Isoflurane anesthesia attenuates endothelium-dependent pulmonary vasorelaxation by inhibiting the synergistic interaction between nitric oxide and prostacyclin.
BACKGROUND
Endothelium-derived nitric oxide causes vasodilation in part by increasing the dilator activity of other endothelium-derived mediators, including prostacyclin and a K+ATP channel-dependent hyperpolarizing factor. Although previous studies have proposed that isoflurane (ISO) depresses endothelium-dependent vasorelaxation by inhibiting endothelium-derived nitric oxide activity, the effects of ISO on the interactions among endothelium-derived dilators have not been characterized. The aim of this study was to determine the mechanisms underlying the inhibitory effect of ISO on endothelium-dependent relaxation in canine pulmonary arteries. Specifically, the goal was to assess the effects of ISO on the individual actions and on the synergistic interactions of these endothelium-derived mediators.


METHODS
Canine pulmonary arterial rings were suspended for isometric tension recording. The effects of 1 minimum alveolar concentration ISO (0.4 mM) on vasorelaxation responses to bradykinin, A23187, acetylcholine, cromakalim, and SIN-1 were assessed in phenylephrine-precontracted rings with and without pretreatment with a nitric oxide synthase inhibitor (N omega-nitro-L-arginine methyl ester; L-NAME), a cyclooxygenase inhibitor (indomethacin), or a K+ATP channel inhibitor (glybenclamide).


RESULTS
Isofluane attenuated pulmonary vasorelaxation induced by bradykinin, A23187, and cromakalim but had no effect on relaxation induced by acetylcholine or SIN-1. Neither the nitric oxide-mediated nor the prostacyclin-mediated components of relaxation induced by bradykinin and A23187 were altered by ISO. However, ISO abolished the K+ATP-mediated component of relaxation and the K+ATP-dependent synergistic interaction between nitric oxide and prostacyclin.


CONCLUSIONS
These results suggest that ISO selectively attenuates endothelium-dependent relaxation in canine pulmonary arteries. It exerts its inhibitory effect by interfering with a synergistic interaction between nitric oxide and prostacyclin, possibly via an effect on K+ATP channels.
Gambone
L M
LM
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
Murray
P A
PA
Flavahan
N A
NA
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D004285:Dogs; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000502:physiology*; D011464:Epoprostenol / Q000502:physiology*; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects*
D018685:Anesthetics, Inhalation; D015221:Potassium Channels; D010656:Phenylephrine; D009569:Nitric Oxide; D000001:Calcimycin; D007530:Isoflurane; D011464:Epoprostenol; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester