Brief Daily Episode of Normoxia Inhibits Cardioprotection Conferred by Chronic Continuous Hypoxia. Role of Oxidative Stress and BK Ca Channels
2013
The purpose of the present study was to assess the impact of brief daily reoxygenation during adaptation to chronic continuous
hypoxia (CCH) on protective cardiac phenotype. Adult male Wistar rats were kept at CCH (10% oxygen) for 5, 15 or 30 days; a subgroup
of animals was exposed to room air daily for a single 60-min period. While 5 days of CCH did not affect myocardial infarction induced
by 20-min coronary artery occlusion and 3-h reperfusion, 15 days reduced infarct size from 62% of the area at risk in normoxic
controls to 52%, and this protective effect was more pronounced after 30 days (41%). Susceptibility to ischemic ventricular arrhythmias
exhibited reciprocal development. CCH increased myocardial abundance of mitochondrial superoxide dismutase (MnSOD) without affecting
malondialdehyde concentration. Daily reoxygenation abolished both the infarct size-limiting effect of CCH and MnSOD upregulation,
and increased malondialdehyde (by 53%). Ventricular cardiomyocytes isolated from CCH rats exhibited better survival and
lower lactate dehydrogenase release caused by simulated ischemia/reperfusion than cells from normoxic and daily reoxygenated groups.
The cytoprotective effects of CCH were attenuated by the large-conductance Ca2+-activated K+ (BKCa) channel blocker paxilline, while
the opener NS1619 reduced cell injury in the normoxic group but not in the CCH group. Daily reoxygenation restored the NS1619-
induced protection, whereas paxilline had no effect, resembling the pattern observed in the normoxic group. The results suggest that CCH
is cardioprotective and brief daily reoxygenation blunts its salutary effects, possibly by a mechanism involving oxidative stress and attenuation
of the activation of mitochondrial BKCa channels.
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