Hypoxic Conditioning Suppresses Nitric Oxide Production upon Myocardial Reperfusion

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 ± 7 to 14 ± 2 lmol/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.

Endothelin-Converting Enzyme Inhibition in the Rat Model of Acute Heart Failure: Heart Function and Neurohormonal Activation

“…This suggests that eNOS plays an important role in NO-induced acute hypotension (52). Furthermore, as was recently published by Ryou et al (57), a decrease in myocardial eNOS content by 30% was associated with a 60% reduction of enzyme activity and suppressed NO formation upon reperfusion of coronary arteries. Thus, it is plausible that reducing the increase of eNOS expression after ECE inhibition, as observed in our study, may be associated with a decrease of excessive NO generation during the development of myocardial ischemia in an employed model of coronary microembolization.…”

Intermittent hypoxia training protects cerebrovascular function in Alzheimer's disease

“…Since typical IHT protocols expose subjects to moderate hypoxia intermittently for less than 2 h/day over at most three weeks, the stimulus for pulmonary hypertension and right ventricular hypertrophy should be minimal. In addition, IHT stimulates vasodilatory NO production, [111][112][113] which should delay the pulmonary hypertensive effects of hypoxia. Thus, it was not surprising that rats treated for 21 consecutive days with IHT had no right ventricular hypertrophy.…”

Normobaric, intermittent hypoxia conditioning is cardio- and vasoprotective in rats

“…In previous canine studies, we found that the same 20-day IHC program reduced myocardial NO production during IR. 62 Whether the IHC-induced reduction in the endothelial dysfunction observed in the current study resulted from reduced NO overproduction and oxidative stress remains to be determined.…”

“…Myocardial IR may cause acute NO overproduction and oxidative stress, 58,62 which would damage both myocardium and the coronary vasculature. 63 Recently, we reported that myocardial infarction caused endothelial dysfunction in rat aorta, 64 and Zhao et al showed that myocardial IR produced endothelial dysfunction in mesentery vessels.…”