Age-related Attenuation of Isoflurane Preconditioning in Human Atrial Cardiomyocytes: Roles for Mitochondrial Respiration and Sarcolemmal Adenosine Triphosphate–sensitive Potassium Channel Activity

Background:Clinical trials suggest that anesthetic-induced preconditioning (APC) produces cardioprotection in humans, but the mechanisms of APC and significance of aging for APC in humans are not well understood. Here, the impact of age on the role of two major effectors of APC, mitochondria and sarcolemmal adenosine triphosphate–sensitive potassium (sarcKATP) channels, in preconditioning of the human atrial myocardium were investigated. Methods:Right atrial appendages were obtained from adult patients undergoing cardiac surgery and assigned to mid-aged (MA) and old-aged (OA) groups. APC was induced by isoflurane in isolated myocardium and isolated cardiomyocytes. Mitochondrial oxygen consumption measurements, myocyte survival testing, and patch clamp techniques were used to investigate mitochondrial respiratory function and sarcKATP channel activity. Results:After in vitro APC with isoflurane, the respiratory function of isolated mitochondria was better preserved after hypoxia–reoxygenation stress in MA than in OA. In isolated intact myocytes, APC significantly decreased oxidative stress–induced cell death in MA but not in OA, and isoflurane protection from cell death was attenuated by the sarcKATP channel inhibitor HMR-1098. Further, the properties of single sarcKATP channels were similar in MA and OA, and isoflurane sensitivity of pinacidil-activated whole cell KATP current was no different between MA and OA myocytes. Conclusion:Anesthetic-induced preconditioning with isoflurane decreases stress-induced cell death and preserves mitochondrial respiratory function to a greater degree in MA than in OA myocytes; however, sarcKATP channel activity is not differentially affected by isoflurane. Therefore, effectiveness of APC in humans may decrease with advancing age partly because of altered mitochondrial function of myocardial cells.

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