Intracoronary levosimendan prevents myocardial ischemic damages and activates survival signaling through ATP-sensitive potassium channel and nitric oxide.
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.
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
Philippe Primo
PP
Caimmi
Claudio
C
Molinari
Francesca
F
Uberti
Ezio
E
Micalizzi
Guido
G
Valente
David A S G
DA
Mary
Giovanni
G
Vacca
Elena
E
Grossini
D000818:Animals; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D006835:Hydrazones / Q000008:administration & dosage*; D036502:Infusions, Intralesional; D054086:KATP Channels / Q000502:physiology*; D017202:Myocardial Ischemia / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009569:Nitric Oxide / Q000502:physiology*; D011724:Pyridazines / Q000008:administration & dosage*; D015398:Signal Transduction / Q000502:physiology; D000077464:Simendan; D016019:Survival Analysis; D013552:Swine
D002316:Cardiotonic Agents; D006835:Hydrazones; D054086:KATP Channels; D011724:Pyridazines; D009569:Nitric Oxide; D000077464:Simendan