Propofol attenuates acetylcholine-induced pulmonary vasorelaxation - Role of nitric oxide and endothelium-derived hyperpolarizing factors

Background: The mechanism by which propofol selectively attenuates the pulmonary vasodilator response to acetylcholine Is unknown. The goals of this study were to identify the contributions of endogenous endothelial mediators (nitric oxide [NO], prostacyclin, and endothelium-derived hyperpolarizing factors [EDHFs]) to acetylcholine-induced pulmonary vasorelaxation, and to delineate the extent to which propofol attenuates responses to these endothelium-derived relaxing factors. Methods: Canine pulmonary arterial rings were suspended for isometric tension recording. The effects of propofol on the vasorelaxation responses to acetylcholine, bradykinin, and the guanylyl cyclase activator, SIN-1, were assessed in phenylephrine-precontracted rings. The contributions of NO, prostacyclin, and EDHFs to acetylcholine-induced vasorelaxation were assessed in control and propofol-treated rings by pretreating the rings with a NO synthase inhibitor (L-NAME), a cyclooxygenase inhibitor (indomethacin), and a cytochrome P450 inhibitor (clotrimazole or SKF 525A) alone and in combination. Results: Propofol caused a dose-dependent rightward shift in the acetylcholine: dose-response relation, whereas it had no effect on the pulmonary vasorelaxant responses to bradykinin or SIN-1. Cyclooxygenase inhibition only attenuated acetylcholine-induced relaxation at high concentrations of the agonist. NO synthase inhibition and cytochrome P450 inhibition each attenuated the response to acetylcholine, and combined inhibition abolished the response. Propofol further attenuated acetylcholine-induced relaxation after NO synthase inhibition and after cytochrome P450 inhibition. Conclusion: These results suggest that acetylcholine-induce pulmonary vasorelaxation is mediated by two components: NO and a cytochrome P450 metabolite likely to be an EDHF. Propofol selectively attenuates acetylcholine-induced relaxation by inhibiting both of these endothelium-derived mediators.