Abstract
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. 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 80mmHg. All hearts were subjected to 33min of global ischemia and 60min of reperfusion. Before ischemia, hearts were perfused with different concentrations of levosimendan (0.03-1μM) for determination of a dose-effect curve. In a second set of experiments, 0.3μM levosimendan was administered in combination with the mBKCa-channel inhibitor paxilline (1μM). Infarct size was determined by TTC staining. In control, animal's infarct size was 58 ± 7%. Levosimendan at a concentration of 0.3μM reduced infarct size to 30 ± 7% (P < 0.05 vs. control). Higher concentrations with 1μM levosimendan did not confer stronger protection. Paxilline completely blocked levosimendan-induced cardioprotection while paxilline alone had no effect on infarct size. This study shows that activation of mBKCa-channels plays a pivotal role in levosimendan-induced preconditioning.
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