Daily reoxygenation decreases myocardial injury and improves post-ischemic recovery after chronic hypoxia

Objective: In contrast to the clinical evidence, experimental studies showed that chronic hypoxia (CH) confers a certain degree of protection against ischaemia-reperfusion damage. We studied the effects of daily reoxygenation during CH (CHReox) on hearts exposed to ischaemia-reperfusion. We also separated the intrinsic effects on the myocardium of CH and CHReox from those related to circulatory and nervous factors. Methods: Fifty-one Sprague-Dawley rats were maintained for 15 days under CH (10% O2) or CHReox (10% O2 + 1 h day-1 exposure to air). Normoxic (N, 21% O2) rats were the control. The animals were randomly assigned to one of the three following protocols: (1) protocol A: hearts (n = 7 per group) were subjected to 30-min occlusion of the left anterior descending (LAD) coronary artery followed by 3-h reperfusion, with measurement of the injury by tetrazolium staining; (2) protocol B: the end-diastolic pressure (EDP) and left ventricular developed pressure × heart rate (LVDP × HR) were measured in Langendorff-perfused isolated hearts (n = 5 per group) during 30-min global ischaemia and 45-min reperfusion; and (3) protocol C: hearts (n = 5 per group) were frozen for the determination of levels of endothelial nitric oxide synthase (eNOS) by Western blotting. Results: CHReox hearts displayed greater phosphorylation of the eNOS and enhanced plasma level of nitrates and nitrites in comparison to CH hearts (P < 0.0001, Bonferroni's post-test). The infarct size was greater in CH than in N hearts (P < 0.0001, Bonferroni's post-test) while it was reduced in CHReox in comparison to CH and N hearts (P < 0.0001). At the end of reperfusion, EDP was higher in CH than CHReox and N hearts (P = 0.01, Bonferroni's post-test) while LVDP × HR was higher in CHReox and N than in CH hearts (P = 0.03, Bonferroni's post-test). Conclusions: Exposure to CH results in impairment of myocardial tolerance to ischaemia-reperfusion, greater injury and reduced recovery of performance, in agreement with clinical evidence. Infarct size, diastolic contracture and myocardial performance have been reduced, respectively, by 63%, 64% and 151% with daily reoxygenation compared with chronic hypoxia by accelerating intrinsic adaptive changes.