Endothelium-derived nitric oxide regulates postischemic myocardial oxygenation and oxygen consumption by modulation of mitochondrial electron transport

Article

关键词: CYTOCHROME-C-OXIDASE;    ISCHEMIA-REPERFUSION;    MESSENGER-RNA;    SYNTHASE;    HEART;    GENERATION;    INJURY;    CONTRIBUTES;    ACTIVATION;    INHIBITORS;   

DOI  :  10.1161/CIRCULATIONAHA.104.527226

来源: SCIE

【 摘 要 】

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 (Po-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 Po-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 Po-2 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 Po-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 < 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 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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