Role of endothelin-1 in hypertension

Endothelin-1 (ET-1) is overexpressed in the vascular wall in certain models of experimental hypertension: deoxycorticosterone acetate salt-treated rats, deoxycorticosterone acetate salt-treated spontaneously hypertensive rats (SHR), stroke-prone SHR, Dahl salt-sensitive rats, angiotensin II-infused rats, and 1-kidney 1 clip Goldblatt rats; it is not overexpressed in SHR, 2-kidney 1-clip hypertensive rats, or L-NAME-treated rats. In hypertensive rats without generalized vascular overexpression, however, expression of ET-1 was often enhanced in intramyocardial coronary arteries, suggesting a role of endothelin in myocardial ischemia in hypertension. In rats overexpressing ET-1, ETA/B and ETA-selective receptor antagonists lowered blood pressure and reduced vascular growth, particularly in small arteries, beyond what could be attributed to blood pressure lowering, suggesting a direct effect of ET-1 on growth. Hypertensive rats treated with endothelin antagonists are protected from stroke and renal injury. The ETA/B antagonist bosentan induced blood-pressure reductions in mildly hypertensive patients similar to those achieved with an angiotensin-converting enzyme inhibitor. Moderately to severely hypertensive patients presented with enhanced expression of prepro-ET-1 mRNA in the endothelium of subcutaneous resistance arteries, suggesting that these stages of hyper-tension may respond particularly well to endothelin antagonism Hypertensive patients with coronary artery disease have increased arterial expression of ET-1, and increased plasma levels of immunoreactive endothelin have been described in black patients. ET-1 plays an important role in atherosclerosis, fur which hypertension is an important risk factor. Thus. ET-1 may be involved in experimental and human hypertension. Endothelin antagonists may prove effective as disease-modifying agents if they are shown clinically, as they are experimentally, to offer target organ protection and reduce lone-term complications of hypertension. This remains to be demonstrated in humans.