Endothelial regulation of coronary vascular tone in vitro: contribution of endothelin receptor subtypes and nitric oxide

Abstract

The functional effects of endothelin-1, endothelin-3 and the ET B receptor agonist [Ala 1,3,11,15]endothelin-1 on pig coronary arteries were characterized in vitro by using the ET A receptor antagonist BQ-123 and the nitric oxide synthesis inhibitor N-nitro- L-arginine. Endothelin-1 (EC 50 value 8.8 nM), endothelin-3 (EC 50 11.6 nM) and [Ala 1,3,11,15]endothelin-1 (EC 50 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 μM) induced concentration-related rightward shift of the response to endothelin-1. The response to the highest concentration of endothelin-1 was reduced by 62% in the presence of 10 μM BQ-123. Application of BQ-123 to vessels precontracted with endothelin-1 caused relaxation by 53%. BQ-123 also inhibited the contractile effect off endothelin-3, whereas the contractile responses to [Ala 1,3,11,15]endothelin-1, serotonin or neuropeptide Y (Y 1 receptor-mediated) were unaffected. In the presence of N-nitro- L-arginine (50 μM) the responses to [Ala 1,3,11,15]endothelin-1 and low concentrations of endothelin-3 were significantly enhanced. 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. The contractile response to ET B stimulation is in part counteracted by release of nitric oxide.