The role of cation and cellular energy homeostasis in ATP-sensitive K+ (KATP) 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 KATP 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 KATP 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 KATP 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.
- ATP-sensitive potassium channels
- Energy metabolism
- Intracellular pH
- Myocardial ischemia
ASJC Scopus subject areas
- Molecular Biology
- Cardiology and Cardiovascular Medicine