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PHARMACOLOGY

VASOACTIVE PEPTIDES
Dr. Fe Barquin September 14-15, 2015
Objectives

Identify vasoactive peptides of


pharmacologic significance;

Describe the biosynthesis, physio- and


pharmacologic action of the following:

Angiotensin
Kinins
Vasopressin
Natriuretic peptides
Vasopeptidase inhibitors
Endothelins
Vasoactive intestinal peptide
Substance P
Neurotensin
Calcitonin gene-related peptide
Adrenomedillin
Neuropeptide Y
Urotensin

ACTIONS OF ANGIOTENSIN II

exerts important actions at vascular smooth


muscles, adrenal cortex, kidney, heart and brain
via receptors by which the renin-angiotensin
system plays a key role in the regulation of fluid
and electrolyte balance and arterial blood
pressure;
Angiotensin II (ANG II)
Effect on Blood Pressure

40 times more potent than norepinephrine;


rapid in onset (10 15 seconds) and sustained
during long-term infusion;
Pressor effects are due to:
1. Direct contraction of vascular-especially
arteriolar-smooth muscles;
2. Action on the brain with reflex bradycardia
(resets the baroreceptor reflex control
of heart rate to a higher pressure);
3.Interacts with the autonomic
nervous system (ANS) by:
(a.) stimulating the autonomic ganglia,
(b.) increases the release of epinephrine
and norepinephrine from the
adrenal medulla
(c.) facilitates sympathetic transmission
by an action at adrenergic nerve
terminals

ANGIOTENSIN
Angiotensinogen
(14 a.a. at the amino terminal of the glycoprotein;
synthesized in the liver) to the circulation

Angiotensin II (ANG II)


Effect on the Adrenal Cortex & Kidney

Acts directly on the zona glomerulosa of the


adrenal cortex to
(1.) stimulate aldosterone synthesis
and release
(2.) at higher concentrations, stimulate
glucocorticoid synthesis

Acts on the kidney to cause


(1.) renal vasoconstriction
(2.) increase proximal tubule sodium
reabsorption
(3.) inhibit the release of renin.
Angiotensin II
Effect on the CNS

In addtion to its effect on blood pressure.


Angiotensin II also acts on the CNS by
(1.) stimulating drinking (dipsogenic
effect)
(2.) increase the secretion of
vasopressin and adrenocorticotropic
hormone (ACTH).

Angiotensin II
Effect on Cell Growth

SUBCLASS

Captopril and many others:


Clinical

SUBCLASS

ALISKERIN

MECHANISM
OF ACTION

EFFECTS

CLINICAL

Angiotensin
Receptor

ANTAGONIST

EPROSARTAN
IRBESARTAN
CANDESARTAN

Selective
competitive
antagonist of
angiotensin
AT1 receptors

TELMISARTAN
OLMESARTAN

Arteriolar
dilatation;
decreased
aldosterone
secretion;
increased
sodium and
water
excretion

Similar to valsartan

Hypertension

VALSATRAN

APPLICATION

APPLICATION

Inhibits
catalytic
activity of
renin

Arteriolar
dilatation;
decreased
aldosterone
secretion;
increased
sodium and
water
excretion

KININS

Y Drugs That Interact with Vasoactive P

CLINICAL

EFFECTS

HYPERTENSION

(appears to be nitric
oxide-dependent &
may involve the
bradykinins B2
receptor-nitric oxidecGMP pathway)

similar to enalapril.

Renin

AT2
Stimulation causes
vasodilatation

INHIBITORS OF THE RENIN


ANGIOTENSIN SYSTEM

SUBCLASS

MECHANISM
OF ACTION

Arteriolar
dilatation;
decreased
aldosterone
secretion;
increased
sodium and
water
excretion

INHIBITORS

AT1 and AT2

(activation of
phospholipase C and
generation of inositol
triphosphate and
diacylglycerol)

Inhibits
conversion of
angiotensin I
to angiotensin
II

Hypertension
heart failure

ENALAPRIL

Receptors - are widely distributed in the body,


- are G protein-coupled and
- located in the plasma membrane of
target cells.
Two distinct types of receptors based on their
differential affinity for antagonists and their
sensitivity to sulfhydryl-reducing agents:

AT1
Most actions of ANG II
are mediated by this
receptor, resulting in
smooth muscle
contraction

APPLICATION

INHIBITORS

ANGIOTENSIN RECEPTORS AND


MECHANISM OF ACTION

CLINICAL

EFFECTS

Converting
Enzyme

(1.) Mitogenic for vascular and cardiac muscle cells


and may contribute to the development of
cardiovascular hypertrophy
(2.) A variety of important effects on the vascular
endothelium (overactivity of the reninangiotensin system is one of the most
significant factors in the development of
hypertensive vascular disease)

MECHANISM
OF ACTION

potent vasodilator peptides formed enzymatically by


the action of enzymes known as kallikreins or
kininogenases acting on protein
substrates called kininogens.
The kallikrein-kinin system has several features in
common with the renin-angiotensin system.
Kininogens precursor of kinins
is present in plasma, lymph, and
interstitial fluid;
two forms:
low molecular weight
(LMW kininogen)
and
high molecular weight
(HMW kininogen, 15-20% of plasma proteins)

LMW Kininogen

HMW Kininogen

Across capillary walls


kallikreins

Plasma kallikreins

kinin

kinin

Effects on the
Cardiovascular System

Produce marked arteriolar vasodilation in several


vascular beds including the heart, skeletal muscle,
kidney, liver and intestine;
Ten times more potent on a molar basis than histamine;
Vasodilation may result from
(a.) direct inhibitory effect on arteriolar smooth muscles
(b.) mediated by the release of nitric oxide or vasodilator
prostaglandins, such as PGE2 and PGI2;
The predominant effect on veins is contraction which
may result from
(a.) direct stimulation of venous smooth muscles,
(b.) release of venoconstrictor prostaglandins
such as PGF2;
Produce contraction of most visceral smooth muscle;
The role of kinin in the regulation of blood pressure is not
clear, though under resting conditions, may play a
role in postexercise hypotension.

METABOLISM of Kinins
Metabolized rapidly (half-life < 15 seconds) by
nonspecific exopeptidases, or endopeptidases,
commonly referred to as kininases;
Kininase I, apparently synthesized in the liver, is a
carboxypeptidase that releases the carboxyl
terminal arginine residue;
Kininase II, present in plasma and vascular
endothelial cells throughout the body is identical to
the angiotensin-converting enzyme (ACE, peptidyl
dipeptidase) that inactivates kinins by cleaving
the carboxyl terminal dipeptide
phenylalanine- arginine;
Like arginine I, bradykinin is almost completely
hydrolysed during a single passage through the
pulmonary vascular bed.
DRUGS AFFECTING THE KALLIKREIN
KININ SYSTEM

Effect of Kinin on
Endocrine & Exocrine Glands

Are present in several glands, including the


pancreas, kidney, intestine, salivary glands, and
sweat glands;
May modulate the tone of salivary and pancreatic
ducts, help regulate gastrointestinal motility, and
act as local modulator of blood flow as a
result of their marked effects
on smooth muscle;
Influence the transepithelial transport of water,
electrolytes, glucose and amino acids and may
regulate the transport of these substances in the
GIT and kidney;
Kallikreins may play a role in the physiologic
activationof various prohormones, including
proinsulin and prorenin.

SUBCLASS

Bradykinin has long been known to produce the


four classic symptom of inflammation
redness, local heat, swelling and pain;
Kinins elicit pain by stimulating nociceptive
afferents in the skin and viscera.

Other Effects of Kinins

Two types of receptors mediate the actions of kinins:


Bradykinin1* and Bradykinin2*
(with subtypes B2A and B2B)
both of which are G protein-coupled;
Mechanism of action and different affinities of the
two receptors have been observed in mice.

CLINICAL
APPLICATION

Kinin

ICATIBANT

Selective
antagonist of
kinin B2
receptors

ECALLANTIDE

Plasma kallekrein
inhibitor

Blocks effects of
kinins on pain,
hyperalgesia
and
inflammation

Hereditary
angioedema

VASOPRESSIN
(Arginine vasopressin; AVP1 Antidiuretic Hormone, ADH)

Plays an important role in the


(1.) long-term control of blood pressure through its
action on the kidney to increase water
reabsorption; and in the
(2.) short-term regulation of arterial pressure by its
vasoconstrictor action;

Bradykinin may play a beneficial protective role in


certain cardiovascular diseases and ischemic
stroke-induced brain injury;
However, it has been implicated in cancer and some
central nervous system diseases.
KININ RECEPTORS &
MECHANISM OF ACTION

EFFECTS

INHIBITOR

Role In Inflammation & Pain

MECHANISM OF
ACTION

Three subtypes of AVP receptors have been


identified and all are G protein-coupled:
V1a receptors mediate the vasoconstrictor
action of AVP;
V1b receptors mediate release of ACTH
by pituitary corticotropes; and,
V2 receptors mediate the antidiuretic action.

V1a effects are mediated by Gq through


(a.) activation of phospholipase C,
(b.) formation of inositol trisphosphate,
(c.) increased activation of adenylcyclase;

V2 effects are mediated by Gs activation of


adenyl cyclase.

DRUGS THAT INTERACT WITH VASOACTIVE


PEPTIDE SYSTEMS
SUBCLASS

MECHANISM OF
ACTION

CLINICAL
EFFECTS

APPLICATIO
N

Vasopressin

ARGININE
VASOPRESSIN

Agonist of
vasopressin V1
& V2 receptors

Vasoconstriction

CONIVAPTAN

Antagonist of
vasopressin V1
& V2 receptors

RELCOVAPTAN

Increased
selectivity for V1
receptor

Vasodilatation

Potential use in
hypertension and
heart failure;
hyponatremia

Vasopressin

ANTAGONISTS

Vasodillatory
shock

AGONISTS

Urodilatin is synthesized in the distal tubules of the


kidneys by alternating processing of the ANP
precursor, elicits potent natriuresis, and diuresis,
and thus functions as a paracrine regulator of
sodium and water, and also relaxes
vascular smooth muscle.
PHARMACODYNAMICS & PHARMACOKINETICS
Three receptor subtypes have been identified:
- ANPA,
- ANPB, and,
- ANPC (also known as NPR1, NPR2, and NPR3)
Natriuretic peptides have a short
half life in the circulation;
Natriuretic peptides are metabolized in
the kidneys, liver, and lungs
by the neutral endopeptidase NEP 24.11;
Natriuretic peptides removed from the circulation by
binding to receptors in the vascular endothelium;

SUBCLASS

NATRIURETIC PEPTIDES

URALITIDE:

Agonist of
natriuretic
peptide
receptors

Increased
sodium and
water excretion;
vasodilatation

CLINICAL
APPLICATION

synthetic form of urodilatin

VASOPEPTIDASE INHIBITORS

New class of cardiovascular drugs that


inhibit two metalloprotease enzymes :
- NEP 24.11
- ACE;
Increase the levels of natriuretic peptides and
decrease the formation of ANG II

thus enhancing
vasodilatation,
reduce vasoconstriction, and
increase sodium and water excretion,

resulting in
reduced peripheral vascular resistance
and blood pressure

SUBCLASS

MECHANISM
OF ACTION

EFFECTS

CLINICAL
APPLICATION

Vasopeptidase

INHIBITORS
OMAPATRILAT

Decreases
metabolism of
natriuretic
peptides and
formation of
angiotensin II

Vasodilatation;
increased
sodium and
water excretion

HYPERTENSION;
HEART FAILURE

(1.) atrial stretch via mechanosensitive ion channels;


(2.) volume expansion;
(3.) changing from the standing to the supine position;
(4.) exercise;
(5.) sympathetic stimulation via 1A adrenoceptors,
endothelins via the ETA-receptor subtype;
(6.) glucocorticoids;
(7.) AVP;
(8.) pathologic states, including heart failure, primary
aldosteronism, chronic renal failure, and
inappropriate ADH secretion syndrome.
BNP is synthesized primarily in the heart, in two forms
having either 26 or 32 amino acids, appears to be
volume-related and exhibits natriuretic, diuretic,
and hypotensive activities similar to
ANP at a lower concentration;
CNP consists of 22 amino acids, is located primarily in
the central nervous system but may also be present
in the vascular endothelium, kidneys and intestine,
possess less natriuretic and diuretic activity than ANP
but is a potent vasodilator and may play a role
in the regulation of peripheral resistance.

NESIRITIDE

EFFECTS

HEART
FAILURE

Present in the atria (ANP), brain (BNP) and


other tissues (CNP)
a family of peptides with natriuretic, diuretic,
vasorelaxant, and other properties;
Share a common 17-amino acid disulfide ring with
variable C- and N- terminals;
A fourth peptide, urodilatin, has the same structure as
ANP with an extension of 4 amino acids
at its N-terminal.
ANP is derived from the carboxyl terminal end of a
common precursor, preproANP in the cardiac atrial
cells and the ventricular myocardium, by neurons in
the central and peripheral nervous system,
and in the lungs;
Stimulus to the release of ANP from the heart are by:

MECHANISM
OF ACTION

ENDOTHELINS

Source: Endothelium of blood vessels


Potent vasoconstrictor peptides
Product of different genes and synthesized as
prepro form that is processed to the propeptide
and then to the mature form
Three isoforms:
ET-1, the originally described form
ET-2, and ET-3, each containing 21 amino acids
with two disulfide bridges
(Cystein Cysteine, Cystein Cysteine)

Many blood vessels are innervated;


immune system , thymus, spleen and
lymph nodes
SUBCLASS

MECHANISM
OF ACTION

Cause potent dose-dependent vasoconstriction


in most vascular beds due to direct contraction
of vascular smooth muscles;
Other effects:
A. causes direct positive inotropic and
chronotropic effect on the heart & are potent
coronary vasoconstrictors;
B. On the kidneys, endothelins cause
vasoconstriction, decrease glomerular filtration
rate, sodium and water excretion;
C. In the respiratory system, endothelins cause
potent contraction of the tracheal, and
bronchial smooth muscles;
D. Interact with several endocrine systems:
increasing secretion of renin, aldosterone,
AVP, and ANP;
Cause a variety of actions on the central &
peripheral nervous systems, the GIT system, the
liver, the female & male reproductive systems,
the eye, the skeletal system, and the skin;
ET-1 is a potent mitogen for vascular smooth muscle
cells, cardiac myocytes, and glomerular
mesangial cells.

SUBCLASS

MECHANISM
OF ACTION

EFFECTS

CLINICAL
APPLICATION

Endothelin

BOSENTAN

Nonselective
antagonist of
endothelin
ETA ; ETB
receptors

Vasodilatation

PULMONARY
ARTERIAL
HYPERTENSION

ANTAGONISTS

VASOACTIVE INTESTINAL PEPTIDE (VIP)

A 28-amino acid peptide that belong to the


glucagon-secretin family of peptides
VIP is widely distributed in the
central and peripheral
nervous sytems

where VIP functions


as a major neurotransmitter
In the CNS, it is present in
cholinergic presynaptic neurons;
In the peripheral nervous system,
it is present in neurons innervating the
heart, lungs, GIT & urogental tracts,
skin, eyes, ovaries, and thyroid gland

CLINICAL
APPLICATION

Vasoactive
Intestinal
Peptide

AGONISTS
STEARYL17-NILE

Agonist of
VPAC1 and
VPAC2

ACTIONS

EFFECTS

Vasodilatation;
Multiple
metabolic,
endocrine and
other effects

Type 2
diabetes;
chronic
obstructive
pulmonary
disease

SUBSTANCE P

Belongs to the tachykinin family of peptides


with the common carboxyl terminal sequence
Phe-Gly-Leu-Met;

an undecapeptide;

Other members: neurokinin A & B

(both decapeptides)
In the central nervous system, tachykinin

is a neurotransmitter
In the GIT: tachykinin

is as a neurotransmitter
(in the entire nervous system)
and as a local hormone
As a neurotransmitter, it is implicated in :
o Behavior
o Anxiety
o Depression
o Nausea and vomiting
o Potent arteriolar vasodilator
(mediated by release of nitric oxide
from the endothelium)

o
o
o

Contraction of venous, intestinal


Bronchial smooth muscles
Stimulates secretion of the salivary
glands, diuresis & natriuresis

Actions are mediated by:


Receptors NK1
(dominant receptor in the human brain),
NK2, & NK3
(coupled to inositol triphosphate synthesis
and calcium mobilization)

SUBCLASS

MECHANISM
OF ACTION

CLINICAL

EFFECTS

APPLICATION

SUBCLASS

Substance P

Neurotensin (NT)

AGONISTS

AGONISTS

APREPITANT

FOSAPREPITANT:

Selective
antagonist of
tachykinin NK1
receptors

Blocks several
central
nervous
system effects
of Substance P

Prevention of
chemotherapy
-induced
nausea &
vomiting

PD149163

MECHANISM
OF ACTION

EFFECTS

Agonist of
central
neurotensin
receptors

Interacts
with central
dopamine
systems

Potential for the


treatment of
SCHIZOPHRENIA
and
PARKINSONS
DISEASE

Antagonist of
central and
peripheral
neurotensin
receptors

Blocks some
central and
peripheral
(vasodilator)
actions of
neurotensin

None
identified

CLINICAL
APPLICATION

prodrug that is converted to aprepitant


Neurotensin

ANTAGONISTS

Neurotensin (NT)

A tridecapeptide found in the CNS, GIT,


and the blood circulation;
Synthesized as part of a large precursor that also
contain neuromedin

a six-amino acid NT-like peptide


Plays a dual role as a :
- neurotransmitter or
- neuromodulator
(exerts potent effects including hypothermia,
antinociception* & modulation of dopamine
and glutamate neurotransmission)

*Nociceptor-a receptor for pain which


is stimulated by injury
Has role as local hormone in the periphery
(vasodilatation, inhibition of gastric, & pepsin
secretion, and inhibition of gastric motility, plus
action on the immune system)
In the central nervous system, there are close
associations between NT and dopamine systems
NT may be involved in
clinical disorders involving dopamine pathways
such as schizophrenia,Parkinsons disease,
and drug abuse.

effects of NT are mediated by


three subtypes of NT receptors, designated :
- NTR 1
- NTR 2
- NTR 3 also known as NTS 1 ,
NTS 2, and NTS 3
NTR 1 and NTR 2 receptors belong to the G q
protein-coupled superfamily with seven
transmembrane domains

MECLINERTANT

Calcitonin Gene
Related Peptide (CGRP)
A member of the calcitonin family of peptides which
also includes, calcitonin, adrenomedullin,
and amylin;
It consists of 37 amino acids and like calcitonin is
present in large amounts in the thyroid gland,
and distributed widely in the central and
peripheral nervous systems, cardiovascular &
respiratory systems, and GIT;
CGRP-containing fibers are more abundant around
arteries than veins, in the atria than I ventricles;
In the smooth muscles of the GIT, CGRP is found with
Substance P in some regions and with
acetylcholine in others;
The most potent vasodilator, dilates vascular beds
(coronary circulation particularly sensitive) mediated
via a nonendothelial mechanism through
activation of adenyl cyclase;
CGRP receptors traditionally have been divided into
two types, CGRP1 & CGRP2, but only a single
receptor, CGRP receptor* is identified which
functions to activate both Gs and Gq molecules;
CGRP receptor * has been synthesized and used to
investigate the action of drugs
SUBCLASS

MECHANISM
OF ACTION

EFFECTS

CLINICAL
APPLICATION

Calcitonin
Gene-Related
Peptide
Antagonists
TELCAGEPANT,
OLCEGEPANT

Antagonists
of the CGRP
receptor

Blocks some
central and
peripheral
vasodilator
actions of
CGRP

MIGRAINE

ADRENOMEDULLIN (AM)
It is a 52-amino acid peptide with a six-amino acid
ring and a C-terminal amidation sequence;
Like CGRP, AM belongs to the calcitonin
family of peptides;
A related peptide which has been isolated in humans
and other mamals is a peptide termed
adrenomedullin 2 (or intermedin);
AM is widely distributed in the body, the highest
concentration of which is found in the adrenal
glands, hypothalamus, and
anterior pituitary gland;
High concentration are also present in the kidneys,
lungs, cardiovascular system, and GIT;
EFFECTS of
Adrenomedullin
On the Cardiovascular System:
- Marked long-lasting hypotension;
- Reflex increase in heart rate and cardiac output;
On the Kidneys:
- Increase in sodium excretion and renin release;
On the endocrine system:
- Inhibition of aldosterone and insulin secretion;
On the CNS:
- Increase sympathetic outflow
Effects mediated by:
A receptor closely related to
the CGMP receptor;
Signalling pathway:
activates Gs

and triggers cAMP formation


in vascular smooth muscle cells;
Pharmacodynamics & Clinical Application

Increased levels during intense exercise, in a


number of pathologic states including essential
hypertension, cardiac & renal failure,
and septic shock
(Mechanism: possibly act as a physiologic
antagonist of the action of vasoconstrictors, such
as ET-1 and ANG II);
May protect against cardiovascular overload
and injury;
Treatment of some cardiovascular diseases.

NEUROPEPTIDE Y (NPY)

This 36-amino acid peptide belongs to the family


that also includes peptide YY and pancreatic
polypeptide with the same number
of amino acids each;
One of the most abundant neuropeptides in both
the central and peripheral nervous systems;

- in the sympathetic nervous system,

NPY is frequently
localized in noradrenergic neurons
(apparently functions both as a vasoconstrictor and as
a co-transmitter with norepinephrine);
- Peptide YY and pancreatic polypeptide

both gut endocrine peptides


EFFECTS of
Neuropeptide Y
On the CNS:
1. Increased feeding
(most potent orexigenic molecule);

2.
3.
4.
5.

Hypotension;
Hypothermia;
Respiratory depression; and,
Activation of the
hypothalamic-pituitary-adrenal axis.

Other Effects:
a. Vasoconstriction of cerebral blood vessels;
b. Positive chronotropic and inotropic
actions on the heart;
c. Hypertension;
d. Potent renal vasoconstrictor and suppresses
renin secretion, but causes diuresis
e.
and natriuresis;
f. Pre-junctional neuronal actions include
inhibition of transmitter release from
sympathetic and parasympathetic nerves;
g. Vascular actions include direct
vasoconstriction, and inhibition of
the action of vasodilator.
NYP Y Receptors

Four (4) subtypes: designated as Y1, Y2, Y4 and Y5


Linked to Ca2+ and inhibition of adenylyl cyclase;
Y1 and Y2 are of major importance in the
cardiovascular & other peripheral effects
of the peptide;
Y4 has a high affinity to the
pancreatic polypeptide;
Y5 are found mainly in the CNS and may be
involved in the control of food intake and the
hypothalamic-pituitary-adrenal axis.

SUBCLASS

MECHANISM
OF ACTION

EFFECTS

CLINICAL
APPLICATION

Neuropeptide Y

ANTAGONISTS
BIBP3226

Selective
antagonist of
NYP Y1
receptors

Blocks
vasoconstriction
response to
neurotensin

POTENTIAL
ANTIOBESITY
AGENT

BIIEO246:
Selective for Y2
receptor
MK-0557:Selective for Y5
receptor

UROTENSIN II (UII)

It is an 11-amino acid peptide expressed in the


brain, spinal cord, and kidneys;
Also present in plasma and potential sources of
this peptide include the heart, lungs,
liver, and kidneys;
The stimulus for its release is not known;

UT Receptor

It is a Gq protein-coupled receptor;
Widely distributed in the brain, spinal cord,
heart, vascular smooth muscles, skeletal
muscles, and pancreas;
Some effects of the peptide including
vasoconstriction are mediated by the
phospholipase C, inositol triphosphatediacylglycerol signal transduction pathway.

SUBCLASS

MECHANISM
OF ACTION

EFFECTS

CLINICAL
APPLICATION

Urotensin

ANTAGONISTS
PALOSURAN

Antagonist of
urotensin
receptors

Blocks
vasoconstric
tor action of
urotensin

DIABETIC RENAL
FAILURE

*undergoing preclinical or clinical evaluation.

References
Reid IA. Vasoactive Peptides. In: Katzung BG, Masters SB
and Trevor AJ. eds., Basic & Clinical Pharmacology. McGraw
Hill Medical, 2012: 295 312.

PAROKYA NI GALONERS | TROEZIAN 2018