Cardioprotective Effect Of Nicorandil Against Myocardial Injury Following Cardiac Arrest In Swine

BackgroundDespite significant progress in resuscitation and improved restoration of spontaneous circulation(ROSC),the morbidity and mortality from cardiac arrest remains high.Post-ischemic myocardial dysfunction is the leading cause of the high mortality observed during the 72 h after resuscitation from cardiac arrest.Although this cardiovascular dysfunction is considered transient,there is an association of arterial hypotension and low cardiac output(CO)with poor outcome in post-cardiac arrest patients.Interventions targeting the improvement of postarrest myocardial dysfunction may produce clinical benefits.Nicorandil,an ATP-sensitive potassium(KATP)channel opener,is currently used as a standard drug for the treatment of coronary artery disease in the clinical setting.Evidence has demonstrated that it improves the recovery of the post-ischemic contractile dysfunction of the heart and reduces the infarct size after coronary artery occlusion and reperfusion in basic and clinical studies.However,there is limited data regarding the application of nicorandil in models of cardiac arrest and resuscitation,which is characterized by complex pathophysiological changes.OBJECTIVE:In the present study,we investigated the protective effects of nicorandil on myocardial injury in a swine model of cardiac arrest and resuscitation induced by 4-min untreatedVF.Methods:Ventricular fibrillation was induced electrically for 4 min in anesthetized domestic swine,follwed by cardiopulmonary resuscitation.Sixteen successfully resuscitated animals were randomized to saline control(n=8)or nicorandil(n=8)groups.Nicorandil(150 ?g/kg)was administered by central intravenous injection at onset of restoration of spontaneous circulation(ROSC),followed by 3 ?g/kg/min infusion until reperfusion end.Sham-operated animals received surgery only(n=4).Haemodynamic parameters were monitored continuously including heat rate,mean arterial blood pressure,caridac output,the maximum rate of left ventricular pressure increase(dp/dtmax)and the maximum rate of left ventricular pressure decline(-dp/dtmax).Blood samples were taken at baseline,5,30,180,and 360 min after ROSC for the measurement of cardiac-specific troponin-I and lactate.Left ventricular ejection fraction was assessed by echocardiography at baseline and 6h after ROSC.The animals were euthanized 6h after ROSC,and the cardiac tissue was removed for analysis.Myocardial tissue morphology was assessed by light microscopy,and ultrastructure assessed by transmission electron microscopy.Apoptosis of cardiomyocytes was evaluated by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling(TUNEL)staining.Adenosine triphosphate(ATP)was measured using a porcine adenosine triphosphate(ATP)ELISA kit.The expressions of caspase-3,Bax and Bcl-2 were detected using Western Blot.Results:Six hours after ROSC,nicorandil had significantly improved all hemodynamic variables(all P<0.05)except the maximum rate of left ventricular pressure decline and heart rate(P>0.05)compared with the control group.Control animals showed elevated cardiac troponin I and lactate levels compared with sham animals,which were significantly decreased following nicorandil treatment(P<0.05).In the saline control group,the adenosine triphosphate(ATP)content was largely reduced but subsequently rescued by nicorandil(P<0.05).Histopathologic injury was reduced with nicorandil treatment.Nicorandil reduced cardiomyocyte apoptosis as evidenced by reduced terminal deoxynucleotidyl transferase dUTP nick-end labeling(TUNEL)-positive cells,decreased Bax and caspase-3 expression,and increased Bcl-2 expression in the myocardium(all P<0.05).Conclusion:Nicorandil exhibited cardioprotective effects on myocardial injury following cardiac arrest via improvement in post-resuscitation myocardial dysfunction and energy metabolism,reduction in myocardial histopathologic injury,and antiapoptotic effects.