Inhibitory effect of fentanyl on acetylcholine-induced relaxation in rat aorta

Background: Previous study has shown that fentanyl. attenuates acetylcholine-induced vasorelaxation. The goal of the current in vitro study was to Identify the muscarinic receptor subtype that is mainly involved in the fentanyl-induced attenuation of endothelium-dependent relaxation elicited by acetylcholine. Methods: The effects of fentanyl and muscarinic receptor antagonists on the acetylcholine concentration-response curve were assessed in aortic vascular smooth muscle ring preparations precontracted with phenylephrine. In the rings pretreated independently with pirenzepine, 4-diphenylacetoxyl-N-methylpiperidine methiodide, and naloxone, acetylcholine concentration-response curves were generated in the presence and absence of fentanyl. The effect of fentanyl on the concentration-response curve for calcium ionophore A23187 was assessed. Results: Fentanyl (0.297 x 10(-6), 0.785 x 10(-6) m) attenuated acetylcholine-induced vasorelaxation in ring preparations with or without 10(-6) m naloxone. Pirenzepine (10(-7) to 10(-6) m) and 4-diphenylacetoxyl-N-methylpiperidine methiodide (10(-9) to 10(-8) m) produced a parallel rightward shift in the acetylcholine concentration-response curve. The concentrations (- log M) of pirenzepine and 4-diphenylacetoxyl-N-methylpiperidine methiodide necessary to displace the concentration-response curve of an acetylcholine by twofold were estimated to be 6.886 +/- 0.070 and 9.256 +/- 0.087, respectively. Methoctramine, 10(-7) M, did not alter the acetylcholine concentration-response curve. Fentanyl, 0.785 X 10-6 m, attenuated acetylcholine-induced vasorelaxation in the rings pretreated with 10(-7) m pirenzepine but had no effect on vasorelaxation in the rings pretreated with 10(-8) m 4-diphenylacetoxyl-N-methylpiperidine methiodide. Fentanyl, 0.785 X 10-6 m, did not significantly alter calcium ionophore A23187-induced vasorelaxation. Conclusions. These results indicate that fentanyl attenuates acetylcholine-induced vasorelaxation via an inhibitory effect at a level proximal to nitric oxide synthase activation on the pathway involving endothelial M-3 muscarinic receptor activation in rat aorta.