Impact of Ca2+-Sensitive Potassium Channels in Levosimendan-Induced Postconditioning
- 39 Downloads
Small and big conductance Ca2+-sensitive potassium (KCa) channels are involved in cardioprotective measures aiming at reducing myocardial reperfusion injury. For levosimendan, infarct size–reducing effects were shown. Whether activation of these channels is involved in levosimendan-induced postconditioning is unknown. We hypothesized that levosimendan exerts a concentration-dependent cardioprotective effect and that both types of Ca2+-sensitive potassium channels are involved.
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. At the onset of reperfusion, hearts were perfused with various concentrations of levosimendan (0.03–1 μM) in order to determine a concentration-response relationship. To elucidate the involvement of KCa-channels for the observed cardioprotection, in the second set of experiments, 0.3 μM levosimendan was administered in combination with the subtype-specific KCa-channel inhibitors paxilline (1 μM, big KCa-channel) and NS8593 (0.1 μM, small KCa-channel) respectively. Infarct size was determined by tetrazolium chloride (TTC) staining.
Infarct size in controls was 60 ± 7% and 59 ± 6% respectively. Levosimendan at a concentration of 0.3 μM reduced infarct size to 30 ± 5% (P < 0.0001 vs. control). Higher concentrations of levosimendan did not induce a stronger effect. Paxilline but not NS8593 completely abolished levosimendan-induced cardioprotection while both substances alone had no effect on infarct size.
Cardioprotection by levosimendan-induced postconditioning shows a binary phenomenon, either ineffective or with maximal effect. The cardioprotective effect requires activation of big but not small KCa channels.
KeywordsPharmacology Ca2+ sensitizer Cardioprotection
In partial fulfillment of the requirements for an MD thesis (M. van de Snepscheut). We thank J. Reinle and L. Goetze for their practical support.
This study was supported by institutional and departmental sources.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Informed consent was obtained from all individual participants included in the study.
- 10.Jenkins DP, Strobaek D, Hougaard C, Jensen ML, Hummel R, Sorensen US, et al. Negative gating modulation by (R)-N-(benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine (NS8593) depends on residues in the inner pore vestibule: pharmacological evidence of deep-pore gating of K (Ca)2 channels. Mol Pharmacol. 2011;79(6):899–909.CrossRefGoogle Scholar
- 15.Levin R, Degrange M, Del Mazo C, Tanus E, Porcile R. Preoperative levosimendan decreases mortality and the development of low cardiac output in high-risk patients with severe left ventricular dysfunction undergoing coronary artery bypass grafting with cardiopulmonary bypass. Exp Clin Cardiol. 2012;17(3):125–30.PubMedPubMedCentralGoogle Scholar