Endothelin as a regulator of cardiovascular function in health and disease

The endothelins are a family of endothelium-derived peptides that possess characteristically sustained vasoconstrictor properties. Endothelin-1 appears to be the predominant member of the family generated by vascular endothelial cells. In addition to its direct vascular effects, endothelin-1 has inotropic and mitogenic properties, influences homeostasis of salt and water, alters central and peripheral sympathetic activity and stimulates the renin-angiotensin-aldosterone system. Studies with endothelin receptor antagonists have indicated that endothelin-1 probably has complex opposing vascular effects mediated through vascular smooth muscle and endothelial ET(A) and ET(B)receptors. Endogenous generation of endothelin-1 appears to contribute to maintenance of basal vascular tone and blood pressure through activation of vascular smooth muscle ET(A)receptors. At the same time, endogenous endothelin-1 acts through endothelial ET(B) receptors to stimulate formation of nitric oxide tonically and to oppose vasoconstriction. In view of the multiple cardiovascular actions of endothelin-1, there has been much interest in its contribution to the pathophysiology of hypertension. Results of most studies suggest that generation of, or sensitivity to, endothelin-1 is no greater in hypertensive than it is in normotensive subjects. Nonetheless, the deleterious vascular effects of endogenous endothelin-1 may be accentuated by reduced generation of nitric oxide caused by hypertensive endothelial dysfunction. It also appears likely that endothelin participates in the adverse cardiac and vascular remodelling of hypertension, as well as in hypertensive renal damage. Irrespective of whether vascular endothelin activity is increased in hypertension, anti-endothelin agents do produce vasodilatation and lower blood pressure in hypertensive humans. There is more persuasive evidence for increased endothelin-1 activity in secondary forms of hypertension, including pre-eclampsia and renal hypertension. Endothelin-1 also appears to play an important role in pulmonary hypertension, both primary and secondary to diseases such as chronic heart failure. The hypotensive effects of endothelin converting enzyme inhibitors and endothelin receptor antagonists should be useful in the treatment of hypertension and related diseases. Development of such agents will increase knowledge of the physiological and pathological roles of the endothelins, and should generate drugs with novel benefits.