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

We previously demonstrated that pinacidil does not affect Na _i⁺ 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 K_ATP channel-induced cardioprotection. Employing ²³Na and ³¹P nuclear magnetic resonance spectroscopy with perfused rat hearts, reperfusion Na_i⁺ 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 Na_i⁺ 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 Na_i⁺ 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 Na_i⁺ and cellular energy, respectively. Both pinacidil and RbCl infusion blunted ouabain's elevation of reperfusion Na _i⁺, 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 Ca ²⁺, and its beneficial effects were resistant to ouabain-induced early reperfusion Ca²⁺ increases. In conclusion, K_ATP channel-induced cardioprotection does not require moderation of Na _i⁺ accumulation, cellular energy depletion, or acidosis during ischemia. K_ATP channel-induced cardioprotection is largely independent of the accelerated reperfusion Na_i⁺ recovery it induces and does not require early reperfusion reductions of tissue Ca ²⁺. A larger role for early reperfusion cellular energy cannot be excluded.