Participation of endothelium-derived relaxing factor and role of cyclic GMP in inhibitory effects of endothelium on contractile responses elicited by alpha-adrenoceptor agonists in rat aorta.

The participation of NO production and the role of cyclic GMP in inhibitory function of endothelium were investigated in rat aortic rings exposed to alpha-adrenoceptor agonists. Both endothelium and 8-Br cyclic GMP (in endothelium-denuded rings) depressed more markedly not only maximal contractions but also equipotent contractions elicited by two partial agonists (indanidine and B-HT 920) than responses to the full agonist phenylephrine. The influence of endothelium on maximal responses to the three agonists was abolished by both the nitric oxide (NO)-synthase inhibitor NG-nitro-L-arginine methylester (L-NAME, 30 microM) and by the guanylate cyclase inhibitor methylene blue (methylene blue, 0.3 and 1 microM). Both endothelium and 8-Br cyclic GMP (in endothelium-denuded rings) increased the EC50 value of phenylephrine. This effect was more pronounced in the case of endothelium (10-fold), however, than in the case of 8-Br cyclic GMP (fourfold at 30 microM), and the rightward shift produced by endothelium remained significant (twofold) in the presence of L-NAME or methylene blue. In addition, the effect of 8-Br cyclic GMP on phenylephrine-induced contractions was considerably enhanced in the presence of endothelium or after partial alkylation of receptors by phenoxybenzamine in endothelium-denuded rings. These results indicate that the L-arginine-NO-cyclic GMP pathway accounts for most of the inhibitory influence of endothelium on alpha-adrenergic responses in aortic rings. They indicate differential effects of cyclic GMP depending on the agonist and show that 8-Br cyclic GMP does not impair the basal inhibitory effect of endothelium on aortic contraction to alpha-adrenergic agonists.