Influence of $\text{N}{}^{\mathrm{\omega }}\text{-}\text{nitro-}\text{L}\text{-arginine}$ methyl ester, LY83583, glybenclamide and L158809 on pulmonary circulation

Abstract

The effects of $\text{N}{}^{\mathrm{\omega }}\text{-}\text{nitro-}\text{L}\text{-arginine}$ methyl ester, an inhibitor of nitric oxide synthase; 6-anilino-5,8-quinolinedione (LY83583), an inhibitor of soluble guanylate cyclase; glybenclamide, a ATP-sensitive K⁺ channel blocking agent; and 5,7-dimethyl-2-ethyl-3-[[2′-(1H-tetrazol-5-yl)-[1,1′]-biphenyl-4-yl]methyl]-3H-imidazo[4,5-b]pyridine (L158809), an angiotensin II type I receptor antagonist, on the response to ventilatory hypoxia were investigated in the isolated blood-perfused rat lung. Under conditions of controlled pulmonary blood flow, and constant left atrial pressure, injections of glybenclamide into the pulmonary arterial perfusion circuit significantly increased baseline pulmonary arterial perfusion pressure, whereas administration of $\text{N}{}^{\mathrm{\omega }}\text{-}\text{nitro}\text{-}\text{L}\text{-}\text{arginine}$ methyl ester produced smaller increases in baseline tone. Ventilatory hypoxia (3% O₂-5% CO₂-92% N₂) significantly increased pulmonary arterial perfusion pressure and the response was reproducible with respect to time. Following administration of $\text{N}{}^{\mathrm{\omega }}\text{-}\text{nitro-}\text{L}\text{-arginine}$ methyl ester or LY83583, the response to hypoxia was significantly increased, whereas the response to hypoxia was not changed by glybenclamide or atropine. $\text{N}{}^{\mathrm{\omega }}\text{-}\text{Nitro-}\text{L}\text{-arginine}$ methyl ester also significantly enhanced pressor responses to angiotensin II, but had no effect on the pressor response to serotonin. When pulmonary vascular tone was increased with hypoxia, vasodilator responses to acetylcholine were inhibited by $\text{N}{}^{\mathrm{\omega }}\text{-}\text{nitro-}\text{L}\text{-arginine}$ methyl ester and vasodilator responses to levcromakalim were reduced by glybenclamide. In addition, L158809 did not alter the pressor response to hypoxia, whereas responses to angiotensin II were reduced in a selective manner. The present data demonstrate that glybenclamide, and to a smaller extent, $\text{N}{}^{\mathrm{\omega }}\text{-}\text{nitro-}\text{L}\text{-arginine}$ methyl ester, significantly increased baseline pulmonary arterial pressure, suggesting that activation of ATP-sensitive K⁺ channels, and to a smaller extent, tonic release of nitric oxide, modulate baseline tone in the pulmonary circulation of the rat. The results of the present study also show that $\text{N}{}^{\mathrm{\omega }}\text{-}\text{nitro-}\text{L}\text{-arginine}$ methyl ester and LY83583 enhance the pressor response to hypoxia, but that glybenclamide and L158809 have no effect on the response to hypoxia, suggesting that the response to hypoxia is modulated by nitric oxide production and the activation of soluble guanylate cyclase, but not by alterations in ATP-sensitive K⁺ channel activity or changes in angiotensin II levels in the isolated blood-perfused rat lung.