Vasoactive peptides

1
Vasoactive peptides

• By
• S.Bohlooli, PhD

2
Vasoactive peptides

• Vasoconstrictors
• Angiotensin II
• Vasopressin
• Endothelins
• Neuropeptide Y
• urotensin

• Vasodilators
• Bradykinin
• Natriuetic peptids
• Vasoactive intestinal peptide
• Substance P
• Neurotensin
• Calcitonin gene related peptide
• adernomedullin

3
Angiotensin

• Biosynthesis
• Renin and factors controlling renin secretion
• Renal vascular receptor
• Macula Densa
• Sympathetic nervous system
• Angiotensin
• Pharmacologic alteration of renin release

4
Formation of angiotensin peptides
5
Actions of Angiotensin II

• Blood pressure arteriolar
• Adrenal cortex aldosterone biosynthesis
• Kidney renal vasoconstrictor, sodium
  reabsorption
• Central nervous system dipsogenic effect,
  vasopressin?, ACTH ?
• Cell growth mitogenic

6
Angiotensin receptors mechanism of action

• AT1
• AT2

7
Multiple mechanisms of AT1 receptor-effector
coupling
8
Inhibition of the renin angiotensin system

• Block of renin secretion
• clonidine and propranolol
• Renin inhibitors
• Aliskiren ,remikiren, enalkiren
• Converting enzyme inhibitors
• Captopril and enalapril
• Angiotensin antagonists AT1
• Losartan , valsartan

9
Kinins

• Biosynthesis
• Kallikreins
• Kininogens
• Formation of kinins in plasma tissues

10
the kallikrein-kinin and renin-angiotensin
systems.
11
Structure kinin agonsits antagonists
12
Actions of kinins

• Cardiovascular system
• arteriodilator, venoconstrictor
• Endocrine exocrine glands
• Pancreas, kidney, intestine, salivary glands
• Inflammation
• Redness, local heat, swelling, pain
• Sensory nerves
• Pain producing substance

13
Kinin receptors mechanism of action

• B1 inflammatory response, collagen synthesis,
  cell multiplication
• B2
• B2A
• B2B

14
Drugs affecting the kallikrein kinin system

• Icatibant antagonist of B2, oral
• Aprotinin kallikrein inhibitor

15
Vasopressin

• Long term control of blood pressure
• Water reabsorption
• Short term control of blood pressure
• Vasoconstrictor

16
Vasopressin receptor agonists
17
Vasopressin receptors antagonists
18
(No Transcript)
19
Natriuretic peptides

• ANP arterial natriuretic peptide
• BNP brain natriuretic peptide
• CNP c-type natriuretic peptide

20
Structures
21
Pharmcodynamics pharmcokinetics

• ANPA
• coupled to guanylyl cyclase
• ANPB
• coupled to guanylyl cyclase
• ANPC
• BNP as nesiritide

22
Vasopeptidase inhibitors

• Inhibits two metalloprotease enzymes
• NEP 24.11 and ACE
• Increase level of natriutetic peptides and
  decreased formation of angiotensin II
• Omapatrilat, sampatrilat, fasidotrilat

23
Endothelins

• Potent vasoconstrictor peptides
• 3 isoforms were identified
• ET-1, ET-2, ET-3
• 21-amino-acid peptide
• Receptors ETA, ETB

24
Structures of the endothelin
25
Endothelins actions

• Dose dependent vasoconstriction
• Coronary, kidney
• Potent constriction of tracheal and bronchial
  smooth muscle
• Endocrine system increased secrestion of renin,
  aldosterone, vasopressin, atrial natriuretic
  peptide
• Potent mitogen of vascular smooth muscle

26
Generation of endothelin-1 (ET-1) in the vascular
endothelium
27
Inhibitors of endothelin synthesis and action

• Receptor antagonists
• nonselective antagonist
• Bosentan has been associated with fatal
  hepatotoxicity
• ETA-selective antagonists
• sitaxentan, ambrisentan
• Endothelin converting enzyme inhibitors
• Phosphoramidon

28
Effects of endothelin antagonists

• Vasodilation
• Potentail use
• Heart failure, pulmonary hypertension
• Essential hypertension, atherosclerosis
• Myocardial infarction , cardiac hypertrophy

29
Substance P

• Belongs to tachykinin family
• Neurokinin A , Neurokinin B
• Substance P
• Actions anxiety, depression, nausea, emesis
• Effect on smooth muscle artriodilator,
  venoconstrictor
• Receptors NK1, NK2, NK3
• Receptor Antagonists aprepitant