Ranolazine Exert its Beneficial Effects in myocardial infarction like Ischemic preconditioning mediators by Increasing Myocardial Nitric oxide, Adenosine, Bradykinin and K+ATPase Levels

Abstract

Abstract Objectives: This study was to investigate cardioprotective effects of ranolazine and to explore possible secondary mechanisms beyond the cellular studies have demonstrated inhibition of late sodium channel(INaL) leads to reduction in calcium load during cardiac ischemia. We hypothesized that ranolazine-induce Nitric oxide, Adenosine, Bradykinin and K+ATPase like ischemic preconditioning. Methods: Ischemia-reperfusion injury was established using Langendroff’s technique. 20minute ischemia and 40minute reperfusion to coronary artery to isolated heart was model of myocardial infarction. There were following groups: Control(Ischeamia-Reperfusion), Ischemic preconditioning, ranolazine(100µmol/L), ranolazine+L-NAME(30µmol/L) and ranolazine+Aminoguanidine(30µmol/L), ranolazine+Theophylline(50µmol/L), ranolazine+Aminophylline(50µmol/L), ranolazine+Enalapiril(100µmol/L), ranolazine+Losartan(50µmol/L), ranolazine+5-hydroxydecanoate(30µmol/L), ranolazine+glimepiride(50µmol/L) in perfusate. Results: Ranolazine found cardioprotection(Infarct Size:5.334± 0.422 v/s control 65.667±0.558; LDH:101.500±1.147U/L v/s control 155.500±0.957U/L; CK-MB: 100.167±1.302U/L v/s control 198.500±1.803U/L) Ischemic Preconditioning found cardioprotection(Infarct Size:5.1667±0.478 v/s control 65.667±0.558; LDH:101.667±2.789U/L v/s control 155.500±0.958U/L; CK-MB: 97.167±1.721U/L v/s control 198.500±1.803U/L) Ranolazine+L-NAME(Infarct Size:64.167±0.872 v/s control ranolazine 5.334± 0.422; LDH: 154.667±1.256U/L v/s control ranolazine 101.500±1.147; CK-MB:200.167±1.537U/L v/s control ranolizine 100.167±1.302U/L) Ranolazine+Aminoguanidine(Infarct Size: 64.500±0.885 v/s control ranolazine 5.334± 0.422; LDH: 154.833±1.1377U/L v/s control ranolazine 101.500±1.147U/L; CK-MB:198.333±1.145U/L v/s control ranolizine 100.167±1.302U/L) Ranolazine+Theophylline (Infarct Size: 64.667±0.760 v/s control ranolazine 5.334± 0.422; LDH: 155.167±1.301U/L v/s control ranolazine 101.500±1.147; CK-MB:199.167±1.376U/L v/s control ranolizine 100.167±1.302U/L) Ranolazine+Aminophylline (Infarct Size: 65.167±0.601 v/s control ranolazine 5.334± 0.422; LDH: 155.333±0.615U/L v/s control ranolazine 101.500±1.147U/L; CK-MB: 199.500± 1.765U/L v/s control ranolizine 100.167±1.302U/L) Ranolazine+Enalapiril (Infarct Size: 64.667±0.615 v/s control ranolazine 5.334± 0.422; LDH: 154.667± 1.085U/L v/s control ranolazine 101.500±1.147; CK-MB: 201.8333±1.990U/L v/s control ranolizine 100.167±1.302U/L) Ranolazine+Losartan (Infarct Size: 63.667±1.282 v/s control ranolazine 5.334± 0.422; LDH: 155.167± 0.909U/L v/s control ranolazine 101.500±1.147U/L; CK-MB: 199.500±2.349U/L v/s control ranolizine 100.167±1.302U/L) Ranolazine+5-hydroxydecanoate (Infarct Size: 63.833±1.352 v/s control ranolazine 5.334± 0.422; LDH: 154.667±1.054U/L v/s control ranolazine 101.500±1.147; CK-MB: 201.833±1.815U/L v/s control ranolizine 100.167±1.302U/L) Ranolazine+Glimepiride (Infarct Size: 63.667±0.989 v/s control ranolazine 5.334± 0.422; LDH: 155.833±1.352U/L v/s control ranolazine 101.500±1.147U/L; CK-MB: 199.833±1.579U/L v/s control ranolizine 100.167±1.302U/L) Conclusions: As per confirmation Ranolazine and ischemic preconditioning have brought cardioprotection as reduced Infract Size, LDH & CK-MB. Wereas, treatment of L-NAME, Aminoguanidine, Theoplylline, Aminoplylline, Enalapiril, Losartan, 5-hydroxydecanoate & Glimepiride increased infract size, LDH & CK-MB. Hence it is proved that ranolazine involves Nitric oxide, Adenosine, Bradykinin and K+ATPase as secondary messenger in cardioprotection like ischemic preconditioning.