INHIBITION OF ENDOGENOUS NITRIC-OXIDE SYNTHASE POTENTIATES NITROVASODILATORS IN EXPERIMENTAL PULMONARY-HYPERTENSION

Background: The role of endogenous nitric oxide (NO) in the regulation of pulmonary vascular tone is complex. Inhibition of endogenous NO sy nthase, potentially through upregulation of guanylyl cyclase, results in an increase in potency of nitrovasodilators in the systemic circula tion. This study considered whether inhibition of endogenous NO syntha se would increase the potency of nitrovasodilators, but not of cyclic adenosine monophosphate-dependent vasodilators, in the pulmonary vascu lature. Methods: We used the isolated buffer-perfused rabbit lung. Pre parations were randomized to receive either pretreatment with N-G-nitr o-L-arginine methyl ester (or L-NAME, an inhibitor of endogenous NO sy nthase) or no pretreatment. Stable pulmonary hypertension was then pro duced by infusing the thromboxane A(2) analog U46619. The dose-respons e characteristics of two nitrovasodilators, sodium nitroprusside and n itroglycerin, and two nonnitrovasodilators, prostaglandin E(1) and 5'- N-ethylcarboxamidoadenosine, were studied. Results: inhibition of endo genous NO synthase caused no significant changes in baseline pulmonary artery pressure but did significantly reduce the U46619 infusion rate required to produce pulmonary hypertension. Pretreatment with L-NAME (vs. no L-NAME) resulted in significantly lower values of the log medi an effective dose with sodium nitroprusside and nitroglycerin. In cont rast, pretreatment with L-NAME resulted in no changes in the dose-resp onse characteristics of the cyclic adenosine monophosphate-mediated, N O-independent vasodilators prostaglandin E(1) and 5'-N-ethylcarboxamid ondenosine. Conclusions: These data suggest that endogenous NO synthas e is not an important regulator of basal pulmonary tone in this model but is an important modulator of pulmonary vascular responses to vasoc onstriction and to nitrovasodilators. The pulmonary vasodilator effect s of nitrovasodilators, but not of nonnitrovasodilators, may depend on the level of activity of NO synthase.