Zhao Xue, He Guanglong, Chen Yeong-Renn, Pandian Ramasamy P, Kuppusamy Periannan, Zweier Jay L
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, USA.
Circulation. 2005 Jun 7;111(22):2966-72. doi: 10.1161/CIRCULATIONAHA.104.527226.
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.
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.
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.
一氧化氮（NO）在缺血后心肌中的生成增加，且NO在体外可控制线粒体氧消耗。因此，我们研究了内皮型一氧化氮合酶（eNOS）衍生的NO在体内对缺血后心脏氧消耗调节中的作用。
小鼠接受30分钟冠状动脉结扎，随后再灌注60分钟。通过电子顺磁共振血氧测定法监测心肌氧分压（Po2）。在野生型、用N-硝基-L-精氨酸甲酯（L-NAME）处理（饮用水中浓度为1 mg/mL）的小鼠以及eNOS基因敲除（eNOS-/-）小鼠中，基线心肌Po2值（分别为8.6±0.7、10.0±1.2和10.1±1.2 mmHg）或缺血30分钟时测得的值（分别为1.4±0.6、2.3±0.9和3.1±1.4 mmHg）之间未观察到差异。再灌注后，心肌Po2显著升高（每组与基线相比P<0.001），但在L-NAME处理的小鼠和eNOS-/-小鼠中（分别为17.4±1.6和20.4±1.9 mmHg）远低于野生型小鼠（46.5±1.7 mmHg；P<0.001）。在野生型小鼠再灌注早期观察到心肌Po2的短暂峰值。再灌注早期未观察到反应性充血。内皮型NO降低了心率-血压乘积（P<0.05），上调了细胞色素c氧化酶（CcO）mRNA表达（P<0.01），而CcO活性无变化，并抑制了NADH脱氢酶（NADH-DH）活性（P<0.01），NADH-DH mRNA表达未改变。野生型小鼠心脏中过氧亚硝酸盐介导的酪氨酸硝化作用高于eNOS-/-或L-NAME处理的心脏。
eNOS衍生的NO通过基于NADH-DH和CcO酶活性及mRNA表达的改变来调节线粒体呼吸，从而显著抑制缺血后心脏的体内氧消耗。再灌注心肌中显著的心肌高氧合可能是触发缺血后重塑的关键因素。
