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

Background: The mechanism by which propofol selectively attenuates the pulm onary vasodilator response to acetylcholine Is unknown. The goals of this s tudy 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 endoth elium-derived relaxing factors. Methods: Canine pulmonary arterial rings were suspended for isometric tensi on recording. The effects of propofol on the vasorelaxation responses to ac etylcholine, bradykinin, and the guanylyl cyclase activator, SIN-1, were as sessed in phenylephrine-precontracted rings. The contributions of NO, prost acyclin, and EDHFs to acetylcholine-induced vasorelaxation were assessed in control and propofol-treated rings by pretreating the rings with a NO synt hase inhibitor (L-NAME), a cyclooxygenase inhibitor (indomethacin), and a c ytochrome P450 inhibitor (clotrimazole or SKF 525A) alone and in combinatio n. Results: Propofol caused a dose-dependent rightward shift in the acetylchol ine: dose-response relation, whereas it had no effect on the pulmonary vaso relaxant responses to bradykinin or SIN-1. Cyclooxygenase inhibition only a ttenuated acetylcholine-induced relaxation at high concentrations of the ag onist. NO synthase inhibition and cytochrome P450 inhibition each attenuate d the response to acetylcholine, and combined inhibition abolished the resp onse. Propofol further attenuated acetylcholine-induced relaxation after NO synthase inhibition and after cytochrome P450 inhibition. Conclusion: These results suggest that acetylcholine-induce pulmonary vasor elaxation is mediated by two components: NO and a cytochrome P450 metabolit e likely to be an EDHF. Propofol selectively attenuates acetylcholine-induc ed relaxation by inhibiting both of these endothelium-derived mediators.