© 2000 American Heart Association, Inc.
Integrative Physiology |
Downregulation of Endothelial Nitric Oxide Synthase in Rat Aorta After Prolonged Hypoxia In Vivo
From the Meakins-Christie Laboratories (M.T., K.G., M.N., D.E.), McGill University, Montréal, Québec; Université de Montréal (G.T.), Montréal, Québec; and St Michael’s Hospital (M.E.W.), University of Toronto, Toronto, Ontario, Canada.
Correspondence to M.E. Ward, St Michael’s Hospital, Room 6042 Bond Wing, 30 Bond St, Toronto, Ontario, M5B 1W8 Canada. E-mail wardm{at}smh.toronto.on.ca
Abstract—The goal of this study was to determine whether hypoxia alters expression of endothelial nitric oxide synthase (eNOS) in the systemic circulation. Rats breathed either air or 10% oxygen for 12 hours, 48 hours, or 7 days. Thoracic aortas were excised and either mounted in organ bath myographs or frozen in liquid nitrogen for later extraction of protein and RNA. eNOS protein (Western blotting) was decreased (20% of normoxic control) after 12 hours, 48 hours, and 7 days of hypoxia. eNOS mRNA (ribonuclease protection assay) was similarly reduced. Acetylcholine (10-4 mol/L) reversed phenylephrine (10-5 mol/L) preconstriction by 53.3±5.6% in aortic rings from normoxic rats and 26.1±4.8% in rings from rats exposed to hypoxia for 48 hours (P<0.05), with comparable impairment of relaxation by the calcium ionophore A23187 (10-5 mol/L). Responses to diethylamine nitric oxide and 8-bromo-cGMP were unaffected. Aortic cGMP levels after incubation with acetylcholine (10-6 mol/L) averaged 14.0±1.8 fmol/mg in rings from normoxic rats compared with 8.7±1.0 fmol/mg in rings from hypoxic rats (P<0.05). Similarly, nitrate concentration (by capillary electrophoresis) in the media in which the rings were incubated was reduced in the hypoxic group (5.6±0.23 µmol/L for hypoxic rats and 7.8±0.7 µmol/L for normoxic rats). Impaired endothelial NO release may handicap the vascular responses that defend vital organ function during hypoxia.
Key Words: endothelium • systemic vasculature • hypoxic vasodilation • autoregulation
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