Hypoxic conditioning suppresses nitric oxide production upon myocardial reperfusion

Myoung Gwi Ryou, Jie Sun, Kevin N. Oguayo, Eugenia B. Manukhina, H. Fred Downey, Robert T. Mallet

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Abstract

Physiologically modulated concentrations of nitric oxide (NO) are generally beneficial, but excessive NO can injure myocardium by producing cytotoxic peroxynitrite. Recently we reported that intermittent, normobaric hypoxia conditioning (IHC) produced robust cardioprotection against infarction and lethal arrhythmias in a canine model of coronary occlusion-reperfusion. This study tested the hypothesis that IHC suppresses myocardial nitric oxide synthase (NOS) activity and thereby dampens explosive, excessive NO formation upon reperfusion of occluded coronary arteries. Mongrel dogs were conditioned by a 20 d program of IHC (FIO 2 9.5-10%; 5-10 min hypoxia/cycle, 5-8 cycles/d with intervening 4 min normoxia). One day later, ventricular myocardium was sampled for NOS activity assays, and immunoblot detection of the endothelial NOS isoform (eNOS). In separate experiments, myocardial nitrite (NO 2 -) release, an index of NO formation, was measured at baseline and during reperfusion following 1 h occlusion of the left anterior descending coronary artery (LAD). Values in IHC dogs were compared with respective values in non-conditioned, control dogs. IHC lowered left and right ventricular NOS activities by 60%, from 100-115 to 40-45 mU/g protein (P < 0.01), and decreased eNOS content by 30% (P < 0.05). IHC dampened cumulative NO 2 - release during the first 5 min reperfusion from 32 ± 7to14 ± 2 imol/g (P < 0.05), but did not alter hyperemic LAD flow (15 ± 2 vs. 13 ± 2 ml/g). Thus, IHC suppressed myocardial NOS activity, eNOS content, and excessive NO formation upon reperfusion without compromising reactive hyperemia. Attenuation of the NOS/NO system may contribute to IHC-induced protection of myocardium from ischemia-reperfusion injury.

Original languageEnglish
Pages (from-to)766-774
Number of pages9
JournalExperimental Biology and Medicine
Volume233
Issue number6
DOIs
Publication statusPublished - 1 Jun 2008

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Keywords

  • Cardioprotection
  • Dogs
  • Intermittent hypoxia
  • Myocardial ischemia
  • Nitric oxide synthase

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