Endothelin, endothelin receptors, and endothelin antagonists

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Abstract

Endothelin is a peptide with potent biologic effects in vascular and nonvascular cells. Its effects are mediated by two receptors, ETA and ETB, and possibly also by a third receptor, ETc. In vascular smooth muscle cells, endothelin causes profound contraction and also has proliferative effects, mainly through activation of ETA but also through ETB receptors. Activation of endothelin receptors on vascular smooth muscle explains the profound vasoconstriction observed in isolated blood vessels as well as with infusion of the peptide in vivo. Endothelial cells can express ETB receptors linked to the formation of nitric oxide or prostacyclin. Activation of these receptors leads to the transient vasodilation observed with intravascular infusion of the peptide. In vascular smooth muscle, activation of endothelin receptors stimulates phospholipase C, with concomitant formation of inositol triphosphate and diacylglycerol. These events lead to the release of intracellular calcium and initiation of contraction. In addition, endothelin can activate voltage-operated calcium channels via Gj proteins, thereby increasing influx of extracellular calcium. The latter phenomenon may explain the ability of calcium antagonists to inhibit endothelin-induced contractions. Normally, circulating endothelin levels, as well as production of the peptide in isolated blood vessels, are rather low due to the absence of stimuli and the presence of potent inhibitory mechanisms. Important stimulators of endothelin production are thrombin, angiotensin II, arginine vasopressin, and transforming growth factor-β, as well as certain cytokines and physicochemical factors such as hypoxia. Circulating endothelin levels are increased in any form of vascular disease, such as atherosclerosis, and in various forms of vasculitis, coronary artery disease, acute myocardial infarction, pulmonary hypertension, renal disease, and miscellaneous disorders. The role of endothelin in hypertension remains controversial. Endothelin antagonists block either ETA or ETB receptors. Various molecules are currently under preclinical and clinical investigation. These tools will delineate the exact physiological role of endothelin as well as its contribution to different disease states of the cardiovascular system

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