Intracoronary levosimendan prevents myocardial ischemic damages and activates survival signaling through ATP-sensitive potassium channel and nitric oxide.

Objective:Levosimendanhasbeenreportedtoexertcardioprotection.In thisstudy, wehaveexaminedthecardiaceffectsofdifferentdosesof intracoronary levosimendan on ischemia/reperfusion injuries, and the involvement of KATP channels and nitric oxide (NO). Methods: The experiments were performed in a total of 56 anesthetized pigs. In 21 pigs, 1.5, 5 and 12 mg min � 1 levosimendan was infused over 15 min into the coronary artery at the onset of 1 h reperfusion following 2-h ischemia and the effects on cardiac function, infarcted area, and on apoptosis/ autophagy were examined. In addition, the activation of Akt and extracellular receptor kinase (ERK) was analyzed. The findings were compared withthoseobtainedinafurther14pigswherethehighestdoselevosimendanwasinfusedafterglibenclamideand L-nitro-argininemethylester(LNAME). Results: Intracoronary 1.5, 5 and 12 mg min � 1 levosimendan caused an increase of segmental shortening, dP/dtmax and cardiac output of 7.8%, 22.6%, and 31.6%; 7.6%, 16.9%, and 21.6%; 2.8%, 5.9%, and 6.2%, respectively, from values measured at the end of ischemia. The beneficial effects elicited by levosimendan were still evident at the end of reperfusion when the increase of segmental shortening, dP/dtmax and cardiac output caused by the three doses of levosimendan amounted to 3.7%, 13.3%, and 16.5%; 1.5%, 9.4%, and 11%; 1.4%, 2.7%, and 3.9%, respectively. When doses of 5 and 12 mg min � 1 levosimendan were used, a reduction of infarcted area to about 69% and 67% of area at risk was observed, and was significantly different from that of about 79% measured in control animals. In addition, after intracoronary levosimendan, the inhibition of apoptosis and activation of autophagy and a dose-related increase of the level of phosphorylation of ERK and Akt were observed. These responses were completely prevented by glibenclamide and significantly reduced by L-NAME. Conclusions:The results of this study show that intracoronary levosimendan reduces cell death induced by ischemia/reperfusion in a dose-dependent manner and activates survival signaling through KATP channel opening and NO. These findings support interesting implications for cardioprotection in interventional cardiology and cardiac surgery. # 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.