ENDOTHELIN AT PATHOPHYSIOLOGICAL CONCENTRATIONS MEDIATES CORONARY VASOCONSTRICTION VIA THE ENDOTHELIN-A RECEPTOR

Background Endothelin-1 (ET-1) is an endothelium-derived vasoconstrict or peptide. Controversy persists regarding the predominant ET receptor that mediates coronary vasoconstriction at pathophysiological concent rations. The aim of the present study was to test the hypothesis that ET mediates local coronary vasoconstriction via the ET-A receptor at l ow concentrations of exogenous ET-1 designed to mimic pathophysiologic al states compared with pharmacological concentrations. Methods and Re sults ET-1 (group 1, n=5) or sarafotoxin, a specific ET-B receptor ago nist (group 3, n=6) (each at 2 ng/kg per minute), was infused into the left circumflex coronary artery in the anesthetized dog. In group 2 d ogs (n=5), the same dose of ET-1 was infused with 4 mu g/kg per minute of the specific ET-A receptor antagonist FR-139317. In group 4 (n=5), the same dose of sarafotoxin was infused with 50 mu g/kg per minute o f the specific inhibitor of nitric oxide formation, N-G-monomethyl-L-a rginine (L-NMMA). No difference in hemodynamics, coronary blood How (C BF), coronary vascular resistance (CVR), or coronary artery diameter ( CAD) was observed at baseline between the groups. In group 1, intracor onary ET-1 significantly decreased CBF and CAD in association with an increase in CVR. The percentage decrease in CBF and CAD in the group t hat received ET-1 and the ET-A receptor antagonist (group 2) was signi ficantly less than that in the group that received ET-1 alone (group 1 ) (-12+/-3% versus -48+/-6% [P<.001] and -4.6+/-0.8 versus 1.0+/-0.3 [ P<.05], respectively). The administration of the ET-A receptor antagon ist (group 2) abolished the ET-mediated increase in CVR (7+/-5% versus 105+/-21%, P<.005). There was no significant effect on CBF, CVR, or C AD in the group receiving sarafotoxin alone (group 3). The administrat ion of L-NMMA and sarafotoxin (group 4) resulted in a significant perc entage decrease in CBF compared with the group that received sarafotox in alone (-28+/-7% versus -8+/-2% [P<.05]). Conclusions The present st udy demonstrates that low concentrations of exogenous ET-1, which may mimic pathophysiological concentrations, result in coronary vasoconstr iction mediated predominantly via the ET-A receptor because such vasoc onstriction is significantly attenuated by blockade with FR-139317. Th e ET-B receptor may have a dual vasoconstrictive and vasodilatory effe ct.