Basal nitric oxide release differentially modulates vasodilations by pinacidil and levcromakalim in goat coronary...

In the current investigation, the role of basal nitric oxide (NO) in modulating the vasorelaxant responses to pinacidil and levcromakalim was examined in goat isolated coronary artery. Pinacidil (10(-8) 10(-4) M) elicited concentration-dependent relaxations of the coronary artery ring segments (with intact endothelium) constricted with 30 mM K+ saline solution. The EC50 of the vasodilator was 2.57 x 10(-6) M (95% CL, 1.9-3.46 x 10(-6) M). The removal of endothelium by mechanical rubbing caused a rightward shift in the concentration-response curve of pinacidil with a corresponding increase in EC50 value (1.90 x 10(-5) M; 95% CL, 1.12-3.23 x 10(-5) M). Similar to endothelium removal, treatment of endothelium-intact rings either with the NO synthesis inhibitor L-NAME (NG-nitro-L-arginine methyl ester; 3 x 10(-5) M) or the guanylate cyclase inhibitor, methylene blue (3 x 10(-6) M) resulted in a marked inhibition in the relaxant responses to pinacidil. Hence, the EC50 values of the potassium channel opener were significantly higher in tissues treated either with L-NAME (7.41 x 10(-6) M; 95% CL, 6.02-9.12 x 10(-6) M) or methylene blue (2.29 x 10(-5) M; 95% CL, 1.58-3.31 x 109-5) M) as compared to untreated controls. The ATP-sensitive potassium (KATP) channel blocker glibenclamide, which caused a significant rightward shift in the concentration-relaxation curve of pinacidil in control tissues, was found to be less potent in antagonising the relaxant responses of the KATP channel opener in endothelium-denuded rings and in rings with intact endothelium but treated with either L-NAME or methylene blue. In contrast to the observations made with pinacidil, the vasodilator responses to another KATP channel opener, levcromakalim, were potentiated in the absence of basal NO. Thus, the EC50 of levcromakalim was 1.33 x 10(-8) M (95% CL, 0.8-2.21 x 10(-8) M) in control tissues with intact endothelium, which was significantly higher than those obtained in endothelium-deprived rings (4.81 x 10(-9) M; 95% CL, 4.04-5.73 x 10(-9) M) or endothelium intact rings treated either with L-NAME (2.63 x 10(-9) M; 95% CL, 1.58-4.36 x 10(-9) M) or methylene blue (2.82 x 10(-9) M; 95% CL, 1.7-4.68 x 10(-9) M). The selective modulation by basal NO of the arterial relaxations elicited with the KATP channel openers was evident from the findings that papaverine-induced relaxations were not affected in the absence of basal NO. Taken together, the results of the present study suggest that basal NO differentially modulates the interaction of pinacidil and levcromakalim with the KATP channels in goat coronary artery through a cGMP-dependent pathway.