ENDOTHELIN-1 MODULATES VASCULAR SMOOTH-MUSCLE STRUCTURE AND VASOMOTION - IMPLICATIONS IN CARDIOVASCULAR PATHOLOGY

Endothelin-1 modulates vascular smooth muscle tone by exerting potent vasoconstrictor actions through the ET(A) receptor subtype located on the membranes of vascular smooth muscle cells. This receptor subtype a lso mediates the growth-promoting actions of this peptide in vascular smooth muscle cells. The ET(A) receptor is distinct, however, from the endothelin receptor subtype located on the endothelium; the anatomica lly and functionally distinct ET(B) receptor mediates the release of t he endothelium-derived factor nitric oxide, a labile substance which n ot only produces potent vasodilation but also possesses anti-mitogenic activity. This report describes the interaction between these two vas oactive factors in the control of cardiovascular function. Under norma l conditions the endothelium serves to modulate the contractile and pr oliferative actions of endothelin-1. However, many cardiovascular diso rders (e.g., hypertension, atherosclerosis, vascular restenosis, subar achnoid hemorrhage, etc.) are associated with both abnormal endothelia l cell function, resulting in an inability to synthesize and/or releas e nitric oxide, and elevated circulating levels of endothelin-1. Since the resultant loss/inhibition of nitric oxide will augment both the c ontractile and proliferative actions of endothelin-1, this has the pot ential to promote vasoconstriction and smooth muscle hyperplasia/hyper trophy at the site of any such lesion. Since evidence is accumulating that both endothelin-1 and nitric oxide play pivotal roles in the cont rol of both vascular smooth muscle tone and growth, any imbalance betw een these two counter-regulatory systems is likely to have profound pa thological consequences within the cardiovascular system.