Overall Summary and Evaluation

Bosentan is a competitive inhibitor of endothelin receptors. In vitro, bosentan potently inhibits binding of endothelin-1 to human ET-A and ET-B receptors. Potency on ET-A receptors was only slightly greater than potency on ET-B receptors. Functionally, bosentan inhibits contractile effects of endothelin-1 in rat aorta and human blood internal mammary artery and vein. Oral administration of bosentan to rats inhibits pressor effects of big ET-1, which is the precursor to ET-1. Although bosentan decreases systemic blood pressure in rat models of hypertension, it does not lower blood pressure in normotensive rats and dogs at doses that block pressor effects of exogenous endothelin. Administration of bosentan increases plasma levels of endothelin; the consequence of this increase is not clear.