Due to the potent vasoconstrictor action of endothelin-1 and its synthesis throughout the vasculature and other tissues, most investigators believe that it is an active participant in the pathogenesis of hypertension. However, the autocrine and paracrine nature of the endothelin system has made its role difficult to define. In recent years, it has become apparent that endothelin-1 contributes to the regulation of renal salt and water excretion and that it is a major contributor to the hypertension associated with salt-dependency. Evidence suggests that endothelin-1 within the renal medulla is activated in conditions of salt loading and inhibits reabsorption of sodium in a nitric oxide-dependent manner. Blockade of endothelin A receptors lowers arterial pressure in animal models of salt- dependent hypertension. Furthermore, circulating levels of endothelin-1 are generally higher in African-Americans compared to white Americans as is the prevalence of salt-dependent hypertension. Therefore, it would appear that use of endothelin A-selective receptor antagonists should be targeted to those individuals at risk for salt-dependent hypertension. Blockade of endothelin B receptors would not be desirable because of their important role in eliminating a salt load. (C) 2000 Lippincott Williams and Wilkins.