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.