The effect of ARB in diabetic nephropathy

The increased activity of the reninangiotensinaldosterone system (RAAS) is an

important pathogenetic factor in the development of nephropathy in diabetic patients. The
damaging factor of this system is the end-product, angiotensin II, and the damaging effects
are vasoconstriction, increase of aldosterone secretion, growth, fibrosis, thrombosis,
inflammation and oxidation. Theoretically, on this basis, blockade of the RAAS should
have a beneficial effect on the development of diabetic nephropathy. The main goal in the
treatment of diabetic nephropathy is control of the glycaemic status and aggressive
antihypertensive therapy, primarily with RAAS-blocking agents. It was demonstrated
recently that angiotensin II receptor blockers (ARBs) have a slowing effect on the
progression of diabetic nephropathy (RENAAL and IDNT trials) or on the development of
proteinuria (IRMA) in type 2 diabetes. These effects are specific and independent of the
decrease in blood pressure. Theoretically, the combination of an angiotensin-converting
enzyme inhibitor (ACEI) and an ARB can lead to a more complete blockade of the RAAS.
A new study (ONTARGET) has now started to investigate whether treatment with a
combination of an ACEI and an ARB has a more potent beneficial effect on the
cardiovascular events and the nephropathy in type 2 diabetic patients as compared with
separate treatment with the two agents.17
The principal aim in the treatment of diabetic nephropathy is control of the
glycaemia and aggressive antihypertensive therapy, decreasing the blood pressure (BP)
below 130/85 mmHg. The question is what antihypertensive therapy should be used. At
first sight, it might seem paradoxical to treat diabetic nephropathy by inhibition of the
reninangiotensinaldosterone system (RAAS), because the blood renin levels in diabetic
subjects are low rather than high.17
RAAS and its blockade in diabetic nephropathy
Recent human and experimental studies have revealed that there is an increased
local activity of the RAAS and an increased production of angiotensin II (Ang II) in the
kidney. Ang II has known cardiovascular and renal-damaging effects: vasoconstriction,
increase in aldosterone secretion, growth, fibrosis, thrombosis, inflammation and
oxidation, which are mediated by the angiotensin AT1 receptor. Consequently, prevention
of the effects of Ang II mediated by the AT1 receptor seems to have a beneficial effect on
the progression of diabetic nephropathy. It was demonstrated earlier that blockade of the

RAAS by angiotensin-converting enzyme inhibitors (ACEIs) can have a beneficial effect

on the progression of diabetic nephropath. This specific nephron protective effect may be
explained by the vasodilatating effects of ACEIs on the glomerular efferent arterioles.
Clinical trials have confirmed the beneficial effect of these treatments: ACEIs decreased
the proteinuria and attenuated the progression of the renal disease in diabetic subject;
however, according to other published data, ACEIs were not superior to other
antihypertensive agents in slowing down the progression of type 2 diabetic nephropathy.
Angiotensin receptor blockers (ARBs) represent a new class of antihypertensive drugs that
block the RAAS. They selectively block the AT1 receptor and in this way inhibit the
vasoconstrictive and tissue-damaging effects of Ang II in diabetes, including growth,
inflammation and thrombosis.17
Trials with AT1 receptor blockers in type 2 diabetic nephropathy
Three trials recently have studied the ARBs in patients with diabetic nephropathy.
The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan
(RENAAL) study investigated the effects of the ARB, losartan, in 1513 patients with type
2 diabetes and nephropath. In this study, which lasted for 3.4 years, one group received
losartan, while the other group received conventional antihypertensive agents (placebo
group). The target BP was <140/90 mmHg. The main question was whether the treatment
with losartan could influence the primary end-point (the composite of death, ESRD and
doubling of serum creatinine) and the secondary end-points (composite of morbidity and
mortality from cardiovascular causes, proteinuria and the rate of progression of the renal
disease).17
Losartan reduced the relative risk of the primary composite end-point as compared
with the placebo group by 16% (P < 0.02), reduced the incidence of doubling of serum
creatinine by 25% (P < 0.006) and reduced ESRD by 28% (P < 0.02). The proteinuria was
also significantly decreased. Extrapolating from the observed data, this reduction
corresponds to an average delay of 2 years in the need for dialysis or transplantation as
estimated by the authors. There was no significant difference in relation to the risk of
death, or cardiovascular morbidity and mortality.17
The Irbesartan Diabetic Nephropathy Trial (IDNT) investigated the effects of
irbesartan and amlodipine on the rate of progression of diabetic nephropathy in 1715
subjects with type 2 diabetic nephropath. The duration of the study was a mean of 2.6

years. The first group was treated with irbesartan, the second with amlodipine and the third
with conventional antihypertensive drugs (placebo group). It was planned to achieve a BP
goal of <135/85 mmHg. The primary and secondary end-points were very similar to those
in the RENAAL study. Irbesartan demonstrated a relative risk (RR) reduction vs placebo
by 20% of the composite end-point (P < 0.02), by 33% of the doubling of serum creatinine
(P < 0.003) and by 23% of ESRD (P < 0.07). Irbesartan displayed an even more significant
RR reduction vs amlodipine, by 23% of the composite end-point (P < 0.006), and by 37%
of the doubling of serum creatinine (P < 0.001). In this comparison, the incidence of ESRD
was on the borderline of significance, vs both the placebo and amlodipine. The ARB
treatment significantly decreased the proteinuria. The RR of death, cardiovascular
morbidity and mortality was not significantly changed in either comparison.17
The worldwide largest (n = 28 400) trial to date is the Ongoing Telmisartan Alone
in combination with Ramipril Global Endpoint Trial (ONTARGET). This trial recently
started in type 2 diabetic patients, to investigate the effects of combined ACEIARB
therapy. The patients will be treated randomly with telmisartan or ramipril separately and
with a combination of the two agents. In addition to the primary composite (of
cardiovascular death) and secondary end-points, the occurrence of nephropathy will be
investigated. Experience in the recent past indicated that the most successful strategy for
the treatment of diabetic nephropathy is the inhibition or blockade of the RAAS, using
ACEIs or ARBs.17

The effect of ARB in stress related disorders

Effects of AT1 receptor blockade during stress. Peripheral administration of the
AT1 antagonist candesartan blocks brain AT1 receptors and prevents the hormonal and
sympathoadrenal response to isolation stress. To determine whether or not Ang II and
AT1 receptors played significant roles in the regulation of the stress reaction, we studied
the response of the organism to stress after sustained blockade of peripheral and brain
AT1 receptors. We first developed an animal model of brainAT1 receptor blockade after
peripheral administration of the receptor antagonist, a model necessary to relate our

findings in a meaningful way to clinical conditions in human populations. We found that

peripheral administration of a selective, potent, insurmountable AT1 antagonist such as
candesartan, when administered for 2 weeks, significantly decreased AT1 receptor
binding, not only in peripheral tissues and circumventricular organs, but also in the
hypothalamic paraventricular nucleus and in the nucleus of the solitary tract, indicating
that candesartan readily crosses the blood brain barrier. Chronic peripheral
administration of candesartan inhibits brain AT1 receptor binding to a higher degree
than its acute peripheral administration. This indicated an unsuspected and excellent
penetration of candesartan into the brain, resulting at the higher doses used in an almost
complete blockade of brain AT1 receptors.18
We tested the effect of AT1 receptor blockade with candesartan administered for
2 weeks before submitting the animals to the stress of isolation, a clinically relevant
model resulting, in rodents, from the restriction from freely regulating exposure to novel
surroundings and access to familiar territory. Twenty-four hours of isolation enhance
AT1 receptor expression in the paraventricular nucleus to an extent similar to the
increase in AT1 receptors that occurs during repeated immobilization stress, increased
pituitary ACT decreased pituitary vasopressin and increased adrenal corticosterone,
aldosterone, catecholamines and metabolites, and the adrenal transcription of tyrosine
hydroxylase, the rate-limiting enzyme in catecholamine synthesis, hallmarks of the
stress reaction. Pretreatment with candesartan blocked AT1 receptor binding after
isolation not only in peripheral tissues but also in the brain, in a manner similar to that
previously observed in unstressed animals, prevented the increase in pituitary ACTH
and adrenal corticosterone and the decrease in pituitary vasopressin during isolation,
decreased the adrenomedullary catecholamine response, including the isolation-induced
increase in tyrosine hydroxylase transcription, and decreased the urinary excretion of
catecholamines, corticosterone and vasopressin.18
Our results demonstrated that simultaneous antagonism of peripheral and brain
AT1 receptors could represent an advantage in the control of the stress reaction. If
blockade of pathologically enhanced responses to stress has beneficial effects, centrally
acting insurmountable AT1 antagonists such as candesartan could have a place in the
therapy of stress-related disorders.18
Effect of pretreatment with candesartan on an acute stress induced disorder

To establish whether or not AT1 receptor blockade could be of therapeutic

benefit, we initiated a study of the effects of candesartan on the development of stressinduced disorders. We first studied the effect of candesartan on the incidence of
gastric ulcers induced by cold-restraint, a commonly used and clinically relevant
experimental model for acute stress-induced gastric damage. Stress induces acute
gastric mucosa lesions by a variety of mechanisms, including psychological factors
influencing individual vulnerability, stimulation of specific brain path-ways regulating
autonomic function, decreased blood flow to the mucosa, increase in muscular
contractility, mast cell degranulation, leukocyte activation and increased free radical
generation resulting in increased lipid peroxidation. Maintenance of gastric blood
flow is important to protect the mucosa from endogenous and exogenous damaging
factors, and Ang II, through AT1 receptor stimulation, increases vascular tone in
resistance arteries including those of the gastric vasculature leading to decreased
blood flow and ischemia. We speculated that AT1 receptor inhibition with candesartan
could protect gastric blood flow during stress and reduced gastric ulcer formation.18
We found that candesartan dramatically decreased the number of ulcerations
produced by cold-restraint stress, protecting the gastric mucosa from stress-induced
injury. Several interrelated mechanisms are probably involved in the protective effect
of the AT1 antagonist including the reduction of the stress-induced adrenomedullary
catecholamine formation and release, increase in gastric blood flow and antiinflammatory effects. The protection of gastric blood flow after administration of AT1
receptor antagonists is probably mediated by inhibition of receptors localized to the
endothelium of arteries located in the gastric mucosa and is similar to the protective
effect on cerebral blood flow during brain ischemia.18
We found that stress markedly increased the expression of the pro
inflammatory cytokine tumor necrosis factor a (TNF-a), the adhesion molecule
intercellular adhesionmolecule-1 (ICAM-1) and the number of infiltrating neutrophils
in the gastric mucosa, which play crucial roles in the progression of gastric injury.
Activated neutrophils release inflammatory mediators capable of damaging
endothelial cells and inhibition of neutrophil infiltration prevents the stress-induced
reduction of mucosal flow and the production of gastric lesions. Ang II promotes
tissue inflammation; enhancing neutrophil infiltration through AT1 receptor
stimulation increased expression of TNF-a, ICAM-1 and P-selectin. We demonstrated
that pretreatment with the AT1 antagonist decreased the stress-induced overexpression

of TNF-a and ICAM-1 overexpression and the neutrophil infiltration in the gastric
mucosa indicating that the anti-inflammatory effects of AT1 blockade could be
relevant for the protection of stress-induced lesions. These results show that inhibition
of AT1 receptors, by combined local and systemic mechanisms, protects gastric blood
flow inhibits the pro inflammatory cascade preventing the gastric ischemia and
inflammation characteristic of a major stress response and protecting the gastric
mucosa from stress-induced ulcerations.18
AT1 blockade did not prevent the increase in adrenalcorticosterone produced
by cold-restraint as it did in response to isolation. This demonstrated that Ang II
regulates the stress reaction differently depending on the kind and intensity of the
stress. Preservation of the glucocorticoid response during stress may contribute to the
therapeutic effect of candesartan, because corticoids have been proposed to protect
against gastric ulceration. Thus, our experiments demonstrate a clear protective antistress effect of candesartan in an acute stress-induced disorder.18
17. Sonkodi S, Mogyorosi A. Treatment of diabetic nephropathy with angiotensin II
blockers. Nephrology Dialysis Transplantation. 2003 Jul 1;18(suppl 5):v21-3.
18. Saavedra JM, Ando H, Armando I, Baiardi G, Bregonzio C, Juorio A, Macova M.
Anti-stress and anti-anxiety effects of centrally acting angiotensin II AT 1 receptor
antagonists. Regulatory peptides. 2005 Jun 30;128(3):227-38.