A study of the roles of endothelium-derived relaxing factor and endothelin in the regulation of coronary blood flow.In vivo experiments.

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We investigated the effect of cumulative doses of N^G-nitro-L-arginine methyl ester (LNAME), an inhibitor of nitric oxide (NO) synthesis, on coronary blood flow of anesthetized and conscious dogs. It was also examined whether the inhibition of EDNO synthesis enhances the effects of exogenous vasoconstrictor agents, neuropeptide Y (NPY), clonidine (CL) and ergonovine (EM), on the coronary vasculature. (1)Four doses of LNAME(10^<-5>M, 10^<-4>M, 10^<-3>M, and 10^<-2>M in the LCX blodd) were infused into the left circumflex artery (LCX). All dogs were pretreated with 8-phenyltheophylline and aspirin to inhibit endogenous adenosine and vasodilator prostaglandin, respectively. In 10 anesthetized dogs, systolic blood pressure was increased with 10^<-2>M of LNAME and heart rate was decreased with (〕SY.gtoreq.〔)10^<-3>M of LNAME.All doses of LNAME significantly decreased the LCX blood flow in a dose-dependent manner without affecting rate-pressure product. In 7 conscious dogs, LNAME showed similar effects to those seen in anesthetized dogs. Thus, there is a basal NO release from the endothelium in the coronary resistance vessels of anesthetized and conscious dogs. (2)Of the 15 anesthetized dogs, 9 were pretreated with intracoronary LNAME (300muM in the LCX blood) and the other 6 with normal saline. Three doses of NPY (4.3, 43, 430 ng/kg), 2 doses of CL (30 and 300 ng/kg) and one dose of EM (20 mug/kg)were infused into the LCX.NPY increased the coronary vascular resistance (CVR) in a dose-dependent manner in both groups and there was no significant difference in the dose-response relation between LNAME- and saline-treated groups. CL increased CVR in both groups and there was no difference between two groups. In contrast, EM increased CVR to a greater degree in LNAME-treated group than in saline-treated group. Thus, the inhibition of EDNO synthesis by LNAME did not result in the enhancement of the vasoconstrictor effects of NPY and CL, whi