Evidence that nitric oxide from the endothelium attenuates inherent tone in isolated pulmonary arteries from rats with hypoxic pulmonary hypertension.

1. The inherent contractile tone, and its modulation by the endothelium, have been studied in isolated pulmonary artery preparations taken from rats in which pulmonary hypertension was induced by exposure to a hypoxic environment (10% O2) for 14 days. Control rats were housed in room air. 2. All preparations in which the endothelium was left intact relaxed in response to acetylcholine (43 +/- 4% and 54 +/- 9%, reversal of the noradrenaline-induced contraction in control and hypoxic rats, respectively) indicating that the endothelium was functional in both groups of rats. 3. Exposure of the preparations to Ca(2+)-free physiological salt solution containing 2 mM EGTA for 30-40 min had no effect on preparations from control rats but caused relaxation in preparations from hypoxic rats. The relaxation (taken as a measure of the inherent tone in the preparations) was larger in preparations without endothelium (14.5 +/- 1.9 mN mm-2; n = 5) than in preparations with endothelium (9.1 +/- 1.2 mN mm-2; n = 5). 4. In preparations from hypoxic rats the magnitudes of the contractions to 80 mM K+ and to noradrenaline (0.1 microM) were less than in preparations from control rats. This may have been because the preparations from hypoxic rats were already partially contracted due to the inherent tone. 5.The nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 0.1-1 100 microM)had negligible effect on preparations from control rats or on endothelium-denuded preparations from hypoxic rats, but produced concentration-dependent contractions (maximum contraction 7.4 +/- 0.7 mN mm-2 (n = 4) with 100 micro M) in endothelium-intact preparations from hypoxic rats. This effect of L-NAME was prevented by L-arginine (1 mM) but not by D-arginine (1 mM).6. Contractions to L-NAME were also seen in endothelium-intact arteries from control rats if the preparations were first partially contracted by exposure to K+, endothelin, U46619 (thromboxane mimetic)or noradrenaline.7 It is concluded that isolated pulmonary artery rings from hypoxic rats, but not those from control rats, have substantial inherent tone. This inherent tone is normally attenuated by the generation of an endothelium-derived factor that is probably NO. A stimulus for the release of NO from the endothelium may be the contraction of the underlying smooth muscle, whether the contraction is inherent in the tissue, as in preparations from hypoxic rats, or is induced by a vasoconstrictor spasmogen.