Endothelin Inhibition as a Biologic Target for Treating Hypertension

Endothelin, a 21-amino-acid peptide, binds to a specific receptor on vascular smooth muscle cells, thereby inducing vasoconstriction. Although plasma levels are not consistently elevated in hypertension, there is evidence that endothelin has an important role in its pathogenesis. Administration of endothelin antagonists has lowered blood pressure and reduced end-organ damage in some animal models. It has also reduced the cross-sectional area of neointima due both to hypertension and vascular injury. Coadministration of endothelin and angiotensin II to rats produced a synergistic hypertensive effect. Similarly, coadministration of an endothelin antagonist with an angiotensin converting enzyme inhibitor resulted in a synergistic lowering of blood pressure. Several preliminary clinical studies have been done. The endothelin antagonist bosentan has decreased vascular resistance and blood pressure and increased cardiac index in patients with congestive heart failure. Plasma endothelin levels are elevated in the acute phase of myocardial infarction and in chronic heart failure. The magnitude of this increase, measured 3 days after patients experienced myocardial infarction, had a significance at least equal to known risk factors in predicting 1 year survival. Thus, there are reasons to believe that endothelin antagonists may become a useful tool in the management of various cardiovascular disorders.