ENDOTHELIN-1 PRODUCES PULMONARY VASODILATION IN THE INTACT NEWBORN LAMB

The vascular endothelium mediates, in part, pulmonary vascular tone. B ecause endothelin-1 (ET-1), a paracrine hormone produced by vascular e ndothelial cells, has vasoactive properties, we investigated the hemod ynamic effects of intra-pulmonary injections of ET-1 in eight intact n ewborn lambs at rest and during pulmonary hypertension. At rest, ET-1 (50-1,000 ng/kg) did not change pulmonary arterial pressure. During pu lmonary hypertension induced by the infusion of U46619 (a thromboxane A2 mimic), ET-1 (50-1,000 ng/kg) produced a selective dose-dependent d ecrease in pulmonary arterial pressure (5.8 +/- 3.9 to 32.9 +/- 6.9%; P < 0.05). Similarly, during pulmonary hypertension induced by alveola r hypoxia, ET-1 (50-500 ng/kg) produced a selective dose-dependent dec rease in pulmonary arterial pressure (7.2 +/- 3.6 to 26.1 +/- 3.3%; P < 0.05). The decrease in pulmonary arterial pressure produced by ET-1 (250 ng/kg) was attenuated by N(omega)-nitro-L-arginine (an inhibitor of endothelium-derived nitric oxide synthesis, 23.7 +/- 3.4 vs. 12.5 /- 4.7%; P < 0.05) and by glibenclamide (an ATP-gated potassium-channe l blocker, 25.2 +/- 5.0 vs. 9.6 +/- 5.3%; P < 0.05) but not by meclofe namic acid (an inhibitor of prostaglandin synthesis). ET-1 is a pulmon ary vasodilator during pulmonary hypertension in the intact newborn la mb. The vasodilating properties are mediated, in part, by release of e ndothelium-derived nitric oxide, and by activation of ATP-gated potass ium channels.