vascular endothelium

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  • 1. Biology of vascular endothelium Presented by: Priya Jaswal M.Pharmacology ( Ist yr)

2. Endothelium is a largest endocrine organ. The endothelium is a thin layer of cells which lines the interior surface of blood vessels and lymphatic vessels forming an interface between circulating blood and lymph in the lumen and the rest of the vessel wall. The cells which form the endothelium are called endothelial cells. Endothelial cells in direct contact with blood are called vascular endothelial cells where as those in direct contact with lymph are known as lymphatic endothelial cells. 3. The basic constituents of the walls of blood vessels are Endothelial cells Smooth muscle cells Extracellular matrix Elastin Collagen, Glycosoaminoglycans. The three concentric layers Intima, Media Adventitia 4. These can be vasodilatory factors such as nitric oxide (NO), prostacyclin (PGI2) endothelium derived hyperpolarizing factor (EDHF) These can be vasoconstrictive factors such as thromboxane (TXA2) endothelin-1 (ET-1). 5. VASODILATORS ROLE NITRIC OXIDE maintenance of basal vasodilator tone of the blood vessels Reduce platelet and monocyte stickiness Reduce oxidation of LDL Reduce release of superoxide free radicals. PROSTACYCLIN It is synthesized from arachadonic acid It mainly involve PGI2 and PGE2 It relaxes the vascular smooth muscle It helps in the release of NO from endothelium ENDOTHELIUM DERIVED HYPERPOLARIZATION FACTOR Relax smooth muscle 6. In 1980,Furchgott and Zawadzki first described endothelium dependent relaxation of blood vessels by acetylcholine. Further studies in 1984 revealed that other factors such as bradykinin, histamine and 5-hydroxytryptamine releases endothelium derived relaxing factor (EDRF), which can modulate vessel tone. In 1988 Palmer et al could detect NO production both biologically and chemically by chemiluminescence. The following year in 1989 the enzyme responsible for NO production, NO synthase, was discovered and NO pathway was proposed. 7. A chemical compound with formula NO is a free radical gas. It is first identified as endothelial derived releasing factor(E D R F ). Nitric oxide differs from other neurotransmitter and hormones in a way that it is not regulated by storage, release , or targeted degradation. NO does not require receptor for its action when synthesized, it immediately utilized. Ca++ calmodulin complex is necessary for nitric oxide synthesis. 8. NOS I or n NOS Central and peripheral neuronal cells, brain, spinal cord, platelets. Ca++ dependent, used for neuronal communication Constitutive NOS II or I NOS Most nucleated cells, particularly macrophages Independent of intracellular Ca++ and its regulation depend upon de novo synthesis. Inducible in presence of inflammatory cytokines, bacterial liposaccharides. NOS III or e NOS Present on Vascular endothelial cells and neuronal cells Ca+2 dependent Vascular regulation 9. Nitric Oxide plays important role in body systems : Relaxation of vascular smooth muscle cells. Inhibits platelet aggregation and adhesion. Plays a role in long term memory. Vasodilation Reduces leukocyte adhesion. NO is a powerful stimulator of cell division,maturation and differentiation : plays role in wound healing and tissue repair. 10. Prostacyclin (or PGI2) is a prostaglandin member of the family of lipid molecules known as eicosanoids. It inhibits platelet activation and is also an effective vasodilator. In 1960s, ,Professor John Vane, began to explore the role of prostaglandins in anaphylaxis and respiratory diseases. Sir John discovered that aspirin and other oral anti-inflammatory drugs work by inhibiting the synthesis of prostaglandins. Sir John and a team had identified a lipid mediator they called PG-X, which inhibits platelet aggregation. 11. . The endothelium controls vascular tone not only by releasing NO and prostacyclin, but also by other pathways causing hyperpolarization of the underlying smooth muscle cells. This characteristic was at the origin of the term endothelium- derived hyperpolarizing factor (EDHF). However, this factor includes different mechanisms. Arachidonic acid metabolites derived from the COX, L0X and cytochrome P450 pathways, H2O2, CO, H2S and various peptides can be released by endothelial cells. These factors activate different families of K+ channels and causes hyperpolarization of the vascular smooth muscle cells contribute to the mechanisms leading to their relaxation. 12. Although the phenomenon of EDHF has been observed and reported in scientific literature, to date the chemical identity of the factor(s) has not been determined. 1) In some cases, members of a class of arachidonic acid derivatives, the epoxyeicosatrienoic acids (EETs), have been found to mediate the vasodilatation. These compounds are formed by epoxidation of any one of four double bonds of the arachidonic acid carbon backbone by cytochrome p450 epoxygenase enzymes. 13. 2) In some cases hydrogen peroxide has been suggested to function as an EDHF in some vascular beds; although this is not true in all cases,sometimes it also causes inhibiton of K+. 3) It has been suggested that EDHF is Potassium Ions (K+) as the activation of endothelial K+_Ca+ channels causes an efflux of K+ from endothelial cells towards the extracellular space. 4) Direct intercellular communication via gap junctions allows passive spread of agonist-induced endothelial hyperpolarization through the vessel wall. In some arteries, eicosanoids and K+ ions may themselves initiate a endothelial hyperpolarization. 14. The endothelium not only mediates relaxation but is a source of contracting factors. Endothelium-dependent contractions are elicited by physical and chemical stimuli (i.e.hypoxia, pressure, and stretch) and autacoids, local and circulating hormones. Endothelin-1 (ET-1) Thromboxane A2 (TXA2), prostaglandin H2 (PGH2) Angiotensin- II Reactive oxygen species(ROS); these are known to be potent EDCFs. 15. Prostaglandin H2 (PGH2) and Thromboxane A2 (TXA2) act primarily as vasoconstrictors. These substances, once produced diffuse to the underlying vascular smooth muscle cells and through the activation of specific receptors (TP receptors) induce contraction. 16. Endothelin-1 (ET-1) was first identified in 1988 as an endothelial cell-derived peptide with the greatest vasoconstrictor property. Factors known to promote endothelin-1 production include inflammatory mediators, hypoxia, and vascular shear stress. Endothelin production is inhibited by nitric oxide, nitric oxide donor drugs, and dilator prostanoids ET-1 is a peptide secreted mostly by vascular endothelial cells, the predominant isoform expressed in vasculature and the most potent vasoconstrictor currently known. 17. Endothelin has three isoforms: ET-1 ,ET-2 and ET-3. Endothelin-1 receptors : These are of 4 types ETA, ETB1, ETB3, ETc ETA mediates vasoconstriction ; found in the smooth muscle and binding of endothelin to ETA increases vasoconstriction. ETB1 mediates vasodilation : When endothelin binds to ETB1 receptors, this leads to the release of nitric oxide. ETB3 mediates vasoconstriction. ETC has yet no clearly defined function 18. 3 19. Antagonist- BQ-123 FK 139317 TTA 386 Ambrisentan Sitaxentan Atrasentan Zibotentan Non peptide selective antagonist- PD 151242 , L 754142 ,PD 156707, BMS 182874 SB 234551 Agonist- sarafotoxin (aal-ET1) BQ 3020 IRL 1620 Antagonist- BQ 788, RO468443 IRL2500, A192621 RES 7011 Antagonist- block both ETa & ETb TAK 044 Bosentan SB 209670 ETa receptor ETb receptor 20. Ambrisentan ,dose - 2.5-10mg/od used for pulmonary hypertension. Sitaxentan sodium (TBC-11251) is a medication for the treatment of pulmonary arterial hypertension (PAH). In 2010, Pfizer voluntarily removed sitaxentan from the market due to concerns about liver toxicity. Atrasentan is an experimental drug that is being studied for the treatment of various types of cancer.Atrasentan blocks endothelin induced cell proliferation. Zibotentan (ZD4054) is an anti-cancer drug & endothelin receptor antagonist. It failed a phase III clinical trial for prostate cancer but other trials are planned. 21. Angiotensin II, beyond being produced systemically, can be released by endothelial cell and induce local vascular constriction. Angiotensin II constricts arteries and veins by binding to AT1 receptors located on the smooth muscle, which are coupled to a Gq-protein and the IP3 signal transduction pathway. Angiotensin II causes arterial vasoconstriction leading to increase in B.P. 22. ROS can inhibit endothelium-dependent vasodilator pathways [i.e. the NO pathway and the EDHF pathways] and shift the balance in eicosanoids action from vasodilation and antithrombosis toward vasoconstriction and thrombosis. Superoxide anions reduce the bioavailibility of NO, inhibit its main target, soluble guanylyl cyclase, and inactivate calcium-activated potassium channels. Peroxynitrites inhibit guanylyl cyclase, superoxide dismutases and decrease the EDHF component. 23. Endothelial dysfunction is a systemic pathological state of the endothelium (the inner lining of blood vessels) and can be defined as an imbalance between vasodilating and vasoconstricting substances produced by the endothelium. Endothelial dysfunction can result from and/or contribute to several disease processes, as occurs in hypertension atherosclerosis diabetes septic shock Endothelial dysfunction is a major pathophysiological mechanism that leads towards coronary artery disease and other atherosclerotic diseases. 24. Genetic factors Environmental factors Smoking Aging Hypertension Obesity Diabetes mellitus High carbohydrate intake 25. Endothelial dysfunction Impaired vasomotor tone Prothrombotic state Pro- inflammatory state Proliferation in arterial wall Athero

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