Preconditioning by Levosimendan is Mediated by Activation of Mitochondrial Ca2+-Sensitive Potassium (mBKCa) Channels

Abstract

Purpose: Activation of mitochondrial large-conductance Ca2+-sensitive potassium (mBKCa)-channels is a crucial step for cardioprotection by preconditioning. Whether activation of these channels is involved in levosimendan-induced preconditioning is unknown. We investigated if cardioprotection by levosimendan requires activation of mBKCa-channels in the rat heart in vitro. Methods: In a prospective blinded experimental laboratory investigation, hearts of male Wistar rats were randomized and placed on a Langendorff system, perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. All hearts were subjected to 33 min of global ischemia and 60 min of reperfusion. Before ischemia, hearts were perfused with different concentrations of levosimendan (0.03–1 μM) for determination of a dose-effect curve. In a second set of experiments, 0.3 μM levosimendan was administered in combination with the mBKCa-channel inhibitor paxilline (1 μM). Infarct size was determined by TTC staining. Results: In control, animal’s infarct size was 58 ± 7%. Levosimendan at a concentration of 0.3 μM reduced infarct size to 30 ± 7% (P < 0.05 vs. control). Higher concentrations with 1 μM levosimendan did not confer stronger protection. Paxilline completely blocked levosimendan-induced cardioprotection while paxilline alone had no effect on infarct size. Conclusions: This study shows that activation of mBKCa-channels plays a pivotal role in levosimendan-induced preconditioning