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(23)Na and(31)P 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 Ca(2+)measurements revealed a marked reperfusion Ca(2+)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 Ca(2+)uptake and resultant
reperfusion injury.