Endothelium-derived Relaxing Factor Is Not Responsible for Inhibition of Hypoxic Pulmonary Vasoconstriction by Inhalational Anesthetics

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Abstract
Inhalation anesthetics inhibit hypoxic pulmonary vasconstriction (HPV). One mechanism suggested for this action is stimulation of release of endothelium-derived relaxing factor. The present study has tested this hypothesis. These studies were performed in 66 ventilated and perfused isolated rat lungs. There were three study protocols. Study I examined the effect on HPV on the inhibition of soluble guanylate cyclase by methylene blue (MB). In the presence or absence of MB, the lungs constricted to hypoxia with pulmonary artery pressure increases of 8.6 .+-. 0.2 cmH2O and 11.5 .+-. 0.4 cmH2O, respectively, and halothane, enflurane, and isoflurane caused a reversible 50% decrease in the pulmonary pressor response, but acetylcholine (ACh) was vasodilatory in the saline group and vasoconstrictor in the MB group. In Study II a dose-response curve was established for the potent stimulator (Sin 1) of the enzyme guanylate cyclase. In the presence of MB the dose-response curve for Sin 1 was shifted to the right with an increase in the ED50 for Sin 1 from 44 .mu.M for the control to 85 .mu.M for the MB group. In Study III, baseline pulmonary artery pressure was increased with U46619, and the hypoxic pressor response was increased (28.9 .+-. 2.5 cmH2O), but halothane again caused a 50% decrease (11.0 .+-. 1.8 cmH2O) in the response to hypoxia. In summar, when soluble guanylate cyclase activity is inhibited by MB, the inhibition of hypoxic pulmonary vasoconstriction by halothane, isoflurane, or enflurane was unaltered, and release of endothelium-derived relaxing factor (EDRF) is therefore not an essential mechanism underlying this action.