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

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Abstract
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 (P o 2 ) 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 P o 2 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 P o 2 increased markedly ( P −/− mice (17.4±1.6 and 20.4±1.9 mm Hg) than in wild-type mice (46.5±1.7 mm Hg; P 2 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 P P −/− or L-NAME–treated hearts. Conclusions— eNOS-derived NO markedly suppresses in vivo O 2 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.

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