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 se veral tissues, including the vascular endothelium (ET-1 exclusively) a nd smooth muscle cells. The production and release of endothelin is st imulated by many factors, hormonal and metabolic, and by growth factor s, hypoxia, and shear stress. Released endothelin binds to the endothe lin receptors ET(A) and ET(B), the ET(A) receptors on vascular smooth muscle cells mediating vasoconstriction, and the ET(B) receptors on th e endothelium linked to nitric oxide (NO) and prostacyclin release. Th e ET(A) receptors activate the PLC-IP3-DAG transduction pathway, which through an increase in cytosolic Ca2+ and protein kinase C (PKC) caus es vasoconstriction and stimulation of vascular smooth muscle cell gro wth and proliferation. In the pathogenesis of vascular hypertrophy in hypertension, there is a complex interaction between endothelin, angio tensin II; alpha(1)-adrenergic agonists, Ca2+, and other growth factor s. In animal models of hypertension, endothelin causes vascular hypert rophy, more pronounced in deoxycorticosterone acetate (DOCA)-salt hype rtension in the rat than in the spontaneously hypertensive rat. In hum ans 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 hum an hypertension is scanty, but the development of nonpeptide and recep tor subtype-selective antagonists will permit meaningful studies, incl uding clinical trials of a new class of antihypertensive agents.