizziness (1.8% vs. 2.2%;
P=NS), and fatigue (1.6% vs. 1.5%; P=NS).25 Increased rates of
diarrhea were reported mainly for the 600 mg dose of aliskiren
(9.5% vs. 1.2; P<0.0001) and not at lower doses.25 Consequently,
the highest recommended dose for aliskiren is 300 mg once daily
because of a relatively flat BP response and increased incidence of
adverse events with doses higher than 300 mg a day.
In the treatment of patients with severe hypertension, both
aliskiren and lisinopril were well tolerated and no differences
were noted between groups in the proportion of patients who
reported an adverse event, the type of adverse event, or the rate
of discontinuation due to an adverse event.37
The addition of aliskiren 150 mg or 300 mg to valsartan,
amlodipine, HCTZ, or ramipril therapy did not alter the frequency or type of adverse events compared with their respective
monotherapies.25 In fact, some adverse effects may be avoided
with aliskiren therapy when used in combination with other
antihypertensive agents. The addition of aliskiren to ramipril
therapy reduced the rate of cough (1.8%) compared with ramipril
alone (4.7%);25 in patients receiving aliskiren 150 mg as add-on
therapy to amlodipine 5 mg, the rate of edema was reduced to
2.1% compared with a rate of 11.2% with amlodipine 10 mg.25
Place in Therapy of Pharmacologic Direct Renin Inhibition
Control of hypertension to below-target BP levels is crucial for
reducing rates of adverse cardiovascular events. The National
Health and Nutrition Examination Survey (19992004) showed
an overall prevalence of hypertension (BP 140/90 mm Hg
or use of antihypertensive medication) between 2003 and 2004
of 29.3%.42 For the same period, rates of BP control were 33%,
64%, and 33%, respectively, for all patients with hypertension,
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October 2007
treated patients, and treated patients with diabetes, indicating

that the treatment of hypertension remains suboptimal.42
Aliskiren administered once daily provides another effective
and safe option for the treatment of hypertension as monotherapy.32,34-37 However, approximately 70% of patients with
hypertension, particularly high-risk patients with lower BP
goals and patients whose BP exceeds SBP or DBP target values
by 20 mm Hg or 10 mm Hg, respectively, will require
combination therapy to achieve BP control.43 Aliskiren, which
acts at the rate-limiting step in the RAAS pathway, is a logical
component of combination therapy, because it enhances RAAS
suppression and attenuates the reactive increase in PRA when
added to other classes of antihypertensive agents.32 Combining
agents (such as diuretics, ACEIs, and ARBs) that increase PRA
with an agent (such as aliskiren) that neutralizes this activity
appears to be a rational approach for optimizing BP control.
Combined RAAS inhibition may allow the use of lower doses
of each component to achieve more effective and durable RAAS
suppression with potentially fewer adverse effects.32,33 Patients
with severe hypertension, especially those with renal failure, may
theoretically benefit from even more intensive RAAS inhibition
through the blockade of additional steps of the pathway, but this
approach needs further exploration. Table 2 lists some potential
therapeutic roles for DRIs in the management of hypertension
and its sequelae.
Clinical studies have provided convincing evidence that
aliskiren controls RAAS activity, reduces BP significantly, and
displays good tolerability. Additionally, as with other RAAS
inhibitors, RAAS blockade via direct renin inhibition has the
potential to provide organ protection independent of BP reductions.44 A robust clinical development program is ongoing to
evaluate the renoprotective and cardioprotective effects of aliskiren in which surrogate markers and major clinical outcomes will
be analyzed as primary endpoints (Table 3). What may be on
the horizon is the use of dual RAAS blockade, which includes
TABLE 2
Potential Therapeutic Role of

Direct Renin Inhibitors22,32,33,44
Monotherapy for hypertension

Component of combination therapy for hypertension, with a diuretic,
a CCB, an ACEI, and/or an ARB
Alternative to ACEIs or ARBs in the management of hypertension and

the prevention of organ damage
Alternative to ACEIs in patients with diabetic nephropathy or

cardiovascular disease
Use in patients with diabetic nephropathy or in African American
hypertensive patients, in whom intrarenal angiotensin II formation occurs

via ACE or nonACE-dependent pathways
ACE=angiotensin-converting enzyme; ACEI=ACE inhibitor; ARB=angiotensin

receptor blocker; CCB=calcium channel blocker.
Vol. 13, No. 8, S-b
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TABLE 3
Aliskiren Clinical Development Program: Evaluating Surrogate Markers and Clinical Outcomes
Trial Name
AGELESS
Aliskiren versus ramipril for BP
control in the elderly
Length of
Trial
Objective of Trial
912
Compare the efficacy of aliskiren versus ramipril in

lowering SBP in patients 65 years of age with systolic
hypertension
36 weeks
AVOID*
Aliskiren in the evaluation of
proteinuria in diabetes
754
Determine the effect of adding aliskiren or placebo to

background losartan treatment on proteinuria in diabetic
patients
24 weeks
ALLAY
Aliskiren left ventricular assessment
of hypertrophy
480
Determine the effect of aliskiren alone or in

combination with losartan on the regression of left ventricular mass in overweight hypertensive patients
34 weeks
AVANT GARDE (TIMI 43)

Aliskiren and valsartan versus
placebo in lowering NT-proBNP in
patients stabilized following an ACS
1,152
Determine whether aliskiren, valsartan, or combination

therapy will improve ventricular remodeling in high-risk
patients who have been stabilized following ACS
Percent reduction in UACR
Change in left ventricular mass
9 weeks
ASPIRE
Aliskiren in post-MI patients to
reduce remodeling
860
Determine whether aliskiren attenuates pathological left

ventricular remodeling in high-risk post-MI patients
when added to standard therapy
36 weeks
ALOFT*
Aliskiren observation of heart failure
treatment
320
Determine the safety and tolerability of adding aliskiren

or placebo to standard heart failure treatment in patients
with chronic heart failure
12 weeks
8,400
Determine whether aliskiren with conventional

treatment reduces cardiovascular and renal morbidity
and mortality in high-risk patients with type 2 diabetes
4 years
ALTITUDE
Aliskiren in type 2 diabetes using
cardiorenal disease endpoints
Primary Endpoint
Reduction from baseline in MSSBP
Reduction of NT-proBNP from

baseline
Change in LVESV by echo
Tolerability and safety of aliskiren;

change in BNP
Time to diabetic complications
(secondary prevention trial)
*Study completed, results pending.

ACS=acute coronary syndrome; BNP = B-type natriuretic peptide; BP=blood pressure; echo=echocardiography; LVESV=left ventricular end systolic volume;
MI=myocardial infarction; MSSBP=mean sitting systolic blood pressure; NT-proBNP=N-terminal proB-type natriuretic peptide; SBP=systolic blood pressure;
UACR=urinary albumin/creatinine ratio.
a DRI, as several trials will investigate whether combination

therapy provides enhanced protection and improved outcomes
over monotherapy.
Disclosures
The author discloses no potential bias or conflict of interest relating to this
article.
Summary and Conclusions

The DRI aliskiren is a new orally available, highly specific, and
effective inhibitor of RAAS activity. Both as monotherapy and in
combination with a thiazide diuretic, a CCB, an ACEI, or an ARB,
aliskiren reduces BP in patients with mild to moderate hypertension. Aliskiren has antihypertensive efficacy comparable with that
of these other classes of antihypertensive agents, and counters the
reactive increase in PRA when used in combination with these
agents. In the treatment of patients with severe hypertension,
aliskiren is comparable with lisinopril. Aliskiren has a tolerability
profile similar to that of placebo and ARBs and is well tolerated
when used in combination with other agents. Further studies
will explore its potential as monotherapy or in combination with
other antihypertensives, and for uses beyond BP reduction, such
as renoprotection and cardioprotection.
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26. Dieterle W, Corynen S, Vaidyanathan S, Mann J. Pharmacokinetic

interactions of the oral renin inhibitor aliskiren with lovastatin, atenolol,
celecoxib and cimetidine. Int J Clin Pharmacol Ther. 2005;43:527-35.
8. Muller DN, Fischli W, Clozel JP, et al. Local angiotensin II generation in

the rat heart: role of renin uptake. Circ Res. 1998;82:13-20.
27. Vaidyanathan S, Valencia J, Kemp C, et al. Lack of pharmacokinetic

interactions of aliskiren, a novel direct renin inhibitor for the treatment
of hypertension, with the antihypertensives amlodipine, valsartan,
hydrochlorothiazide (HCTZ) and ramipril in healthy volunteers.
Int J Clin Pract. 2006;60:1343-56.
9. Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer J-D. Pivotal

role of the renin/prorenin receptor in angiotensin II production and cellular
responses to renin. J Clin Invest. 2002;109:1417-27.
10. Nguyen G. Renin/prorenin receptors. Kidney Int. 2006;69:1503-06.
11. Danser AH, van Kats JP, Admiraal PJ, et al. Cardiac renin and
angiotensins. Uptake from plasma versus in situ synthesis. Hypertension.
1994;24:37-48.
12. Nguyen G, Delarue F, Berrou J, Rondeau E, Sraer J-D. Specific
receptor binding of renin on human mesangial cells in culture increases
plasminogen activator inhibitor-1 antigen. Kidney Int. 1996;50:1897-903.
13. Huang Y, Wongamorntham S, Kasting J, et al. Renin increases
mesangial cell transforming growth factor-1 and matrix proteins through
receptor-mediated, angiotensin II-independent mechanisms. Kidney Int.
2006;69:105-13.
28. Zhao C, Vaidyanathan S, Dieterich HA, Yeh C, Howard D, Dole WP.

Assessment of the pharmacokinetic interaction between the oral direct renin
inhibitor aliskiren and furosemide: a study in healthy volunteers [abstract].
Clin Pharmacol Ther. 2007;81(suppl 1):S110.
29. Vaidyanathan S, Reynolds C, Yeh C-M, et al. Pharmacokinetics, safety,
and tolerability of the novel oral direct renin inhibitor aliskiren in elderly
healthy subjects. J Clin Pharmacol. 2007;47:453-60.
30. Vaidyanathan S, Warren V, Yeh C, Bizot MN, Dieterich HA, Dole WP.
Pharmacokinetics, safety, and tolerability of the oral renin inhibitor
aliskiren in patients with hepatic impairment. J Clin Pharmacol.
2007;47:192-200.
14. Nguyen G, Bouzhir L, Delarue F, Rondeau E, Sraer J-D. Evidence of

a renin receptor on human mesangial cells: effects on PAI1 and cGMP
[in French]. Nephrologie. 1998;19:411-16.
31. Vaidyanathan S, Bigler H, Yeh C-M, et al. Safety, tolerability and

pharmacokinetics of the oral direct renin inhibitor aliskiren alone and in
combination with irbesartan in renal impairment. Clin Pharmacol Ther.
2007;46:661-75.
15. Burckle CA, Jan Danser AH, Muller DN, et al. Elevated blood
pressure and heart rate in human renin receptor transgenic rats.
Hypertension. 2006;47(pt 2):552-56.
32. Villamil A, Chrysant SG, Calhoun D, et al. Renin inhibition with

aliskiren provides additive antihypertensive efficacy when used in
combination with hydrochlorothiazide. J Hypertens. 2007;25:217-26.
16. Ichihara A, Hayashi M, Kaneshiro Y, et al. Inhibition of diabetic

nephropathy by a decoy peptide corresponding to the handle region for
nonproteolytic activation of prorenin. J Clin Invest. 2004;114:1128-35.
33. Pool JL, Schmieder RE, Azizi M, et al. Aliskiren, an orally effective renin
inhibitor, provides antihypertensive efficacy alone and in combination with
valsartan. Am J Hypertens. 2007;20:11-20.
17. Staessen JA, Li Y, Richart T. Oral renin inhibitors. Lancet.

2006;368:1449-56.
34. Stanton A, Jensen C, Nussberger J, OBrien E. Blood pressure

lowering in essential hypertension with an oral renin inhibitor, aliskiren.
18. Wood JM, Maibaum J, Rahuel J, et al. Structure-based design of

aliskiren, a novel orally effective renin inhibitor. Biochem Biophys Res
Commun. 2003;308:698-705.
19. Wood JM, Schnell CR, Cumin F, Menard J, Webb RL. Aliskiren, a novel,
orally effective renin inhibitor, lowers blood pressure in marmosets and
spontaneously hypertensive rats. J Hypertens. 2005;23:417-26.
20. Pilz B, Shagdarsuren E, Wellner M, et al. Aliskiren, a human renin
inhibitor, ameliorates cardiac and renal damage in double-transgenic rats.
35. Gradman AH, Schmieder RE, Lins RL, Nussberger J, Chiang Y,

Bedigian MP. Aliskiren, a novel orally effective renin inhibitor, provides
dose-dependent antihypertensive efficacy and placebo-like tolerability in
hypertensive patients. Circulation. 2005;111:1012-18.
24-hour blood pressure control in patients with hypertension.
J Am Coll Cardiol. 2007;49:1157-63.
21. Nussberger J, Wuerzner G, Jensen C, Brunner HR. Angiotensin II

suppression in humans by the orally active renin inhibitor aliskiren
(SPP100): comparison with enalapril. Hypertension. 2002;39:e1-e8.
37. Strasser RH, Puig JG, Farsang C, Croket M, Li J, van Ingen H.

A comparison of the tolerability of the direct renin inhibitor aliskiren
and lisinopril in patients with severe hypertension. J Hum Hypertens
[serial online]. May 31, 2007:doi:10.1038/sj.jhh.1002220.
22. Azizi M, Menard J, Bissery A, et al. Pharmacologic demonstration of

the synergistic effects of a combination of the renin inhibitor aliskiren
and the AT1 receptor antagonist valsartan on the angiotensin II-renin
feedback interruption. J Am Soc Nephrol. 2004;15:3126-33.
38. Jordan J, Engeli S, Boye SW, Le Breton S, Keefe DL. Direct renin
inhibition with aliskiren in obese patients with arterial hypertension.
23. Zhao C, Vaidyanathan S, Yeh C-M, Maboudian M, Armin Dieterich

H. Aliskiren exhibits similar pharmacokinetics in healthy volunteers and
patients with type 2 diabetes mellitus. Clin Pharmacokinet. 2006;45:1125-34.
24. Vaidyanathan S, Jermany J, Yeh C, Bizot M-N, Camisasca R. Aliskiren, a
novel orally effective renin inhibitor, exhibits similar pharmacokinetics and
pharmacodynamics in Japanese and Caucasian subjects. Br J Clin Pharmacol.
2006;62:690-98.
25. Weir MR, Bush C, Anderson DR, Zhang J, Keefe D, Satlin A.
Antihypertensive efficacy, safety and tolerability of the oral renin inhibitor
aliskiren in patients with hypertension: a pooled analysis. J Am Soc
Hypertens. 2007;1:264-77.
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39. Drummond W, Munger MA, Essop MR, Maboudian M, Khan M,

Keefe DL. Antihypertensive efficacy of the oral direct renin inhibitor
aliskiren as add-on therapy in patients not responding to amlodipine
monotherapy. J Clin Hypertens. 2007;9:742-50.
40. Uresin Y, Taylor A, Kilo C, et al. Aliskiren, a novel renin inhibitor,
has greater BP lowering than ramipril and additional BP lowering when
combined with ramipril in patients with diabetes and hypertension.
Abstract presented at: 16th European Meeting on Hypertension;
June 12-15, 2006; Madrid, Spain.
41. Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A. Efficacy
and safety of combined use of aliskiren and valsartan in patients with
hypertension: a randomised, double-blind trial. Lancet. 2007;370:221-29.
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42. Ong KL, Cheung BMY, Man YB, Lau CP, Lam KSL. Prevalence,
awareness, treatment, and control of hypertension among United States
adults 1999-2004. Hypertension. 2007;49:69-75.
44. Stanton A. Therapeutic potential of renin inhibitors in the management

of cardiovascular disorders. Am J Cardiovasc Drugs. 2003;3:389-94.
43. Pool JL. Is it time to move to multidrug combinations? Am J Hypertens.

2003;16:36S-40S.
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Vol. 13, No. 8, S-b
October 2007
JMCP
Importance of Blood Pressure Control

Over a 24-Hour Period
Abstract
Background: The circadian rhythm of blood pressure (BP) is associated
with a high span during the awake period and a low span during the sleep
period. Of interest is that cardiovascular (CV) events occur more frequently
in the early morning period, the time when BP and heart rate rise steeply.
Objective: To provide an overview of circadian BP and its correlation
with adverse clinical outcomes and to discuss strategies for optimizing
BP control over 24 hours.
Summary: Patients who have an excessive morning surge in BP and those
who lack the normal nocturnal BP fall (nondippers) have been shown to
have an excessive incidence of strokes, heart failure, and other CV events.
While there are numerous pathophysiologic mechanisms underlying abnormalities in the 24-hour BP profile, including abnormalities in sympathetic
nervous system activity, salt and volume balance, and activation of the
renin-angiotensin aldosterone system, for many patients the mechanisms
remain unclear. Nevertheless, several of these known abnormalities can
be modified by clinical interventions, including proper timing of antihypertensive drug therapy and use of classes of antihypertensives for which a
substrate exists to induce a pharmacologic effect. It is particularly important to use therapies that will provide control throughout a 24-hour dosing
interval.
Conclusion: While interventional strategies have not yet been shown to
alter clinical outcomes, it is important to be cognizant of their physiologic
basis and take them into consideration when making decisions regarding
appropriate antihypertensive therapy.
Keywords: Antihypertensive agents; Blood pressure monitoring,
ambulatory; Circadian rhythm; Hypertension
Author
William B. White, MD, is a professor, Department of Medicine,

and chief, Division of Hypertension and Clinical Pharmacology, Pat
and Jim Calhoun Cardiology Center, University of Connecticut Health
Center, Farmington. In addition, he is lead physician, Hypertension and
Vascular Diseases faculty practice, Cardiology Center, John Dempsey
Hospital, and medical director, Clinical Trials Unit, Farmington.
Author Correspondence: William B. White, MD, Division
of Hypertension and Clinical Pharmacology, Pat and Jim Calhoun
Cardiology Center , University of Connecticut School of Medicine,
Farmington, CT 06030-3940; Tel: (860) 679-2104;
E-mail: wwhite@nso1.uchc.edu
JMCP
rterial blood pressure (BP) has a daily variation characterized by substantial reductions during sleep, a rapid
rise upon awakening, and increased variability during
the awake period in ambulant normal subjects and hypertensive
patients. The patterns of the circadian variation of BP were first
established by Millar-Craig et al. using continuous intra-arterial
monitoring.1 This novel study showed that BP was highest in
early to mid-morning and then fell progressively throughout the
day. In addition, the study showed that BP was lowest at night
(nocturnal dip) but rose before awakening (morning surge).1
These findings demonstrated the potential importance of the
circadian rhythm of BP in the management of hypertension, a
factor that has been acknowledged since the mid-1960s2 but did
not become part of the clinical hypertension domain until the
21st century.
Following the descriptive findings related to BP variability,
researchers began to evaluate the physiologic characteristics that
produce the BP rise during the early morning and the substantial
BP reductions during sleep. The timing and amplitude of the natural rhythm of BP is influenced by intrinsic factors, such as neurohormonal regulation, but the effects of extrinsic factors, such
as physical activity and dietary sodium, may be of greater significance. Additionally, behavioral influences, such as mental activity
and emotional state,3 and lifestyle factors, such as smoking
cigarettes and drinking alcohol, can also affect the natural
rhythm of BP.4
Excessive BP levels during the course of a 24-hour period
plausibly contribute to adverse cardiac outcomes, especially when
the relationship between the early morning peak in cardio
vascular (CV) events with the postawakening morning surge
in BP is considered. Increases in the incidence of sudden death,
nonfatal myocardial infarction (MI), unstable angina, and stroke
in the morning indicate that a patients physiologic status may
play an important role in the onset of CV events.5 Intuitively,
it appears that 24-hour control of BP should have an important
clinical impact on the early morning increases in CV events.
Early Morning BP Surge
Blood pressure rises sharply in the morning in response to the
activation of the sympathetic nervous system when one arises.6-10
This early morning surge is associated with other important
hemodynamic and neurohormonal changes, including increases
in heart rate, vascular tone and blood viscosity, and decreases
in vagal activity.6,11-13 The activity of the sympathetic nervous
system is quiescent during sleep, whereas awakening selectively
increases epinephrine levels.8 Subsequent increases in BP and
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Importance of Blood Pressure Control Over a 24-Hour Period
heart rate are controlled by direct sympathetic neural input into

the heart and vasculature in response to increases in activity and
upright posture, rather than by an endogenous surge of plasma
catecholamines.9
TABLE
Correlation Between Morning Blood

Pressure Surge and Cardiovascular Events21
AM Surge
(n=53)
NondippersThe Loss of the Nocturnal Decline in BP
Baseline data
The normal circadian rhythm of BP has a nocturnal decrease

of 15% to 25% in BP compared with awake values. However,
in 25% to 40% of patients with hypertension, a nondipper
pattern is present. Since the 1980s, the nondipping pattern has
been arbitrarily defined as when the BP reduction during sleep
is less than 10% compared with BP while awake. Blunting of the
nocturnal decrease in BP in patients with hypertension occurs
for a variety of reasons, both in patients with essential hypertension and with secondary forms of hypertension. Clinical studies
in patients with hypertension have found that a blunted nocturnal BP decrease occurs when there is an increase in adrenergic
activity and a decrease in vagal activity during sleep.14-16 In some
patients, there is even a significant increase in BP during sleep
(and in the supine position), which leads to a reverse dippers
or riser patterna finding that is associated with substantial
cardiac morbidity.17 Japanese investigators also reported that a
profile in which the nocturnal BP is >20% less than the awake BP
has been associated with increased white matter ischemic lesions
in the brain.17 Thus, knowledge of the circadian profile of an
individual patient (through 24-hour ambulatory BP monitoring)
with hypertension may aid in identifying increased risk.
Silent ischemic infarcts
Clinical Implications of the Circadian Variability of BP

As stated above, the early morning BP surge is associated
with an increase in the incidence of CV events, including stroke
and MI.18-20 Pooled analyses of event data indicate that there is
a 40% higher relative risk of acute MI, a 29% increased risk of
sudden cardiac death, and a 49% higher relative risk of stroke
between 6 a.m. and noon than during the rest of the day.19,20
In actual terms, this corresponds to approximately 1 in 11MIs,
1 in 15 sudden deaths, and 1 in 8 strokes occurring in the
early morning period when BP, heart rate, and the rate-pressure
product increases most steeply.19,20
For many years, epidemiologic studies have shown that the
timing of onset of CV events strongly parallels the circadian
rhythm of BP. In an interesting analysis in Japan, Kario et al.21
demonstrated a 2.7-fold increase in the risk of a future stroke in
older patients with hypertension who were in the top decile of
the morning BP surge (>34 mm Hg; Table). For each 10 mm Hg
increase in the morning BP surge, there was a 24% increase in
stroke risk (P=0.004). While it would be of great interest to perform a clinical trial devised to address the relationship between
a reduction in the early morning BP and a possible reduction in
CV events, this is unlikely to occur because of the enormous
sample size required and the long period of follow-up that would
be necessary.22
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Vol. 13, No. 8, S-b
Non-Surge
(n=466)
Prevalence (%)
70
48
Average number
2.32.6
132.6
57*
33
19.0
7.3
Multiple ischemic infarcts

Prevalence (%)
Prospective data
Ischemic strokes (%)
* P<0.001.
P<0.01.
Loss of the nocturnal decline in BP has been associated with

increased risk of cardiac, kidney, and vascular target-organ injury
compared with patients whose decline in BP at night is normal,23
and can be independent of the clinic and 24-hour mean BP
values.24,25 Additionally, patients with hypertension who exhibit
a nocturnal BP increase compared with daytime BP (risers)
have the worst prognosis for stroke and cardiac events.17,24
However, there is also some evidence that patients with marked
nocturnal BP declines (extreme dippers) are at risk of lacunar
strokes and silent myocardial ischemia.26
Clinical Factors That Affect the Circadian Rhythm of BP
Physical activity is the major determinant of BP rise during the
day.25,27 As mentioned earlier, the influence of sleep and wakefulness on BP is mediated through cyclic variations of the autonomic
nervous system. In the early morning, BP naturally rises sharply
in response to activation of the sympathetic nervous system upon
arousal.4,6,8 Sleep deprivation increases sympathetic activity and
may disrupt circadian rhythmicity. The circadian BP rhythmin
particular, the nocturnal decline in BPcan be affected by
sodium intake in patients with hypertension.28 In fact, Uzu
et al.29 showed that a nondipper nocturnal BP pattern can be
converted to a dipper pattern in response to salt restriction in
salt-sensitive patients with hypertension.
The renin-angiotensin aldosterone system (RAAS), mainly
via production of angiotensin II (Ang II), is a key regulator of BP.
Renin secretion is activated in the early morning before arousal
as a result of sympathetic neuronal activation.30,31 In addition,
both renin and aldosterone demonstrate significant circadian
patterns in both normotensive and hypertensive individuals,31
with peak values detected early morning, then falling to their
lowest point in late evening (Figure 1).32,33 A similar pattern has
been observed for Ang II.30
October 2007
JMCP
How Antihypertensive Therapies Affect the 24-Hour

Blood Pressure Based on the Pathophysiology of the
Circadian Rhythm
The morning surge in hypertension, which is associated with
increases in stroke events in older patients with hypertension,
is mediated in part by the sympathetic nervous system and
through the RAAS. A loss of decline in nocturnal BP is probably
mediated through both RAAS activation and volume excess.
These findings have led to the evaluation of the potential for
blockade of the systems that lead to these abnormal profiles
in circadian BP. Notwithstanding, the pharmacodynamics of
antihypertensive drugs must play a role here, since control
of nocturnal BP and BP during the early morning period will
require that agents either have a reasonably long half-life or else
be administered twice daily.
Modification of the timing of drug administration can alter
the circadian BP profile. In fact, modification of the time of drug
administration for many of the antihypertensive agents may
affect the extent of 24-hour BP control and modify the circadian
rhythm, including the conversion from a nondipper to a dipper
profile.34,35 These effects are most uniform with blockers of the
RAAS, which typically will have a substantial effect on nocturnal
BP when they are administered at night while also maintaining
adequate control during the daytime.35
Drugs with long duration of action may be particularly
useful for blunting the early morning surge in BP. White et al.36
evaluated the effects of telmisartan alone and in combination
with hydrochlorothiazide (HCTZ) on 24-hour BP, including the
early morning period (Figure 2). Patients with hypertension
received telmisartan 40 mg per day. If BP remained uncontrolled
after 2 weeks, the dose was increased to 80 mg per day; if BP
was still uncontrolled after another 4 weeks, HCTZ 12.5 mg was
added and continued for a final 4-week period. Twenty-four-hour
ambulatory BP monitoring was performed at baseline and at the
end of the treatment period in 1,628 patients. Telmisartan alone
and in combination with HCTZ produced significant reductions
in both daytime and nighttime mean BP. The effect was more
dramatic in patients with early morning surges, as shown in
Figure 2.
Since most analyses have shown that renin activity begins
to rise during the night and peaks in the morning period
(Figure 1), another pharmacologic approach to consider in the
treatment of nocturnal and early morning hypertension would
be a long-acting direct renin inhibitor (DRI). Stanton et al.37
have provided data supporting the concept that aliskiren, a
DRI with a plasma half-life of approximately 25-30 hours,
might provide efficacy in patients with abnormal circadian BP
variability, particularly in the high-risk populations discussed
here (Figure 3). In this early trial of the agent, intermediate
and higher doses (150 mg and 300 mg) were assessed in a trial
compared with high-dose losartan (100 mg daily) and placebo.
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As noted, the reductions in nocturnal BP were substantial with

aliskiren 300 mg daily (Figure 3) and occurred when renin
secretion begins to peak. Oh et al.38 also reported the results
of a trial in 216 patients with hypertension who were randomized to 8weeks treatment with aliskiren 150 mg, 300 mg, or
600 mg once daily or with placebo. Aliskiren significantly
reduced mean 24-hour ambulatory BP compared with placebo
at all dosages. Consistent with its long pharmacologic half-life,
aliskiren effectively lowered BP throughout the 24-hour dosing
period, persisting overnight and throughout the high-risk period
in the early hours of the morning. Furthermore, no rebound
effect was seen in this study after withdrawal of aliskiren.
Perhaps the most important clinical benefit of ambulatory
BP monitoring in patients with hypertension and comorbid
illnesses is to confirm that these patients have adequate control
over a 24-hour period (Figure 4). Additionally, while there are
potential benefits of conversion of a nondipping pattern to a
dipping pattern, the possibility remains that excessive BP reduction at night might be associated with orthostatic hypotension
or excessive hypotension during sleep in certain individuals,
particularly the elderly.28,39 Ideally, changes in drug administration time could be followed by repeat ambulatory BP monitoring to assess the effects of therapy and rule out an excessive BP
fall during the night.39 However, this practice is not likely to be
covered by most third-party insurance payers. An alternative is to
perform 1 ambulatory BP study that is paired with frequent selfor home BP measurement in order to obtain a frame of reference
for future patient assessment using home BP measurements.
Conclusions
The importance of adequate BP control over the entire 24-hour
period, particularly the early morning hours, cannot be overemphasized. Several of the pathophysiologic systems responsible for
the circadian BP variability, especially salt balance and the RAAS,
can be modulated by appropriate, long-acting therapy, and such
interventions may result in improved clinical outcomes.
The confirmation that correcting 24-hour BP profiles results
in clinical outcomes benefit will require clinical trials that
specifically test this hypothesis. One example would be studies in which patients are randomized to different drug-dosing
schedules with efficacy confirmed by sequential ambulatory BP
monitoring versus standard office measurements. These outcomes could be initially composed of surrogate measures, such
as changes in left ventricular hypertrophy, vascular structure and
function, ischemic brain lesions, or proteinuria. If they suggest
benefits, then large-scale studies with conventional CV endpoints
would be justified and helpful for determining precisely when
to use ambulatory BP monitoring in the clinical management of
patients with hypertension.
Disclosures
The author has served as a consultant to Boehringer and Novartis.
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Vol. 13, No. 8, S-b
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October 2007
JMCP
notes
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October 2007
Vol. 13, No. 8, S-b
www.amcp.org
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Renin-Angiotensin Aldosterone System and Hypertension:

Current Approaches and Future Directions

Supplement Policy Statement

Supplements to the Journal of Managed Care Pharmacy are

Steven A. Atlas, MD, is an associate professor of medicine, Mount Sinai School

S2 Epidemiology and Unmet Needs in Hypertension

S9 The Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition

S21 Direct Renin Inhibition: Focus on Aliskiren

S34 Importance of Blood Pressure Control Over a 24-Hour Period

Epidemiology and Unmet Needs in Hypertension

John M. Flack, MD, MPH, FAHA, is a specialist in clinical

S2 Supplement to Journal of Managed Care Pharmacy

pproximately 72 million people in the United States have

Vol. 13, No. 8, S-b

Epidemiology and Unmet Needs in Hypertension

Vol. 13, No. 8, S-b

when differences in the primary prevention of clinical outcomes

Supplement to Journal of Managed Care Pharmacy S3

Epidemiology and Unmet Needs in Hypertension

condition.19 Seventy-five percent of people were unaware that

S4 Supplement to Journal of Managed Care Pharmacy

Vol. 13, No. 8, S-b

Epidemiology and Unmet Needs in Hypertension

aggregate of reasons for patient noncompliance, which relate to

Vol. 13, No. 8, S-b

When BP levels are >20/10 mm Hg above normal (per JNC 7) or

Lifestyle and Behavioral Changes

Approximately 2 g (87 mmol) of

Approximately 4.7 g (120 mmol) of

Fewer than 2 drinks (1 oz or 30 mL of

Smoking acutely raises blood pressure.

Supplement to Journal of Managed Care Pharmacy S5

Epidemiology and Unmet Needs in Hypertension

protection that can be statistically disentangled from reductions

Direct Renin Inhibitors

One pharmacologic approach has been targeted at the RAAS,

Vol. 13, No. 8, S-b

Epidemiology and Unmet Needs in Hypertension

14. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity

Vol. 13, No. 8, S-b

Supplement to Journal of Managed Care Pharmacy S7

Epidemiology and Unmet Needs in Hypertension

40. Villamil A, Chrysant SG, Calhoun D, et al. Renin inhibition with

39. Oparil S, Yarows SA, Patel S, Fang H, Zhang J, Satlin A. Efficacy

S8 Supplement to Journal of Managed Care Pharmacy

Vol. 13, No. 8, S-b

The Renin-Angiotensin Aldosterone System:

Steven A. Atlas, MD, is an associate professor of medicine,

Vol. 13, No. 8, S-b

he renin-angiotensin aldosterone system (RAAS) plays an

Supplement to Journal of Managed Care Pharmacy S9

The Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition

regulator of sodium and potassium balance.4 These landmark

associated with a decline in plasma concentration and/or tissue

Vol. 13, No. 8, S-b

The Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition

on heart cells or a generalized systemic effect,8 but evidence for

Vol. 13, No. 8, S-b

nervous system, and adrenal cortex (stimulation of aldosterone

Supplement to Journal of Managed Care Pharmacy S11

The Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition

in vascular smooth muscle and inhibit growth and remodeling

Classical Endocrine Pathway of Angiotensin Biosynthesis