Objectives: Protons produced during ischemia may increase intracellular Na+ (Na+i) through Na+/H+ exchange, and may lead to Ca2+ overload through Na+/Ca2+ exchange to cause myocardial stunning. This study investigated whether an increase in the H+ buffering capacity of the perfusate or a reduction of H+ production by a brief hypoxic preperfusion before ischemia would reduce myocardial stunning. We also investigated whether the protective effect of these maneuvers depends on the free [Ca2+] of the perfusate. Methods: Isolated rat hearts were preperfused with oxygenated or hypoxic buffer (pH 7.4) containing 100 mM of either sucrose or HEPES for 10 min, followed by 15 min of total ischemia and 30 min of reperfusion. To investigate the dependence of the effects of HEPES or a brief hypoxic preperfusion, the free Ca2+ concentration in the buffer was changed from 1.25 mM to 2.5 mM in some hearts. Results: Oxygenated preperfusion with buffer containing HEPES and 1.25 or 2.5 mM Ca2+ improved the metabolic and functional recovery with a decrease in the accumulation of Na+i during ischemia and in 45Ca2+ uptake during reperfusion. A brief hypoxic preperfusion with 1.25 mM Ca2+ provided a similar protective effect whereas no protective effect was observed when the [Ca2+] was raised to 2.5 mM. Conclusions: An increase in the H+ buffering capacity or a brief hypoxic preperfusion reduced myocardial stunning with improved metabolic recovery, and reduced Ca2+ uptake. However, the effects of these interventions were affected differently by the free [Ca2+] of the perfusate, which suggests that they work, at least in part, through some different mechanism(s).
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