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Intermittent, normobaric hypoxia evokes adaptive modifications of nitric oxide synthase in canine myocardium

Background: 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, and that IHC dampens explosive, cytotoxic NO formation upon reperfusion of occluded coronary arteries. Hypothesis: IHC suppresses myocardial nitric oxide synthase (NOS) activity and contents of NOS isoforms. Methods: Mongrel dogs were conditioned by a 20 d IHC program (FIO2 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 endothelial and inducible NOS isoforms (eNOS, iNOS) and phosphorylated eNOS. Values in IHC dogs were compared with respective values in non‐conditioned, control dogs. Results: 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 and iNOS contents by 30 and 50%, respectively (P<0.05). IHC increased fractional phosphorylation of eNOS S1177 by < 2.5‐fold without altering T495 phosphorylation, a pattern that activates eNOS. Conclusions: IHC suppressed myocardial NOS activity, and eNOS and iNOS contents, but enhanced S1177 phosphorylation of the remaining eNOS. Thus, potentially cardioprotective attenuation of NOS activity may be due primarily to IHC suppression of iNOS. Support: NIH AT‐003598