EDRF SUPPRESSES AN UNIDENTIFIED VASOCONSTRICTOR MECHANISM IN HYPERTENSIVE RAT LUNGS

To test whether endothelium-derived relaxing factor (EDRF) plays a role in regulating the hypertensive pulmonary vascular bed, we compared effects of the inhibitor of EDRF production, N(omega)-nitro-L-arginine (L-NNA), on resting vascular tone in lungs and conduit pulmonary arteries isolated from control and chronically hypoxic rats. In contrast to no effect on normoxic vascular tone in salt solution-perfused normotensive lungs, 100 muM L-NNA caused a marked, L-arginine-sensitive, precapillary vasoconstriction in unstimulated hypertensive lungs. Bioassay of hypertensive lung perfusate did not detect a circulating vasoconstrictor, and L-NNA vasoconstriction was not inhibited by blockers of cyclooxygenase, 5-lipoxygenase, platelet-activating factor receptors, alpha-adrenoceptors, and serotonin 5-HT2 receptors or by scavengers of superoxide anion and H2O2. Inhibitors of endothelin-1 (ET-1) production and vasoconstriction tended to blunt the response, but accumulation of perfusate ET-1 was not increased in hypertensive lungs. L-NNA vasoconstriction was blocked by Ca2+-free plus ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid perfusion but not by nifedipine. Quiescent, endothelium-intact hypertensive but not normotensive conduit pulmonary artery rings were markedly constricted by 200 muM L-NNA. The onset but not the peak of the response was blunted by meclofenamate. The response was reduced slightly by the ET(A) receptor antagonist, BQ 123. L-NNA had little effect on denuded hypertensive arteries, and treatment with dilators showed they had constricted spontaneously. Both the L-NNA and the spontaneous constrictions were readily inhibited by nifedipine. These results indicate that in rat hypertensive pulmonary arteries, the basal release of EDRF suppresses vasoconstrictor mechanisms which are not expressed in normotensive arteries.