TY - JOUR
T1 - Endothelium-derived nitric oxide regulates postischemic myocardial oxygenation and oxygen consumption by modulation of mitochondrial electron transport
AU - Zhao, Xue
AU - He, Guanglong
AU - Chen, Yeong Renn
AU - Pandian, Ramasamy P.
AU - Kuppusamy, Periannan
AU - Zweier, Jay L.
PY - 2005/6/7
Y1 - 2005/6/7
N2 - 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.
AB - 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.
KW - Enzymes
KW - Free radicals
KW - Ischemia
KW - Nitric oxide
KW - Reperfusion
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U2 - 10.1161/CIRCULATIONAHA.104.527226
DO - 10.1161/CIRCULATIONAHA.104.527226
M3 - Article
C2 - 15939832
AN - SCOPUS:20444494969
SN - 0009-7322
VL - 111
SP - 2966
EP - 2972
JO - Circulation
JF - Circulation
IS - 22
ER -