Early reperfusion levels of Na+ and Ca2+ are strongly associated with postischemic functional recovery but are disassociated from KATP channel-induced cardioprotection

We previously demonstrated that pinacidil does not affect Nai+ accumulation, cellular energy depletion, or acidosis during myocardial ischemia, but dramatically improves the cationic/energetic status during reperfusion. We investigated the role of this latter effect in KATP channel-induced cardioprotection. Employing 23Na and 31P nuclear magnetic resonance spectroscopy with perfused rat hearts, reperfusion Nai+ was altered with brief infusions of ouabain and/or RbCl to transiently decrease or increase Na+/K+ ATPase activity. The increases and decreases in functional recovery (%LVDP-R) with pinacidil or ouabain, respectively, were largely unaltered by each other’s presence. Early reperfusion Nai+ and cellular energy were greatly altered by ouabain and indicated linear relationships with %LVDP-R. Pinacidil shifted these relationships to higher %LVDP-R. Increasing early reperfusion Nai+ decreased %LVDP-R but did not diminish pinacidil’s capacity to improve %LVDP-R. Approximately 75% and 45% of the pinacidil-induced improvements in %LVDP-R, could be disassociated from early reperfusion Nai+ and cellular energy, respectively. Both pinacidil and RbCl infusion blunted ouabain’s elevation of reperfusion Nai+, but RbCl did not improve %LVDP-R. Atomic absorption tissue Ca2+ measurements indicated that pinacidil reduced late reperfusion Ca2+ uptake, but did not reduce early reperfusion Ca2+, and its beneficial effects were resistant to ouabain-induced early reperfusion Ca2+ increases. In conclusion, KATP channel-induced cardioprotection does not require moderation of Nai+ accumulation, cellular energy depletion, or acidosis during ischemia. KATP channel-induced cardioprotection is largely independent of the accelerated reperfusion Nai+ recovery it induces and does not require early reperfusion reductions of tissue Ca2+. A larger role for early reperfusion cellular energy cannot be excluded.