ENDOTHELIAL REGULATION OF CORONARY VASCULAR TONE IN-VITRO - CONTRIBUTION OF ENDOTHELIN RECEPTOR SUBTYPES AND NITRIC-OXIDE

The functional effects of endothelin-1, endothelin-3 and the ET(B) rec eptor agonist [Ala1,3,11,15]endothelin-I on pig coronary arteries were characterized in vitro by using the ET(A) receptor antagonist BO-123 and the nitric oxide synthesis inhibitor N-nitro-L-arginine. Endotheli n-1 (EC50 value 8.8 nM), endothelin-3 (EC50 11.6 nM) and [Ala1,3,11,15 ]endothelin-I (EC50 42 nM) evoked concentration-dependent contractions with maximal responses that were 151 +/- 21, 85 +/- 12 and 11 +/- 2%, respectively, of contractions evoked by 127 mM K+. BQ-123 (0.1-10 muM ) induced concentration-related rightward shift of the response to end othelin-1. The response to the highest concentration of endothelin-1 w as reduced by 62% in the presence of 10 muM BQ-123. Application of BQ- 123 to vessels precontracted with endothelin-1 caused relaxation by 53 %. BQ-123 also inhibited the contractile effect of endothelin-3, where as the contractile responses to [Ala 1,3,11,15]endothelin-1, serotonin or neuropeptide Y (Y1 receptor-mediated) were unaffected. In the pres ence of N-nitro-L-arginine (50 muM) the responses to [Ala1,3,11,15]end othelin-1 and low concentrations of endothelin-3 were significantly en hanced. The present results show that endothelin-induced contractions of porcine coronary arteries are efficiently prevented and reversed by BQ-123 indicating that the responses are evoked by ET(A) receptors. A portion of the contraction seems to be mediated by ET(B) receptors. T he contractile response to ET(B) stimulation is in part counteracted b y release of nitric oxide.