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 fr om rats in which pulmonary hypertension was induced by exposure to a h ypoxic environment (10% O-2) for 14 days. Control rats were housed in room air. 2 All preparations in which the endothelium was left intact relaxed in response to acetylchoiine (43 +/- 4% and 54 +/- 9%, reversa l 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 Ca2+-free physiolog ical 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 endotheli um (14.5 +/- 1.9 mN mm(-2); n = 5) than in preparations with endotheli um (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 mu M) were less than in preparations from control rats. This may h ave been because the preparations from hypoxic rats were already parti ally contracted due to the inherent tone. 5 The nitric oxide (NO) synt hase inhibitor, N-G-nitro-L-arginine methyl ester (L-NAME, 0.1-100 mu M) had negligible effect on preparations from control rats or on endot helium-denuded preparations from hypoxic rats, but produced concentrat ion-dependent contractions (maximum contraction 7.4 +/- 0.7 mN mm(-2) (n = 4) With 100 mu M) in endothelium-intact preparations from hypoxic rats. This effect of L-NAME was prevented by L-arginine (1 mM) but no t by D-arginine (1 mM). 6 Contractions to L-NAME were also seen in end othelium-intact arteries from control rats if the preparations were fi rst partially contracted by exposure to K+, endothelin, U46619 (thromb oxane-mimetic) or noradrenaline. 7 It is concluded that isolated pulmo nary artery rings from hypoxic rats, but not those from control rats, have substantial inherent tone. This inherent tone is normally attenua ted by the generation of an endothelium-derived factor that is probabl y 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.