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Vasoactive peptides

Vasoactive peptides. By S.Bohlooli, PhD. Vasoconstrictors: Angiotensin II Vasopressin Endothelins Neuropeptide Y urotensin. Vasodilators: Bradykinin Natriuetic peptids Vasoactive intestinal peptide Substance P Neurotensin Calcitonin gene related peptide adernomedullin.

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Vasoactive peptides

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  1. Vasoactive peptides By S.Bohlooli, PhD

  2. Vasoconstrictors: Angiotensin II Vasopressin Endothelins Neuropeptide Y urotensin Vasodilators: Bradykinin Natriuetic peptids Vasoactive intestinal peptide Substance P Neurotensin Calcitonin gene related peptide adernomedullin Vasoactive peptides

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

  19. Structures

  20. Pharmcodynamics & pharmcokinetics • ANPA • coupled to guanylyl cyclase • ANPB • coupled to guanylyl cyclase • ANPC • BNP as nesiritide

  21. 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

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

  23. Structures of the endothelin

  24. 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

  25. Generation of endothelin-1 (ET-1) in the vascular endothelium

  26. 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

  27. Effects of endothelin antagonists • Vasodilation • Potentail use: • Heart failure, pulmonary hypertension • Essential hypertension, atherosclerosis • Myocardial infarction , cardiac hypertrophy

  28. 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

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