Pharmacological preconditioning by levosimendan is mediated by inducible nitric oxide synthase and mitochondrial KATP channel activation in the in vivo anesthetized rabbit heart model.
BACKGROUND
Provocation of fatal cardiac arrhythmias has limited the use of inotropic agents as heart failure therapy. Levosimendan (LEV) is a new inodilator, whose mechanism of action includes calcium sensitization of contractile proteins and the opening of ATP-dependent potassium channels.


OBJECTIVE
The aim of this investigation was to test whether the administration of LEV has cardioprotective and antiarrhythmic effects against ischemia and reperfusion injury in a manner similar to ischemic preconditioning (IPC) in a well-standardized model of reperfusion arrhythmias in anesthetized adult male rabbits (n=122) subjected to 30 min occlusion of the left coronary artery followed by 120 min of reperfusion.


RESULTS
Pretreatment with either 1 cycle of IPC, LEV (0.1 micromol/kg, i.v.), or IPC+LEV prior to the period of coronary occlusion offers significant infarct size reduction (21.6+/-1.6%, 22.1+/-2.2%, and 21.4+/-1.4%, respectively vs 38.7+/-3.6% in saline control group; P<0.01) and antiarrhythmic effects. IPC, LEV and IPC+LEV treatment significantly attenuated the incidence of life-threatening arrhythmias like sustained VT (13%, 13% and 13%, respectively vs 100% in saline control group; P<0.005) and other arrhythmias (25%, 25% and 13%, respectively vs 100% in saline control group; P<0.005), and increased the number of surviving animals without arrhythmias. Pretreatment with 5-HD, N(omega)-nitro-L-arginine methyl ester (L-NAME, a nonspecific NOS inhibitor) and the specific iNOS inhibitor 1400 W [N-(-3-(aminomethyl)benzyl) acetamidine] abolished the beneficial effects of IPC, and LEV on reperfusion induced arrhythmias and cardioprotection suggesting that benefits have been achieved via both the selective activation of cardiomyocyte mitochondrial K(ATP) channels and NO. One cycle of IPC and LEV pretreatment significantly preserved the level of ATP in the 30 min ischemic heart and 120 min reperfused heart.


CONCLUSIONS
The present study demonstrates similarities between acute LEV treatment and IPC of the rabbit myocardium in terms of survival, cardioprotection, antiarrhythmic activity, and metabolic status.
Das
Biswadeep
B
Department of Pharmacology, Sikkim Manipal Institute of Medical Sciences, 5th Mile, Tadong, Gangtok, Sikkim, India. biswadeepdas@hotmail.com
Sarkar
Chayna
C
D000255:Adenosine Triphosphate / Q000378:metabolism; D000758:Anesthesia; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control; D001794:Blood Pressure / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006835:Hydrazones / Q000494:pharmacology*; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy; D009569:Nitric Oxide / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000502:physiology*; D015221:Potassium Channels / Q000502:physiology*; D011724:Pyridazines / Q000494:pharmacology*; D011817:Rabbits; D000077464:Simendan
D006835:Hydrazones; D015221:Potassium Channels; D011724:Pyridazines; C117780:mitochondrial K(ATP) channel; D009569:Nitric Oxide; D000077464:Simendan; D000255:Adenosine Triphosphate; D052247:Nitric Oxide Synthase Type II