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.