Enhanced vasoconstrictor responses in eNOS deficient mice.
Previous studies suggest that vasoconstriction is modulated by nitric oxide (NO). Contractions to ET-1 and/or thromboxane may be enhanced during chronic deficiency in expression or activity of NO synthase (NOS). Multiple isoforms of NOS are expressed within the vessel wall and purely pharmacological approaches cannot define the role of each. We tested the hypothesis that vasoconstriction to endothelin-1 (ET-1) and/or the thromboxane mimetic, U46619, is enhanced under conditions of chronic, selective deficiency in endothelial NOS (eNOS-/-) by examining responses in aorta from eNOS-/- mice compared to wild type (eNOS+/+). ET-1 produced dose-dependent contraction of aorta from eNOS+/+ mice that was increased twofold following acute inhibition of all NOS isoforms with N(G)-nitro-L-arginine (L-NNA). In eNOS-/- mice, contractions to ET-1 were increased twofold compared to eNOS+/+. L-NNA had no effect. Although contraction of the aorta to thromboxane mimetic U46619 was increased at lower concentrations, maximal contractions to U46619 were not increased following acute inhibition of NOS or in eNOS-/- mice. These studies provide direct evidence that vasoconstriction to ET-1 and thromboxane is augmented in the face of eNOS deficiency, demonstrating that eNOS normally inhibits vascular contractile responses.
Lamping
Kathryn
K
Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA. kathryn-lamping@uiowa.edu
Faraci
Frank
F
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D019332:Endothelin-1 / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D019335:Nitroarginine / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D019335:Nitroarginine; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019001:Nitric Oxide Synthase