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Eur J Cardiothorac Surg. 2011 Apr;39(4):e59-67. doi: 10.1016/j.ejcts.2010.11.044. Epub 2011 Jan 17.

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

Author information

1
Department of Cardiac Surgery, Azienda Ospedaliera Universitaria Maggiore della Carità and University of East Piedmont A. Avogadro, corso Mazzini 18, 28100, Novara, Italy. philippe.caimmi@med.unipmn.it

Abstract

OBJECTIVE:

Levosimendan has been reported to exert cardioprotection. In this study, we have examined the cardiac effects of different doses of intracoronary levosimendan on ischemia/reperfusion injuries, and the involvement of K(ATP) 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 μg 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 with those obtained in a further 14 pigs where the highest dose levosimendan was infused after glibenclamide and l-nitro-arginine methyl ester (l-NAME).

RESULTS:

Intracoronary 1.5, 5 and 12 μg min(-1) levosimendan caused an increase of segmental shortening, dP/dt(max) 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/dt(max) 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 μg 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 K(ATP) channel opening and NO. These findings support interesting implications for cardioprotection in interventional cardiology and cardiac surgery.

PMID:
21247774
DOI:
10.1016/j.ejcts.2010.11.044
[Indexed for MEDLINE]

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