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(Circulation. 2005;111:2966-2972.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

Endothelium-Derived Nitric Oxide Regulates Postischemic Myocardial Oxygenation and Oxygen Consumption by Modulation of Mitochondrial Electron Transport

Xue Zhao, MD, PhD^*; Guanglong He, PhD^*; Yeong-Renn Chen, PhD; Ramasamy P. Pandian, PhD; Periannan Kuppusamy, PhD; Jay L. Zweier, MD

From the Center for Biomedical EPR Spectroscopy and Imaging, the Davis Heart and Lung Research Institute, and the Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio.

Correspondence to Guanglong He, PhD, 420 W 12th Ave, Columbus, OH 43210, or Jay L. Zweier, MD, 124A 473 W 12th Ave, Suite 110, Columbus, OH 43210. E-mail he-1{at}medctr.osu.edu or zweier-1@medctr.osu.edu

Received December 2, 2004; revision received January 14, 2005; accepted February 17, 2005.

Background— Nitric oxide (NO) production is increased in postischemic myocardium, and NO can control mitochondrial oxygen consumption in vitro. Therefore, we investigated the role of endothelial NO synthase (eNOS)–derived NO on in vivo regulation of oxygen consumption in the postischemic heart.

Methods and Results— Mice were subjected to 30 minutes of coronary ligation followed by 60 minutes of reperfusion. Myocardial oxygen tension (PO₂) was monitored by electron paramagnetic resonance oximetry. In wild-type, N-nitro-L-arginine methyl ester (L-NAME)–treated (with 1 mg/mL in drinking water), and eNOS knockout (eNOS^–/–) mice, no difference was observed among baseline myocardial PO₂ values (8.6±0.7, 10.0±1.2, and 10.1±1.2 mm Hg, respectively) or those measured at 30 minutes of ischemia (1.4±0.6, 2.3±0.9, and 3.1±1.4 mm Hg, respectively). After reperfusion, myocardial PO₂ increased markedly (P<0.001 versus baseline in each group) but was much lower in L-NAME–treated and eNOS^–/– mice (17.4±1.6 and 20.4±1.9 mm Hg) than in wild-type mice (46.5±1.7 mm Hg; P<0.001). A transient peak of myocardial PO₂ was observed at early reperfusion in wild-type mice. No reactive hyperemia was observed during early reperfusion. Endothelial NO decreased the rate-pressure product (P<0.05), upregulated cytochrome c oxidase (CcO) mRNA expression (P<0.01) with no change in CcO activity, and inhibited NADH dehydrogenase (NADH-DH) activity (P<0.01) without alteration of NADH-DH mRNA expression. Peroxynitrite-mediated tyrosine nitration was higher in hearts from wild-type mice than in eNOS^–/– or L-NAME–treated hearts.

Conclusions— eNOS-derived NO markedly suppresses in vivo O₂ consumption in the postischemic heart through modulation of mitochondrial respiration based on alterations in enzyme activity and mRNA expression of NADH-DH and CcO. The marked myocardial hyperoxygenation in reperfused myocardium may be a critical factor that triggers postischemic remodeling.

Key Words: nitric oxide • enzymes • free radicals • reperfusion • ischemia

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