Experimental approaches to evaluate endothelin-A receptor antagonists

A large body of evidence suggests a substantial role of the endothelin (ET) system in the pathophysiology of a variety of disease states, mainly of the cardiovascular system. Recently bosentan, an ET receptor antagonist, has received approval by the Food and Drug Administration (FDA) for use in pulmonary artery hypertension. The ET system may also be involved in cerebrovascular disorders such as stroke and, most notably, development of cerebral vasospasm following subarachnoid hemorrhage. The pathophysiological mechanisms contributing to the development of a cerebral vasospasm after subarachnoid hemorrhage may be taken as a paradigm to explore mechanisms leading to secondary ischemic brain damages in a variety of insults such as stroke and trauma. The present review provides the evidence to evaluate ET receptor antagonists for potential prophylactic and therapeutic use in patients suffering from subarachnoid hemorrhage. The rationale to develop selective ETA receptor antagonists is given with respect to basic and applied studies. This may be useful to better define the desired profile of action of a given compound, and it may also help to design appropriate preclinical and clinical trials, most desirably in close cooperation with pharmaceutical companies and neurosurgical departments.