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 microM 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 Ca(2+)-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 microM L-NNA. The onset but not the peak of the response was blunted by meclofenamate. The response was reduced slightly by the ETA 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.
Oka
M
M
Department of Medicine, University of Colorado Health Sciences Center, Denver 80262.
Hasunuma
K
K
Webb
S A
SA
Stelzner
T J
TJ
Rodman
D M
DM
McMurtry
I F
IF
D000531:Altitude; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology*; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D019335:Nitroarginine; D011651:Pulmonary Artery / Q000187:drug effects; D011652:Pulmonary Circulation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*
D019335:Nitroarginine; D009569:Nitric Oxide; D001120:Arginine; D001920:Bradykinin