Endothelin, vascular hypertrophy, and hypertension.
The endothelins (ET-1, 2, and 3) constitute a family of 21 amino-acid peptides with potent biological activities. They are synthesized in several tissues, including the vascular endothelium (ET-1 exclusively) and smooth muscle cells. The production and release of endothelin is stimulated by many factors, hormonal and metabolic, and by growth factors, hypoxia, and shear stress. Released endothelin binds to the endothelin receptors ETA and ETB, the ETA receptors on vascular smooth muscle cells mediating vasoconstriction, and the ETB receptors on the endothelium linked to nitric oxide (NO) and prostacyclin release. The ETA receptors activate the PLC-IP3-DAG transduction pathway, which through an increase in cytosolic Ca2+ and protein kinase C (PKC) causes vasoconstriction and stimulation of vascular smooth muscle cell growth and proliferation. In the pathogenesis of vascular hypertrophy in hypertension, there is a complex interaction between endothelin, angiotensin II, alpha-adrenergic agonists, Ca2+, and other growth factors. In animal models of hypertension, endothelin causes vascular hypertrophy, more pronounced in deoxycorticosterone acetate (DOCA)-salt hypertension in the rat than in the spontaneously hypertensive rate. In humans there is an increase in the plasma concentration of endothelin in severe atherosclerotic disease, but not consistently in hypertension. Evidence for the role of endothelin in the vascular hypertrophy of human hypertension is scanty, but the development of nonpeptide and receptor subtype-selective antagonists will permit meaningful studies, including clinical trials of a new class of antihypertensive agents.
Rosendorff
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Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA.
D000595:Amino Acid Sequence; D000818:Animals; D016232:Endothelins / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D006984:Hypertrophy / Q000473:pathology / Q000503:physiopathology; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000502:physiology; D017466:Receptors, Endothelin / Q000502:physiology*
D016232:Endothelins; D006133:Growth Substances; D017466:Receptors, Endothelin; D009569:Nitric Oxide