Experimental Study On Antiarrhythmic Mechanism Of H₂ Receptor Antagonist Cimetidine

Object To explore the possible proarrhythmic target of H2 receptor agonist dimaprit, in order to interpret the ionic mechanism underlying the antiarrhythmic effect of H2 receptor antagonist cimetidine.Methods1. Whole cell patch-clamp measurements. The effects of dimaprit on main ionic currents were observed in enzymatically isolated ventricular myocytes of rabbit.2. In-vivo arrhythmic model induced by ligating coronary artery and administrating adrenalin. A left thoracotomy was performed to expose the heart in anesthetized rabbit. Then the left ventricular branch of coronary artery was ligated and 0.01% adrenalin (0.5ml/kg) was injected simultaneously. The total keeping durations of arrhythmias within 10 minutes after the coronary artery ligation were recorded by ECG. 20 healthy adult rabbits were divided into 4 groups ( n = 5 of each) randomly and different drugs were administered into the marginal ear vein 2 minutes before the coronary artery ligation:①NS group (1ml physiological saline);②Dima group (1ml dimaprit solution at concentration of 12μg/kg);③Dima+CMT group (0.5ml dimaprit solution at concentration of 12μg/kg and 0.5ml cimetidine solution at concentration of 350μg/kg);④CMT group (1ml cimetidine solution at concentration of 2mg/kg).Results1. Dimaprit significantly inhibited INa in a concentration-dependent manner in rabbit myocytes. Oneμmol/L, 3μmol/L, 10μmol/L and 30μmol/L concentrations of dimaprit decreased INa by 26.9%, 39.41%, 48.17% and 52.3%, respectively (P<0.05).2. Cimetidine at 30μmol/L abolished the inhibition of INa induced by 1μmol/L dimaprit. Cimetidine at 1-30μmol/L had no effects on INa.3. Dimaprit at 1-30μmol/L have no significant influences on ICa-L, IK1, Ito, IK,IK,tail and INa/Ca.4. In vivo arrhythmic model via coronary artery ligation combined simultaneously an injection of adrenaline, dimaprit (12μg/kg) increased duration of arrhythmia obviously (P <0.05 vs NS group). In Dima+CMT group, the duration of arrhythmia shortened by 27.91% (P<0.05 vs Dima group),while there is no statistical difference compared with NS group. In CMT group, large dose cimetidine further decreased the duration of arrhythmia (P<0.05 vs NS group).Conclusion1. H2-receptor agonist dimaprit can specifically inhibit INa and has no significant effects on other main currents including ICa-L, IK1, Ito, Ik,IK,tail and INa/Ca in the ventricular myocytes of rabbit.2. H2 receptor agonist dimaprit displayed a proarrhythmic action, which maybe related to its inhibition to INa, accordingly, the anti-arrhythmic effect of H2 receptor antagonist cimetidine was possibly exerted through abolishing the inhibitory action on INa induced by dimaprit.3. The research indicated that dimaprit is a possible specific blocker of INa in rabbit ventricular myocytes, which can be used as a specific pharmacologic tool in experimental study.