Vasoactive peptides are key autacoids with significant roles in regulating vascular smooth muscle, including vasoconstrictors like angiotensin II and endothelins, as well as vasodilators like natriuretic peptides and vasoactive intestinal peptide. They impact multiple physiological functions such as blood pressure regulation, fluid balance, and cardiovascular dynamics. Understanding these peptides is crucial for pharmacological interventions in conditions like hypertension and heart failure.

1. Vasoactive Peptides
Ayesha Rida
M.Phil Pharmacology

2. Introduction
 Vasoactive peptides are autacoids with significant actions on vascular smooth
muscle as well as other tissues
 They include vasoconstrictors, vasodilators, and peptides with mixed effects
 They play important roles as transmitters in the autonomic and central nervous
systems
2

3. Types
 Angiotensin II
 Endothelins
 Neuropeptide Y
 Urotensin
 Bradykinin & related kinins
 Natriuretic peptides
 Vasoactive intestinal peptide
 Substance P
 Neurotensin
 Calcitonin gene related peptide
 Adrenomedullin
Vasoconstrictors Vasodilators
3

4. Vasoconstrictors
4

5. Angiotensin II
 Angiotensin is a peptide hormone
that causes vasoconstriction and
a subsequent increase in blood
pressure
 It is part of the renin-angiotensin
system
 Angiotensin is an oligopeptide
and is a hormone and a powerful
dipsogen
5

6. Synthesis
6

7. Receptors of Angiotensin II
Receptors Mechanism Location
AT1 Gq; ↑ IP3, DAG, Ca2+ Kidney, vascular &
cardiac muscles, Brain
AT2 Unknown
Adrenal gland, heart,
and brain
7

8. Actions of Angiotensin II
Angiotensin II is a very potent pressor agent.
Enhances sympathetic functions by stimulating the release of
norepinephrine and inhibiting its reuptake
Blood Pressure
It acts on the kidney to cause renal vasoconstriction, ↑ Na+
reabsorption & inhibit renin release. Stimulate release of aldosterone
form adrenal gland causing ↑ Na+ reabsorption ↑ fluid volume ↑ BP
Kidney
Stimulate dipsogenic effect and increase vasopressin secretion from
the posterior pituitary gland to increase fluid retentionCNS
It is a mitogenic agent and cause vascular and cardiac hypertrophy Cell Growth
8

9. Inhibition of Angiotensin II
Renin Release
Inhibitors
• Clonidine
• Aliskiren
• β Blockers
ACE Inhibitors
• Captopril
• Lisinopril
• Enalapril
• Benazepril
• Fosinopril
ARBs
• Losartan
• Valsartan
• Olmesartan
• Telmisartan
• candesartan
9

10. Endothelins
 Endothelins derived the name
from the fact that they were
derived and secreted from
endothelial cells
 They were first isolated from aortic
endothelial cells
 They have a key role in vascular
homeostasis
10

11. Types
EP-1
• Predominantly secreted by vascular
endothelium. It is also produced by
neurons in the CNS and in endometrial,
renal mesangial, Sertoli, breast
epithelial and other cells
EP-2
• Kidneys and intestine
EP-3
• Brain, GIT, lungs and kidneys
11

12. Endothelin Synthesis
12

13. Receptors
Receptor type Affinity Location
ETA
High affinity for ET-1 & ET-
2 and low affinity for ET-3
Smooth muscle cells
(where they mediate
vasoconstriction)
ETB
Equal affinities for ET-1,
ET-2 and ET-3
Primarily located on vascular
endothelial cells (where they
mediate release of PGI 2 and
nitric oxide)
Also present on smooth muscle
cells
13

14. Actions of Endothelins
Vasoconstriction and decrease glomerular filtration rate and sodium
and water excretion.
Mitogen for glomerular mesangial cells
Kidney
IV administration of ET-1 causes a rapid and transient decrease in
arterial blood pressure followed by a sustained Increase.
Positive inotropic and chronotropic actions. ET-1 is a potent mitogen
CVS
Increase the secretion of renin, aldosterone, AVP, and ANP
Endocrine
System
They cause potent contraction of tracheal and bronchial smooth
muscle
Respiratory
System
14

15. 15

16. Endothelin Receptor Blockers
Selective ETA
Receptor
Antagonists
• Sitaxentan
• Ambrisentan
• Atrasentan
• BQ-123
• Zibotentan
Dual Antagonists
• Bosentan
• Macitentan
• Tezosentan
Selective ETB
Receptor
Antagonists
• BQ-788
• A192621
16

17. Neuropeptide Y
 Neuropeptide Y (NPY) is a 36-
amino acid neuropeptide that
acts as a neurotransmitter in the
brain and in the ANS
 In the ANS it is produced mainly
by neurons of the sympathetic
nervous system
17

18. Receptors
 Y1 and Y2 receptors are of major
importance in the cardiovascular
and other peripheral effects of the
peptide
 Y4 receptors have a high affinity
for pancreatic polypeptide
 Y5 receptors are found mainly in
the central nervous system and
may be involved in the control of
food intake.
18

19. Actions
 CNS – NPY produces a variety of
CNS effects, including increased
feeding, respiratory depression,
activation of the hypothalamic-
pituitary-adrenal axis &
vasoconstriction of cerebral
blood vessels
 CVS – Positive chronotropic and
inotropic actions on the heart and
hypertension
 Kidneys – Potent renal
vasoconstrictor and suppresses
renin secretion, but can cause
diuresis and natriuresis
19

20. Urotensin
 Urotensin II (UII) was originally
identified in fish
 Human UII is an 11-amino acid
peptide
 It is a strongest known
vasoconstrictor
20

21. Receptor
 The actions of UII are mediated by a Gq protein-coupled receptor referred to as
the UT receptor
 UT receptors are widely distributed in the brain, spinal cord, heart, vascular
smooth muscle, skeletal muscle, and pancreas
 Effects are mediated by the phospholipase C, inositol trisphosphate-
diacylglycerol signal transduction pathway
21

22. Actions
 CNS – When the urotensin II
receptor is activated through an
ICV injection of urotensin II it
causes an increase of
corticotropin releasing factor
which lead to increased plasma
levels of adrencorticotropic
hormones
 CVS – It is the most potent known
vasoconstrictor.
22

23. Antagonists
 Urantide
 Palosuran
23

24. Vasodilators
24

25. Kinins
 Kinins are potent vasodilator
peptides
 They are formed enzymatically by
the action of enzymes known as
kallikreins or kininogenases
acting on protein substrates
called kininogens.
25

26. Types
 Three kinins have been identified
in mammals;
• Bradykinin
• Lysylbradykinin (Kallidin)
• Methionyllysylbradykinin
26

27. Synthesis
27

28. Receptors
Receptor types Affinity
B1 Bradykinin
B2 Bradykinin > Lysylbradykinin > methionyllysylbradykinin
28

29. Effects of Kinins
Vascular
• Arteriolar dilation: inhibit arteriolar smooth muscles & causes the release of
PGE2 and prostacyclin
• Venous contraction: stimulation of venous smooth muscles & release PGF 2α
Inflammation
• Bradykinin produce the four classic symptoms of inflammation—redness, local
heat, swelling, and pain.
Pain
• They elicit pain by stimulating nociceptive afferents in the skin and viscera
Others
• Bradykinin is also thought to be the cause of the dry cough in some patients
on angiotensin-converting enzyme (ACE) inhibitor drugs 29

30. Metabolism
 It is a carboxypeptidase
 Synthesized in liver
 It releases the carboxyl terminal
arginine residue
 It is Angiotensin-converting
Enzyme (ACE)
 Kininase II inactivates kinins by
cleaving the carboxyl terminal
dipeptide phenylalanylarginine
Kininase I Kininase II
30

31. Kinins Inhibitors
 Receptor Blockers – Icatibant
 Synthesis Inhibitors – Aprotinin,
Ecallantide
31

32. Natriuretic Peptides
 Natriuretic peptides (NPs) are hormones which are mainly secreted from heart
and have important natriuretic and kaliuretic properties
 They are of 4 types;
• Atrial natriuretic peptide (ANP)
• B-type (Brain) natriuretic peptide (BNP)
• C-type natriuretic peptide (CNP)
• Urodilatin
32

33. Atrial
Natriuretic
Peptide (ANP)
 ANP, also called Atrial Natriuretic
Factor (ANF), Atrial Natriuretic
Hormone (ANH), is a powerful
vasodilator
 It is released by atrial myocytes in
response to high blood volume
33

34. Synthesis
ANP converting
Enzyme
ANP is secreted in response to:
 Increased Sympathetic stimulation of
β-adrenoceptors
 Raised sodium concentration
 Endothelin, a potent vasoconstrictor
 Exercise 34

35. Brain Natriuretic
Peptide (BNP)
 B-type natriuretic peptide (BNP)
also known as ventricular
natriuretic peptide is secreted by
the ventricles of the heart in
response to excessive stretching
of heart muscle cells
 BNP is named so as it was
originally identified in extracts of
porcine brain
35

36. Synthesis
Furin / Corin
Enzyme
NT – Pro BNP
36

37. C-Type
Natriuretic
Peptide (CNP)
 CNP is located predominantly in
the central nervous system
 It has less natriuretic and diuretic
activity than ANP and BNP but is a
potent vasodilator and may play
a role in the regulation of
peripheral resistance
37

38. Urodilatin
 Urodilatin is synthesized in the
distal tubules of the kidneys
 It elicits potent natriuresis and
diuresis, and thus functions as a
paracrine regulator of sodium
and water excretion
 It also relaxes vascular smooth
muscle.
38

39. Receptors
Receptor Subtypes Ligands
ANPA / NPR1 ANP & BNP
ANPB / NPR2 CNP
ANPC / NPR3
Equal affinity for all
types
39

40. Actions
Dilated afferent glomerular arterioles & constrict efferent ones thus
increasing GFR.
↓ Na+ reabsorption in distal convoluted tubule & collecting duct.
Inhibit renin secretion.
Kidney
Relaxes vascular smooth muscles in arterioles.
Inhibits cardiac hypertrophy. CVS
↓ Aldosterone secretion from zona glomerulosa of the adrenal cortexAdrenal
40

41. Uses of Natriuretic Peptides
Diagnostic use
• Large amounts of ANP secretion has been noted to cause electrolyte
disturbances (hyponatremia) and polyuria. These indications can be a marker of
a large atrial myxoma
• BNP and NT-proBNP are also typically increased in patients with left ventricular
dysfunction
• BNP or NT-proBNP can also be used for screening and prognosis of heart failure
Therapeutic Use
• Recently developed vasopeptidase inhibitors including omapatrilat, sampatrilat,
and fasidotrilat have selective inhibitory activities against neutral endopeptidase
and ACE.
• As a result, they ↑ vasodilation, ↓ vasoconstriction, and ↑ sodium excretion 41

42. Vasoactive
Intestinal
Peptide (VIP)
 Vasoactive intestinal peptide
(VIP) belongs to the glucagon-
secretin family of peptides
 VIP is widely distributed in the
central and peripheral nervous
systems, where it functions as one
of the major peptide
neurotransmitters
 It is also present in key organs of
the immune system including the
thymus, spleen, and lymph nodes
42

43. Receptors
Receptor Location Mechanism
VPAC1 Widely distributed in the
central nervous system
and in the heart, blood
vessels, and other tissues
Binding of VIP to its
receptors results in
activation of adenylyl
cyclase and formation of
cAMPVPAC2
43

44. Actions
 GIT – induce smooth muscle
relaxation, dilating peripheral
blood vessels, decrease acid
secretion, stimulate secretion of
water and electrolytes
 CVS – It causes coronary
vasodilation and have positive
inotropic and chronotropic effect
 CNS – VIP is a crucial component
of the mammalian circadian
timekeeping machinery. It also
help to increase prolactin
secretion
44

45. Substance P
 Substance P belongs to the
tachykinin family of peptides
 It is a neuropeptide, acting as a
neurotransmitter
 It is found in the brain and spinal
cord and is associated with
inflammatory processes and pain
45

46. Receptors
 The receptor for substance P is
neurokinin 1 receptor (NK1-
receptor)
 Substance P and the NK1
receptor are widely distributed in
the brain and are found in brain
regions that are specific to
regulating emotion
(hypothalamus, amygdala, and
the periaqueductal gray)
46

47. Actions of SP
Vascular
• Substance P is a potent vasodilator
• The vasodilation is mediated by release of nitric oxide from the endothelium
Inflammation
• Substance P can be released from the peripheral terminals of sensory nerve
fibers in the skin, muscle, and joints.
• This release is involved in neurogenic inflammation.
GIT
• It causes nausea and emesis
• Causes contraction of intestinal smooth muscles
Kidneys
• Causes diuresis & natriuresis
47

48. SP Antagonists
 Aprepitant is the first antagonist to be approved for chemotherapy-induced
vomiting and nausea.
 Netupitant is also antiemetic
 Maropitant is approved for treatment and prevention of vomiting in cats and
dogs.
 Vestipitant is currently under development for use against insomnia, among other
things.
 Fosaprepitant is a prodrug for aprepitant.
48

49. Neurotensin
 Neurotensin (NT) was first isolated
from the CNS but was found to be
present in the GIT and in the
circulation
 Like many other neuropeptides,
NT serves a dual function as a
neurotransmitter in the CNS and
as a local hormone in the
periphery
49

50. Receptors
Receptor
Sub-type
Family
NTR1
Gq Protein coupled
NTR2
NTR3
Family of sorting
proteins
50

51. Effects
 CNS – hypothermia,
antinociception, and modulation
of dopamine and glutamate
neurotransmission
 CVS – vasodilation, hypotension,
increased vascular permiability
 GIT – inhibition of gastric acid
secretion, pepsin secretion and
gastric motility
 Others - increased secretion of
several anterior pituitary
hormones, hyperglycemia
51

52. Receptor
Antagonist
 Levocabastine (H1 receptor
antagonist) – selective NTR2
antagonist
52

53. Calcitonin Gene
Related Peptide
(CGRP)
 CGRP is a member of the
calcitonin family of peptides
 In humans, it exists in two forms,
α-CGRP and β-CGRP
53

54. CGRP Receptor
 CGRP is mediated by G protein-
coupled calcitonin-like protein
receptor (CLR) co-assembles with
the receptor activity-modifying
protein (RAMP1) to form a
functional single CGRP receptor
that can activate both Gs and Gq
54

55. Effects of CGRP
 CGRP is produced in both peripheral and central neurons
 It is a potent peptide vasodilator
 In the spinal cord, the function and expression of CGRP may differ depending on
the location of synthesis
• If synthesized in the ventral horn of the spinal cord; contribute to the regeneration
of nervous tissue after injury
• If synthesized in the dorsal horn of the spinal cord; linked to the transmission of
pain
55

56. Clinical Significance
 Release of CGRP from trigeminal nerves plays a central role in the
pathophysiology of migraine.
 The peptide is released during migraine attacks
 CGRP binds to and activates CGRP receptors located around meningeal vessels,
causing vasodilation & mast cell degranulation
 Clinical trials with olcegepant and telcagepant have demonstrated that CGRP
antagonism is an effective, well-tolerated treatment for migraine
 These CGRP receptor antagonists target the interface between CLR and RAMP1
and thereby make them more selective for the CGRP receptor
56

57. Adrenomedullin
 Adrenomedullin (AM) was first
discovered in human adrenal
medullary pheochromocytoma
tissue.
 AM is also a member of the
calcitonin family of peptides
57

58. AM Receptor
 Actions of AM are mediated by a
receptor closely related to the
CGRP receptor. CLR co-
assembles with RAMP subtypes 2
and 3
 Binding of AM to CLR activates Gs
and triggers cAMP formation in
vascular smooth muscle cells,
and increases nitric oxide
production in endothelial cells
58

59. AM Distribution & Effects
 The highest concentrations are found in the adrenal glands, hypothalamus, and
anterior pituitary, in the kidneys, lungs, cardiovascular system, and
gastrointestinal tract.
 AM dilates vessels in the kidney, brain, lung, hind limbs, and mesentery, resulting
in hypotension
 The hypotension in turn causes reflex increases in heart rate and cardiac output.
 AM also acts on the kidneys to increase sodium excretion and renin release
 Endocrine effects include inhibition of aldosterone and insulin secretion
59

60. 60

61. 61

62. 62

63. 63

64. References
 Basic & Clinal Pharmacology by Katzung
 Lippincott Illustrated reviews of Pharmacology
 Comprehensive Pharmacy review
 https://en.wikipedia.org/wiki/
 Localization of angiotensin AT1 and AT2 receptors. A. M. Allen, J. Zhuo, F. A. Mendelsohn J Am Soc Nephrol.
1999 Jan; 10 (Suppl 11): S23–S29
 Pandit K, Mukhopadhyay P, Ghosh S, Chowdhury S. Natriuretic peptides: Diagnostic and therapeutic use.
Indian Journal of Endocrinology and Metabolism. 2011;15(Suppl4):S345-S353. doi:10.4103/2230-8210.86978.
 https://psychonautwiki.org/wiki/Substance_P
 Russell FA, King R, Smillie S-J, Kodji X, Brain SD. Calcitonin Gene-Related Peptide: Physiology and
Pathophysiology. Physiological Reviews. 2014;94(4):1099-1142. doi:10.1152/physrev.00034.2013. 64