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 AT 1 AT 2

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: AT 1 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 B 1 : inflammatory response, collagen synthesis, cell multiplication B 2 B 2A B 2B

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

19. Natriuretic peptides ANP: arterial natriuretic peptide BNP: brain natriuretic peptide CNP: c-type natriuretic peptide

20. Structures

21. Pharmcodynamics & pharmcokinetics ANP A coupled to guanylyl cyclase ANP B coupled to guanylyl cyclase ANP C 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: ET A, ET B

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: NK 1, NK 2, NK 3 Receptor Antagonists: aprepitant