Cardiac Slo2.1 Is Required for Volatile Anesthetic Stimulation of K+ Transport and Anesthetic Preconditioning

Background: Anesthetic preconditioning (APC) is a clinically important phenomenon in which volatile anesthetics (VAs) protect tissues such as heart against ischemic injury. The mechanism of APC is thought to involve K+ channels encoded by the Slo gene family, and the authors showed previously that slo-2 is required for APC in Caenorhabditis elegans. Thus, the authors hypothesized that a slo-2 ortholog may mediate APC-induced cardioprotection in mammals. Methods: A perfused heart model of ischemia-reperfusion injury, a fluorescent assay for K+ flux, and mice lacking Slo2.1 (Slick), Slo2.2 (Slack), or both (double knockouts, Slo2.x dKO) were used to test whether these channels are required for APC-induced cardioprotection and for cardiomyocyte or mitochondrial K+ transport. Results: In wild-type (WT) hearts, APC improved post-ischemia-reperfusion functional recovery (APC = 39.5 3.7% of preischemic rate x pressure product vs. 20.3 +/- 2.3% in controls, means +/- SEM, P = 0.00051, unpaired two-tailed t test, n = 8) and lowered infarct size (APC = 29.0 +/- 4.8% of LV area vs. 51.4 +/- 4.5% in controls, P = 0.0043, n = 8). Protection by APC was absent in hearts from Slo2.1(-/-) mice (% recovery APC = 14.6 +/- 2.6% vs. 16.5 +/- 2.1% in controls, P = 0.569, n = 8 to 9, infarct APC = 52.2 +/- 5.4% vs. 53.5 +/- 4.7% in controls, P = 0.865, n = 8 to 9). APC protection was also absent in Slo2.x dKO hearts (% recovery APC = 11.0 +/- 1.7% vs. 11.9 +/- 2.2% in controls, P = 0.725, n = 8, infarct APC = 51.6 +/- 4.4% vs. 50.5 +/- 3.9% in controls, P = 0.855, n = 8). Meanwhile, Slo2.2(-/-) hearts responded similar to WT (% recovery APC = 41.9 +/- 4.0% vs. 18.0 +/- 2.5% in controls, P = 0.00016, n = 8, infarct APC = 25.2 +/- 1.3% vs. 50.8 +/- 3.3% in controls, P < 0.000005, n = 8). Furthermore, VA-stimulated K+ transport seen in cardiomyocytes or mitochondria from WT or Slo2.2(-/-) mice was absent in Slo2.1(-/-) or Slo2.x dKO. Conclusion: Slick (Slo2.1) is required for both VA-stimulated K+ flux and for the APC-induced cardioprotection.