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

Xue Zhao, Guanglong He, Yeong Renn Chen, Ramasamy P. Pandian, Periannan Kuppusamy, Jay L. Zweier

Research output: Contribution to journalArticle

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 (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.

Original languageEnglish (US)
Pages (from-to)2966-2972
Number of pages7
JournalCirculation
Volume111
Issue number22
DOIs
StatePublished - Jun 7 2005
Externally publishedYes

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Electron Transport
Oxygen Consumption
Nitric Oxide
Nitric Oxide Synthase
NADH Dehydrogenase
Reperfusion
NG-Nitroarginine Methyl Ester
Electron Transport Complex IV
Messenger RNA
Myocardium
Peroxynitrous Acid
Oximetry
Nitric Oxide Synthase Type III
Hyperemia
Electron Spin Resonance Spectroscopy
Drinking Water
Ligation
Tyrosine
Respiration
Ischemia

Keywords

  • Enzymes
  • Free radicals
  • Ischemia
  • Nitric oxide
  • Reperfusion

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Endothelium-derived nitric oxide regulates postischemic myocardial oxygenation and oxygen consumption by modulation of mitochondrial electron transport. / Zhao, Xue; He, Guanglong; Chen, Yeong Renn; Pandian, Ramasamy P.; Kuppusamy, Periannan; Zweier, Jay L.

In: Circulation, Vol. 111, No. 22, 07.06.2005, p. 2966-2972.

Research output: Contribution to journalArticle

Zhao, Xue ; He, Guanglong ; Chen, Yeong Renn ; Pandian, Ramasamy P. ; Kuppusamy, Periannan ; Zweier, Jay L. / Endothelium-derived nitric oxide regulates postischemic myocardial oxygenation and oxygen consumption by modulation of mitochondrial electron transport. In: Circulation. 2005 ; Vol. 111, No. 22. pp. 2966-2972.
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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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