Developmental effects of endothelin-1 on the pulmonary circulation in sheep.
Endothelin-1 (ET-1) is a polypeptide that has potent hemodynamic effects on the pulmonary circulation. To determine whether there are changes in these effects with increasing postnatal age, we investigated the effects of ET-1 (250 ng/kg) at rest and during pulmonary hypertension in eight lambs (< 1 wk old) and 11 juvenile sheep (6-12 mo old). At rest, ET-1 did not change pulmonary arterial pressure in lambs, but increased pulmonary arterial pressure by 64.0 +/- 37.5% (p < 0.05) in sheep. During pulmonary hypertension, ET-1 produced greater decreases in pulmonary arterial pressure in lambs than in sheep (26.6 +/- 3.4% versus 18.7 +/- 8.3%, p < 0.05). In juvenile sheep, the increase in resting pulmonary arterial pressure produced by ET-1 was inhibited by meclofenamic acid, an inhibitor of prostaglandin synthesis (40.3 +/- 9.9% versus 2.3 +/- 4.7%, p < 0.05); during pulmonary hypertension, the decrease in pulmonary arterial pressure produced by ET-1 was inhibited by N omega-nitro-L-arginine, an inhibitor of endothelium-derived nitric oxide synthesis (21.4 +/- 10.7% versus 8.0 +/- 3.6%, p < 0.05) and by glybenclamide, an ATP-dependent potassium-channel blocker (18.8 +/- 8.4% versus 4.0 +/- 4.4%, p < 0.05). The hemodynamic effects of ET-1 on the pulmonary circulation are dependent on postnatal age. Pulmonary vasoconstriction is mediated by prostaglandin production, and pulmonary vasodilation is mediated, in part, by release of endothelium-derived nitric oxide and activation of ATP-dependent potassium channels.
Wong
J
J
Department of Pediatrics, University of California, San Francisco 94143.
Vanderford
P A
PA
Fineman
J R
JR
Soifer
S J
SJ
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000375:Aging / Q000502:physiology*; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology*; D008469:Meclofenamic Acid / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D019335:Nitroarginine; D026902:Potassium Channel Blockers; D011450:Prostaglandin Endoperoxides, Synthetic; D011453:Prostaglandins / Q000096:biosynthesis; D011652:Pulmonary Circulation / Q000187:drug effects*; D012756:Sheep; D013928:Thromboxane A2 / Q000031:analogs & derivatives; D014662:Vasoconstrictor Agents
D016232:Endothelins; D026902:Potassium Channel Blockers; D011450:Prostaglandin Endoperoxides, Synthetic; D011453:Prostaglandins; D014662:Vasoconstrictor Agents; D019335:Nitroarginine; D009569:Nitric Oxide; D008469:Meclofenamic Acid; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D001120:Arginine; D005905:Glyburide