Nitric oxide exerts feedback inhibition on EDHF-induced coronary arteriolar dilation in vivo

We tested the hypothesis that nitric oxide (NO) inhibits endothelium-derive d hyperpolarizing factor (EDHF)-induced vasodilation via a negative feedbac k pathway in the coronary microcirculation. Coronary microvascular diameter s were measured using stroboscopic fluorescence microangiography. Bradykini n (BK)-induced dilation was mediated by EDHF, when NO and prostaglandin syn theses were inhibited, or by NO when EDHF and prostaglandin syntheses were blocked. Specifically, BK (20, 50, and 100 ng . kg(-1) . min(-1) ic) caused dose-dependent vasodilation similarly before and after administration of N -G-monomethyl-L-arginine (L-NMMA) (3 mu mol/min ic for 10 min) and indometh acin (Indo, 10 mg/kg iv). The residual dilation to BK with L-NMMA and Indo was completely abolished by suffusion of miconazole or an isosmotic buffer containing high KCl (60 mM), suggesting that this arteriolar vasodilation i s mediated by the cytochrome P-450 derivative EDHF. BK-induced dilation was reduced by 39% after inhibition of EDHF and prostaglandin synthesis, and d ilation was further inhibited by combined blockade with L-NMMA to a 74% red uction in the response. This suggests an involvement for NO in the vasodila tion. After dilation to BK was assessed with L-NMMA and Indo, sodium nitrop russide (SNP, 1-3 mg . kg(-1) . min(-1) ic), an exogenous NO donor, was adm inistered in a dose to increase the diameter to the original control value. Dilation to BK was virtually abolished when administered concomitantly wit h SNP during L-NMMA and Indo (P < 0.01 vs. before SNP), suggesting that NO inhibits EDHF-induced dilation. SNP did not affect adenosine- or papaverine -induced arteriolar dilation in the presence of L-NMMA and Indo, demonstrat ing that the effect of SNP was not nonspecific. In conclusion, our data are the first in vivo evidence to suggest that NO inhibits the production and/ or action of EDHF in the coronary microcirculation.