| Healthy of mankind was threatened by arrhythmia. Severe ventricular arrhythmia is themain reason of sudden cardiac death (SCD), which often occurs in patients with coronary arterydisease and myocardial infarction. In the search for new antiarrhythmic drugs with a morefavourable benefit-risk ratio and anti-ischemic heart disease effects remains an important area ofinvestigation.N-n-butyl haloperidoliodide(F2)wasanovel compoundwhichwas screenedfromaseriesofquaternaryammoniumsaltderivativesofhaloperidolsynthesizedbyourdrugresearchlab. F2 has no extrapyramidal adverse reactions due to its high polarity not to pass theblood-brain barrier, and maintains the effects of coronaryexpansion as well as protective effectson ischemia-reperfusion induced myocardial injury. We have found previously that F2 canterminate the arrhythmia induced by barium chloride (BaCl2) in rats. This study was planned toinvestigate the antiarrhythmic efficacy of F2on ischemia-reperfusion induced arrhythmia, andevaluateitselectrophysiologicalandmechanicalactions.METHODS1. Using the Langendorff-perfused rat heart model, the ventricular arrhythmias wereinducedbyligatingthe left anteriordescendingcoronaryarteryfor 20minutes beforethe releaseof the ligature. Each concentration of F2 was administered 5 min prior to the induction ofregional ischemia. The effects of F2on arrhythmias during periods of ischemia and reperfusionand the effects on PR, QT, RR intervals were investigated. When rat hearts were paced (5 Hz)via the right atrium to prevent bradycardia, the antiarrhythmic effects and the effect on PRintervalof1μmol/LF2wereobserved.2. The Langendorff-perfused rat hearts were used in this study and the His bundleelectrogram (HBE) and the electrocardiogram (ECG) were continuously recorded duringconstant pressure perfusion. The effects of F2 on the conduction system intervals and therefractoryperiodswereobservedundertheexternalstimuli.3. Enzymatically dissociated single ventricular myocytes were used in the whole-cell patchclamp recording experiment. The effects of F2 on the action potential and ionic currents ofventricularmyocyteswereobserved.RESULTS1. F2 can concentration-dependently reduced ischemia- and reperfusion-induced ventricular arrhythmias, and widened PR, RR intervals. The same effects were also observed even in pacedrathearts.2. F2 prolonged principally the atrioventricular nodal conduction time (A-H interval) andthe atrioventricular node effective refractory period (AVNERP) in a concentration-dependentmanner. But F2 only prolonged the intra-atrial conduction time (S-A interval), His-Purkinjeconduction time (H-V interval), atrial effective refractory period and ventricular effectiverefractoryperiodinhighconcentration.3. F2 exerted little effect on the resting membrane potential of ventricular myocytes. F2reduced the action potential amplitude (APA) and decreased the maximal rate of depolarization(Vmax) only in higher concentrations (10 and 100μM). The action potential duration (APD) wasprolonged by 100μM F2,but was shortened a little in lower concentrations (0.1 and 1μM). F2concentration-dependently reduced Ito (IC50 = 38.7μM), ISS (IC50 = 36.6μM) and IK1. Theactivation and inactivation of Ito was not significantly affected by F2. F2 showed a weakuse-dependent blockade and little effects on the voltage-dependent activation and inactivation ofIto. 10μM F2 decreased INa by 28.0±3.9 % with a negative-shift of the voltage-dependentinactivation of INa. L-type Ca+current was reduced concentration-dependently by F2 (IC50 = 0.5μM) with a slowed rate of activation.The voltage dependence of ICa(L) activation was unaffectedby F2, however, the slope factor of steady-state inactivation curves was increased while thehalf-activation voltage was not significantly affected. The tonic block induced by F2 wasprincipal other than use-dependent blockade. F2 produced a slowed recovery of ICa (L) frominactivation.CONCLUSIONS1. F2 could reduce the rate of ischemia- and reperfusion-induced ventricular arrhythmiasdirectlyintheisolatedrathearts.2. F2 principally slowed the atrioventricular nodal conduction and prolongedatrioventricular nodal effective refractory period (AVNERP), which is maybe the antiarrhythmicmechanismofF2byinterruptingtheatrioventricularnodalreentry.3. F2 principally inhibited L-type Ca2+ channel of ventricular myocytes, which is the majormechanism of its suppressing effects on ischemia-reperfusion induced arrhythmias. F2 partlyblocked Itoand Na+ channels of ventricular myocytes maylikelycontributed to synergistic effectonventriculararrhythmias.4. F2could not only exert the effects of coronary expansion as well as protective effects onischemia-reperfusion induced myocardial injury, but also inhibit the ischemia- and reperfusion-inducedventriculararrhythmias. It will showtheadvantages of F2intreatmentofthecoronary artery disease complicated with serious ventricular arrhythmias, as well as ventriculartachycardia induced by thrombolysis therapy to coronary atherosclerotic heart disease andcoronaryarterybypassgrafting.
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