Endothelin in hypertension: a role for receptor antagonists?

The rapid development of endothelin-receptor antagonists has made the endothelin pathway a new therapeutic target in the treatment of cardiovascular diseases, only ten years after the report of its discovery. While the first clinical trials will help to position this new family of compounds in our therapeutic armament for the treatment of essential or secondary forms of hypertension, several preclinical chronic studies already provide a picture of what we can expect from these drugs. Endothelin-receptor antagonists are not effective in all experimental models of hypertension, but those that respond present hypertrophy of small arteries, secondary to a local overexpression of the peptide. Although angiotensin II seems to represent a stimulus for endothelin overexpression in some models, other, as yet undetermined, stimuli are likely in others. Besides their narrow spectrum of antihypertensive activity, endothelin-receptor antagonists may also protect from complications of hypertension by improving end-organ function in a pressure-independent manner. This seems to be the case for the structure and reactivity of resistance arteries, as well as for renal damage. However, it is not clear at this point if cardiac structure and function are improved beyond the benefits produced by blood pressure reduction. The first results in essential hypertensive subjects suggest some degree of efficacy of endothelin-receptor antagonists. Other clinical trials will help to determine if secondary forms of the disease benefit equally or more from this new class of drugs, and if end-organ damage can be reduced beyond blood-pressure reduction.