Endothelin-1 produces pulmonary vasodilation in the intact newborn lamb.
The vascular endothelium mediates, in part, pulmonary vascular tone. Because endothelin-1 (ET-1), a paracrine hormone produced by vascular endothelial cells, has vasoactive properties, we investigated the hemodynamic effects of intrapulmonary injections of ET-1 in eight intact newborn lambs at rest and during pulmonary hypertension. At rest, ET-1 (50-1,000 ng/kg) did not change pulmonary arterial pressure. During pulmonary hypertension induced by the infusion of U46619 (a thromboxane A2 mimic), ET-1 (50-1,000 ng/kg) produced a selective dose-dependent decrease in pulmonary arterial pressure (5.8 +/- 3.9 to 32.9 +/- 6.9%; P < 0.05). Similarly, during pulmonary hypertension induced by alveolar hypoxia, ET-1 (50-500 ng/kg) produced a selective dose-dependent decrease 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-channel blocker, 25.2 +/- 5.0 vs. 9.6 +/- 5.3%; P < 0.05) but not by meclofenamic acid (an inhibitor of prostaglandin synthesis). ET-1 is a pulmonary vasodilator during pulmonary hypertension in the intact newborn lamb. The vasodilating properties are mediated, in part, by release of endothelium-derived nitric oxide, and by activation of ATP-gated potassium channels.
Wong
J
J
Department of Pediatrics, University of California San Francisco 94143-0106.
Vanderford
P A
PA
Fineman
J R
JR
Chang
R
R
Soifer
S J
SJ
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D000831:Animals, Newborn; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000209:etiology / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications; D007269:Injections, Intra-Arterial; D008469:Meclofenamic Acid / Q000494:pharmacology; D019335:Nitroarginine; D011450:Prostaglandin Endoperoxides, Synthetic; D011651:Pulmonary Artery; D011652:Pulmonary Circulation / Q000187:drug effects*; D012146:Rest; D012756:Sheep; D014664:Vasodilation
D016232:Endothelins; D011450:Prostaglandin Endoperoxides, Synthetic; D019335:Nitroarginine; D008469:Meclofenamic Acid; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D001120:Arginine; D005905:Glyburide