[H-3] BOSENTAN BINDING TO HUMAN CORONARY-ARTERY - FUNCTIONAL CORRELATES

The binding characteristics and localization of bosentan, an orally ac tive endothelin-l (ET-1) antagonist, were studied on sections of human coronary artery by in vitro autoradiography. Competition studies were performed to determine the ability of bosentan to prevent [I-125]ET-1 binding to the coronary vasculature. The effects of bosentan on ET-l- induced contraction of the coronary artery were also studied in vitro. [H-3]Bosentan bound to the tunica media of the human coronary artery. Unlabeled bosentan prevented [I-125]ET-1 binding to this vessel in a concentration-dependent manner, and functional studies indicated that bosentan antagonizes ET-1-induced constriction. These data show that b osentan is able to reduce ET-1 binding to the human coronary artery an d ET-1 constrictor effects in vitro. Bosentan is an orally active ET-1 antagonist, and these results suggest that this compound might be use d to block the effects of locally released ET-1 in pathologic conditio ns, such as atherosclerosis, angina, and myocardial ischemia.