1 / 29

PEPTIDES

PEPTIDES. Tissue damage, allergic reactions, viral infections and other inflammatory events activate a series of proteolytic rections that generate BK and KD in the circulation or tissues

etta
Download Presentation

PEPTIDES

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. PEPTIDES

  2. Tissue damage, allergic reactions, viral infections and other inflammatory events activate a series of proteolytic rections that generate BK and KD in the circulation or tissues • Kinin metabolites released by basic carboxypeptidases are B1 rec agonists (binds des-Arg metabolites of kinins) B1 receptors are xpressed by tissue injury and inflammation. These peptides contribute to inflammatory responses as autacoids that act locally to produce pain, vasodilation and increased vascular permeability but also have beneficial effects in the heart kidney and circulation, PG NO EDRF

  3. KALLIKREIN-KININ & RENIN ANGIOTENSIN SYSTEMS

  4. Vasoconstrictors • Angiotensin II • Vasopressin • Endothelins • Neuropeptide Y • Urotensin

  5. VASODILATORS • Bradykinin and related kinins • Natriuretic peptides • Vasoactive intestinal peptide • Substance P • Neurotensin • Calcitonin gene related peptide • Adrenomedullin

  6. PHARMACOLOGY OF KININS • Understanding the roles of kinins have advanced because generation of B1 and B2 receptor knockout mice, also availability of specific receptor antagonists

  7. DEGRADATION OF BRADYKININ

  8. Pain • Powerful algesic agents, BK excites primary sensory neurons and provokes the release of neuropeptides SP, NKA calcitonin gene related peptide • B2→acute BK algesia • B1→pain of chronic inflammation

  9. Inflammation • Plasma kinins ↑ permeability in the microcirculation acting on the small venules to cause disruption of the inter-endothelial junctions • Edema results because of this + increased hydrostatic pressure

  10. Respiratory disease • Kinins play roles in asthma and rhinitis • BK induced bronchoconstriction is blocked by Anticholinergic agents but not by Antihistamines or COX inhib. • CV • Vasodilation, ↓ bp B2 rec on endothelial cells NO, PGI2

  11. Kidney • Regulate urine volume and composition • ↑ renal blood flow, natriuresis

  12. ANGIOTENSIN Angiotensin I is released from angiotensinogen by enzymatic cleavage and renin catalyzes this reaction. Angiotensin (Ang) converting enzyme stimulates conversion of AngI to AngII Degradation of AngII is accomplished by several peptidases.

  13. RENIN ANGIOTENSIN SYSTEM

  14. Renin is an aspartyl protease that specifically catalyzes the hydrolytic release of the decapeptide Ang I from angiotensinogen. Renin in the circulation originates in the kidneys. Enzymes w renin-like activity are present in several extrarenal tissues.

  15. Renin secretion is controlled by a variety of factors, including • a renal vascular receptor • the macula densa • the sympathetic nervous system • angiotensin • pharmacologic alteration of renin release

  16. ACTIONS OF ANGIOTENSIN II Ang II exerts important actions at several sites in the body, including vascular smooth muscle, adrenal cortex, kidney and brain. Through these actions, the renin-Ang system plays a key role in the regulation of fluid and electrolyte balance and arterial blood pressure. Xessive activity of the renin-ang system can result in hypertension and disorders of fluid and electrolyte homeostasis.

  17. BLOOD PRESSURE Ang II is a very potent pressor agent-on a molar basis, ~40 times more potent than NE. The pressor response to iv Ang II is rapid in onset 10-15 seconds and sustained during long-term infusion of the peptide A large component of pressor response to iv Ang II is due to direcxt contraction of vascular-especially arteriolar-smooth muscle.

  18. In addition, Ang II can also increase bp through actions on the brain and autonomic nervous sytem. The pressor response to angiotensin is usually accompanied by little or no reflex bradycardia because the peptide acts on the brain to reset the baroreceptor reflex control of heart rate to a higher pressure.

  19. Ang II also interacts w the autonomic nervous system. It stimulates autonomic ganglia, increases the release of E and NE from the adrenal medulla, and facilitates sympathetic transmission by an action at adrenergic nerve terminals.

  20. Adrenal Cortex Ang II acts directly on the zona glomerulosa of the adrenal cortex to stimulate aldosterone biosynthesis. At higher concentrations, Ang II also stimulates glucocorticoid biosynthesis. Kidney Causes renal vasoconstriction, increase proximal tubular Na reabsorption, and inhibit secretion of renin.

  21. CNS Ang II acts on the CNS to stimulate drinking (dipsogenic effect) and increase the secretion of vasopressin and adrenocorticotropic hormone(ACTH). Cell growth Ang II is mitogenic for vascular and cardiac muscle cells and may contribute to the development of CV hypertrophy. ACE inhibitors and Ang II receptor antagonists prevent morphologic changes (remodeling) following MI.

  22. Ang II receptors are widely distributed in the body. Like the receptors for other peptide hormones, ang II receptors are located on the plasma membrane of target cells, and this permits rapid onset of the various actions of Ang II.

  23. Two distinct subtypes of Ang II receptors are AT1 and AT2 AT1 receptors predominate in vascular smooth muscle AT2 receptors are present at high density in all tissues during fetal development, they are much less abundant in the adult where they are expressed at high conc only in the adrenal medulla , reproductive tissues, vascular endothelium and parts of the brain.

  24. AT1 receptors have a high affinity for losartan and a low affinity for PD 123177(an experimental nonpeptide antagonist) While AT2 receptors have a low affinity for losartan and a high affinity for PD 123177 Ang II and saralasin bind equally to both subtypes.

  25. INHIBITORS OF RENIN-ANG SYSTEM Drugs that block renin secretion Aliskiren, Clonidine, propranolol are such drugs.

  26. CONVERTING ENZYME INHIBITORS Captopril and enalapril are such drugs. They decrease systemic vascular resistance without increasing heart rate, and they promote natriuresis. They are effective in the treatment of hypertension, decreae morbidity and mortalityin heart failure and left ventricular dysfunction after myocardial infarction.

  27. ACE inhibitors not only block the conversion of Ang I to angiotensin II but also inhibit the degradation of other substances, including bradykinin, substance P and enkephalins. The action of ACE inhibitors to inhibit BK metabolism contributes significantly to their hypotensive action and also responsible for some adverse effects, including cough and angioedema. In such cases Angiotensin receptor antagonists might be chosen (class discussion)

  28. ANGIOTENSIN ANTAGONISTS Substitition of sarcosine for the Phenylalanine in position 8 of Ang II results in the formation of potent peptide antagonists of the action of Ang II. Saralasin is the name of the compound. Must be adm iv Nonpeptide antagonists are of much greater interest Losartan and valsartan, eprosartan, irbesartan, candesartan, and telmesartan are AT1 antagonists used in the treatment of hypertension without the adverse effects of ACE inhibitors

More Related