Vasoactive peptides

Dr. Bashir Ibrahim Elnaw

Introduction
Peptides are used by most tissues for
cell to cell communication. They play
important roles in autonomic and
CNS transmission.
Several exert important direct effects
on vascular and smooth muscles.
They include vasoconistrictor and
vasodilator peptides.
 Vasoactive peptides
Vasoconstrictors
Vasodilators:
Bradykinin
:
Natriuretic peptides
Angiotensin II
Vasoactive intestinal
Vasopressin
peptide(VIP)
Endothelins Substance P

Neurotensin
Neuropeptide
Calcitonin gene- related
Y peptide
urotensin adrenomedullin
 1-Angiotensin
Biosynthesis(Fig.1)
Renin and Factors Controlling its
Secretion:
Rennin is a protease that cleaves Ang I from
angiotensinogen.It is snythesized and stored
in the juxtaglomerular apparatus of the
nephron.

Renal vascular receptors function as
stretch receptors with decreased stretch
causing release.

Macula Densa cell receptors are sensitive
to Na+& Cl- delivery in DCT, decreased
delivery causes release.

Also sympathetic nerves through 1
stimulation causes release of rennin.

Angiotensin II inhibits rennin release.

Pharmacologic factors of rennin

release include: Vasodilators
(minoxidil),-agonists, -antagonists,
phosphdiesterase inhibitors (theophylline), most
diuretics, and anesthetics , all increase rennin
release.
 Actions of Angiotensin II
Blood pressure:due to increased arteriolar
vasoconistriction(40 times as
norepinephrine).
Adrenal cortex: aldosterone biosynthesis.
Kidney: renal vasoconstriction, sodium
reabsorption, inhibit renin secretion.
Central nervous system: stimulate drinking
(dipsogenic effect), vasopressin, ACTH
Cell growth: mitogenic for cardiac muscle cell
which may cause heart hypertrophy.
 Angiotensin receptors &
mechanism of action
AT1 receptors with high affinity for
losartan & low for PD
123177(experimental antagonist).
AT2 receptors with high affinity for PD
123177 & low affinity for losartan.
most Ang II actions are mediated by AT1
receptors which are G-protein coupled
that activate PLC, releasing IP3 & DAG.
AT2 stimulation causes vasodilation.
Multiple mechanisms of AT1
receptor-effector coupling
 Inhibition of the Rennin-
Angiotensin System
Block of rennin secretion:
clonidine and propranolol (decrease
sympathetic activity)
Rennin inhibitors:
Aliskiren ,remikiren, enalkiren
Converting enzyme inhibitors
Captopril, Enalapril, Enalaprilat and
lisinopril
Angiotensin II receptor antagonists:AT 1
Losartan , Valsartan
Inhibition of the rennin-angiotensin
system
2-Kinins:(potent
vasodilator peptides)
Biosynthesis
Kallikreins(kininogenases) act on:
Kininogens(proteins)
Formation of kinins in plasma &
tissues(Fig)
 Kallikreins:
-are present in plasma and many
tissues including kidney,pancreas,
intestine, sweat & salivery glands
-plasma prekallikrein can be activated
to kallikrein by trypsin,Hageman
factor and kallikrein itself.
 Kininogens(precursors of kinins and
substrates of kallikreins):
-present in plasma, lymph & intestinal
fluid as LMW and HMW kininogens.
Formation of Kinins in plasma
&tissue:
Three kinins are present in mammals:

Bradykinin released by plasma kallikrein.

Lysylbradykinin(kallidin) released by
tissue kallikrein.

Methionyllysylbradykinin released by
pepsin
The kallikrein-kinin
system.kininaseII is identical to
ACE
The kallikrein-kinin and Rennin-
Angiotensin systems.
Structure of kinin agonsits &
antagonists
 Physiologic & pathologic effects of
kinins:
(A) Effects on the CVS:
-Arteriolar vasodilation in heart, kidney,
intestine, skeletal muscle, liver,this is caused
by direct inhibitory effect, or release of nitric
oxide, or release of vasodilator PGs such as
PGE2 and PGI2.
-Contraction in veins caused by either direct
stimulation of venous smooth muscle, or
release of vasoconistrictor PGs such as PGF2
-Contraction of most visceral smooth muscle.
 An IV injection of kinins produce a
rapid but brief fall in BP due to
arteriolar vasodilation
IV kinins fail to produce a sustained
fall in BP and hypotension due to
reflex increases in HR, myocardial
contractility and cardiac out put
 (B) Effects on Endocrine &
Exocrine glands
Prekallikreins, kallikreins and kinins are
present in pancreas,
kidney,intestine,salivary and sweat glands.
They may act as modulators of blood flow
in these glands.
Kinins may modulate the tone of salivary
and pancreatic ducts & help regulate GIT
motility.
Kinins may regulate transport of water,
electrolytes, glucose and aminoacids in
GIT and kidney.
 Kinins may have a role in activation of
prohormones such as proinsulin & prorennin
(C)Role in inflammation:
Bradykinin produces the four symptoms of

inflammation: redness, local heat, swelling and

pain
It is rapidly generated after tissue injury and

plays a main role in the development and

maintenance of these inflammatory processes.
 (D)Effects on Sensory Nerves:
Kinins are potent pain-producing agents
by stimulating nociceptive nerves in skin.

(E)Other effects:bradykinin may play a

beneficial, protective role in certain CVS
diseases and ischemic stroke induced
brain injury.It may also be implicated in
cancer and some CNS diseases.
 Kinin receptors &
mechanism of action
Actions of kinins are mediated by specific
receptor on cell membrane.
B1: involved in inflammatory response,
collagen synthesis,and cell multiplication
B2 have wide distribution with multiple
biologic effects.They are subdivided into:
B2A
B2B
Drugs affecting the
kallikrein kinin system
Icatibant: antagonist of B2-
receptor, orally active.May be
useful in treatment of angioedema
and pain.
Aprotinin: kallikrein inhibitor that
inhibits kinins synthesis.
 3-Vasopressin(ADH)
Important in long-term control of blood
pressure by increasing kidney water
reabsorption.
Short-term control of arterial blood pressure
by its vasoconistrictor action in low doses.
Released by posterior petuitary in reponse
to rising plasma tonicity or falling BP.
Deficiency causes diabetes insipidus.
Vasopressin receptors and
antagonists:

Vasopressin receptors are all G protein-

coupled receptors. Activate PLC.
V1a receptors mediate vasoconistriction
V1b receptors potentiate the release of
ACTH by pituitary corticotropes
V2 receptors mediate the antidiuretic
action in kidney.Activate adenylylcyclase.
 Vasopressin
Antagonists(cont.
Terlipressin, a synthetic )vasopressin
analog,is more selective for V1 receptors
Desmopressin is a synthetic analog.
Relcovaptan is an antagonist of V1a
receptor for the pressor effect.
Conivaptan has both V1a and V2
antagonistic effects, is used in treatment
of hyponatremia.
Tolvaptan is highly selective for V2
receptors
4-Natriuretic peptides
The atria and other tissues contain
peptides with natriuretic,diuretic and
vasorelaxant effects.They include:
ANP: atrial natriuretic peptide
BNP: brain natriuretic peptide
CNP: C-type natriuretic peptide
Urodilatin that is similar to ANP
Structures:
 ANP is synthesized in atrial cardiac cells
It is released by atrial stretch via
mechanosensetive ion channels, also by
volume expantion, changing from
standing to the supine position,exercise&
by other mechanisms
It causes prompt and marked increase in
sodium excretion and urine flow.This
effect is due to both increased GFR and
decreased Na+ reabsorption in PCT.
It also inhibits secretion of rennin,
aldosterone and vasopressin,this action
also increase Na+ and water excretion.
 ANP causes vasodilation and a decrease
in arterial BP.
Suppression of its production cause an
increase in BP.
BNP is synthesized in the heart.It
produces natriuretic, diuretic and
hypotensive activities similar to ANP.
CNP is found mainly in CNS.It has less
natriuretic and diuretic activities than
ANP and BNP but is a potent vasodilator
Urodilatin is found in DCT in kidney.It
has potent natriuretic & diuretic effects.
Pharmcodynamics &
Natriuretic peptides exert their actions
pharmcokinetics:
by binding to specific G protein
coupled receptors,these are:
ANPA
coupled to guanylyl cyclase
ANPB
coupled to guanylyl cyclase
ANPC
Nesiritide is a BNP receptor agonist
that increases Na+ excretion &
improves hemodynamics in patients
with heart failure.Causes vasodilation.
 Ularitide is a synthetic form of
urodilatin, has beneficial renal and
cardiovascular effects in patients with
decompensated HF or liver cirrhosis.
Drugs that inhibit neutral
endopeptidase that breaks down ANP
are beneficial for cardiovascular
disorders.
5-Vasopeptidase inhibitors
Inhibit two metalloprotease enzymes
NEP 24.11 and ACE
Increase level of natriutetic peptides
and decreased formation of
angiotensin II
Thus they enhance vasodilation,
reduce vasoconistriction and
increase Na+ excretion, thus
reducing PVR & BP.
Omapatrilat, sampatrilat, fasidotrilat,
are agents under clinical trial.
 6-Endothelins
The endothelium of blood vessels
produceces many substances with
vasodilator actions (PGI2, NO) and
vasoconistrictor effects(endothelins)
Endothelins are potent vasoconistrictors.
3 isoforms were identified:
ET-1, ET-2, ET-3
They are all 21-amino-acid peptide
Receptors: ETA, ETB ,which are G protein coupled
receptors
Structures of the
endothelin
 Endothelins: actions
Dose dependent vasoconstriction in most vessels
Positive inotropic and chronotropic actions,and
potent coronary vasoconistriction.
In kidney:vasoconistriction,decreased GFR &Na+
and water excretion.
Potent conistriction of tracheal bronchial muscle.
Endocrine system: increased secrestion of rennin,
aldosterone, vasopressin, atrial natriuretic peptide
Potent mitogen of vascular smooth muscle
Generation of endothelin-1 (ET-1) in
the vascular endothelium
 Inhibitors of endothelin
synthesis and action
Receptor antagonists
nonselective antagonist

Bosentan: has been associated with
fatal hepatotoxicity
ETA-selective antagonists :

sitaxsentan, ambrisentan

Endothelin converting enzyme inhibitors

Phosphoramidon
Physiologic and pathologic
roles of endothelin:
antagonists
Vasodilation
Potential use:
Heart failure, pulmonary hypertension
Essential hypertension, atherosclerosis
Myocardial infarction , cardiac hypertrophy

30/5/2013
7-Vasoactive Intestinal
It is distributed in the CNS & peripheral
Peptide(VIP)
nerves,where it acts as neurotransmitter
It has a wide variety of biologic functions
In CVS:vasodilation in most vessels. In
heart it causes coronary vasodilation and
positive inotropic & chronotropic effects.
Effects are mediated by G protein coupled
receptors, these areVPAC1 and VPAC2
that stimulate adenylylcyclase &cAMP
responsible for the vasodilation.
Receptor agonists &antagonist under
development
 8-Substance P
Belongs to the tachykinin family of peptides:
Neurokinin A , Neurokinin B
Substance P
It is found in the CNS and in GIT acting as
neurotransmitter and enteric nervous system
acting as a local hormone.
Actions:anexity,depression,nausea & emesis.
Effect on smooth muscle: artriodilation
mediated by NO, venoconstriction and
contraction of intestinal and bronchial smooth
muscle.
Receptors: NK1, NK2, NK3
Receptor Antagonists: aprepitant
9-Calcitonin gene related
peptide(CGRP)
Member of calcitonin family which also

include: calcitonin,adrenomedullin and amylin .

CGRP is present in the C cells of thyroid, & in
CNS,PNS,CVS,GIT,& urogenital system
When injected in CNS it produces
hypertension, and suppression of appetite
When injected into systemic circulation it
causes hypotension and tachycardia.It is the
most potent vasodilator ever discovered
Action mediated by CGRP1 and CGRP2
receptors
CGRP released from trigeminal nerves is
central in pathophysiology of migraine.
 10-Neurotensin(NT):
Is found in CNS,GIT and circulation.
Neuromedin N is a similar peptide
Both peptides are secreted in circulation
after food ingestion.
NT serves as a neurotransmitter or
neuromodulator in the CNS and as a local
hormone in the peripheral nervous system.
In the CNS it produces hypothermia,
antinociception & modulation of dopamine
neurotransmission
Peripherally it causes vasodilation,
 hypotension,increased vascular permeability,
increased petuitary hormones secretion,
hyperglycemia, inhibition of GIT acid & pepsin
secretion,and inhibition of GIT motility.
In CNS, NT has close association to dopamine

systems.It may be involved in disorders

involving dopamine pathways such as
schizophrenia,parkinson's disease and drug
abuse.
NT exerts its effects by action on NT1,NT2,

NT3 receptors which G protein coupled

receptors.
Meclinertant in an antagonist of NT receptors.
 11- Adrenomedullin(AM):
It is a member of the calcitonin peptides that is
found in adrenal medulla pheochromocytoma
cells, but also found in many other tissues.
It causes vasodilation in many organs resulting
in long-lasting hypotension,with increased refex
heart rate and cardiac output.
It acts in kidney to increase Na+ excretion.It
also inhibits aldosterone and insulin secretion.
Its actions are mediated by G protein coupled
receptors
AM levels increase with exercise,hypertesion,
cardiac and renal failure& septic shock.
 12-neuropeptide Y(NPY):
It is a member of peptide families that also
include peptide YY and pancreatic polypeptide
Found in both central and peripheral nervous
systems.
In sympathetic nerves it acts as a
vasoconistrictor and co-transmitter with NE.
In the CNS it increases feeding(orexigenic),
hypotenstion,hypothermia,respiratory
depression
Positive inotropic and chronotropic effects
Effects mediated by G protein coupled
receptor
13- Urotensin
Is found in brain, spinal cord & kidney
Is a potent conistrictor of vascular
smooth muscle(the most potent
known vasoconistrictor)
Actions mediated via G protein
coupled UT receptors
Palosuran is an antagonist of UT
receptors,is used in diabetic renal
failure