Sevoflurane preconditioning limits intracellular/mitochondrial Ca2+ in ischemic newborn myocardium

Sevoflurane preconditioning (SPC) in adult hearts reduces myocardial ischemia/reperfusion (I/R) injury, an effect that may be mediated by reductions in intracellular Ca(2+) ([Ca(2+)](i)) and/or mitochondrial Ca(2+) ([Ca(2+)](m)) accumulation during ischemia and reperfusion. Because the physiology, pharmacology, and metabolic responses of the newborn differ from adults, we tested the hypothesis that SPC protects newborn myocardium by limiting [Ca(2+)](i) and [Ca(2+)](m) by a K(ATP) channel-dependent mechanism. Fluorescence spectrofluorometry and nuclear magnetic resonance spectroscopy were used to measure [Ca(2+)](i), [Ca(2+)](m), and adenosine triphosphate (ATP) in 4- to 7-day-old Langendorff-perfused rabbit hearts. Three experimental groups were used to study the effect of SPC on [Ca(2+)](m)/[Ca(2+)](i), ATP, as well as hemodynamics and ischemic injury. The role of mitochondrial K(ATP) channels was assessed by exposing the SPC hearts to the mitochondrial K(ATP) channel blocker 5-hydroxydecanoic acid. Our results show that SPC significantly decreased [Ca(2+)](i) and [Ca(2+)](m) during I/R, as well as decreased creatine kinase release during reperfusion and resulted in higher ATP. 5-Hydroxydecanoic acid abolished the effect of SPC on [Ca(2+)], hemodynamics, ATP, and creatine kinase release. In conclusion, decreased [Ca(2+)](i) and [Ca(2+)](m) observed with SPC is associated with greater ATP recovery as well as diminished cell injury. Mitochondrial K(ATP) channel blockade attenuates the SPC effect during I/R, suggesting that these channels are involved in the protective effects of SPC in the newborn.

The results of this study support the hypothesis that sevoflurane preconditioning protects newborn hearts from calcium overload and ischemic injury via a mechanism dependent on mitochondrial KATP channels.