The effect of K_ATP channel activation on myocardial cationic and energetic status during ischemia and reperfusion: Role in cardioprotection

The role of cation and cellular energy homeostasis in ATP-sensitive K⁺ (K_ATP) channel-induced cardioprotection is poorly understood. To evaluate this, rapidly interleaved ²³Na and ³¹P NMR spectra were acquired from isolated rat hearts exposed to direct K_ATP channel activation from nicorandil or pinacidil. Nicorandil attenuated ATP depletion and intracellular Na⁺ (Na⁺_i) accumulation, delayed the progression of acidosis during zero-flow ischemia and prevented ischemic contracture. The K_ATP channel inhibitor 5-hydroxydecanoate abolished these effects. Pinacidil did not alter Na⁺_i accumulation, ATP depletion or pH during ischemia under the conditions employed. Both agonists greatly improved the post-ischemic functional recovery. Both agonists also dramatically improved the rate and extent of the reperfusion recoveries of Na⁺_i, PCr and ATP. The Na⁺_i and PCr reperfusion recovery rates were tightly correlated, suggesting a causal relationship. Separate atomic absorption tissue Ca²⁺ measurements revealed a marked reperfusion Ca²⁺ uptake, which was reduced two-fold by pinacidil. In conclusion, these results clearly indicate that while K_ATP channel-induced metabolic alterations can vary. the functional cardioprotection resulting from this form of pharmacological preconditioning does not require attenuation of acidosis, cellular energy depletion, or Na⁺_i accumulation during ischemia. Rather than preservation of cationic/energetic status during ischemia, the cardioprotective processes may involve a preserved capability for its rapid restoration during reperfusion. The enhanced reperfusion Na⁺_i recovery may be enabled by the improved reperfusion cellular energy state. This accelerated Na⁺_i recovery could play an important cardioprotective role via a potential causal relationship with the reduction of reperfusion tissue Ca²⁺ uptake and resultant reperfusion injury.