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.


CONCLUSIONS
These results suggest that acetylcholine-induced 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.
Horibe
M
M
Center for Anesthesiology Research, Division of Anesthesiology and Critical Care Medicine, The Cleveland Clinic Foundation, OH 44195, USA.
Ogawa
K
K
Sohn
J T
JT
Murray
P A
PA
D000109:Acetylcholine / Q000494:pharmacology*; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D001685:Biological Factors / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D015742:Propofol / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D018686:Anesthetics, Intravenous; D001685:Biological Factors; D016861:Cyclooxygenase Inhibitors; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D000109:Acetylcholine; D015742:Propofol