Yixue Xue

Effects of dofetilide, a class III antiarrhythmic drug, on various ventricular arrhythmias in dogs.

Dofetilide, a new class III antiarrhythmic agent, was tested in various kinds of canine ventricular arrhythmias to compare its effects with those of other class III agents. Ventricular arrhythmia models used were induced by two-stage coronary ligation, digitalis, epinephrine, coronary ligation and reperfusion, and programmed electrical stimulation (PES). Dofetilide (100 micrograms/kg intravenously) did not suppress automaticity arrhythmias induced by two-stage coronary ligation and epinephrine or the coronary ligation and reperfusion arrhythmias, but suppressed the reentry arrhythmia induced by PES in dogs with old myocardial infarction (MI). This effect was associated with a prolongation of QT interval. Dofetilide also showed antiarrhythmic effect in some dogs with digitalis arrhythmia. Dofetilide increased QT interval and showed negative chronotropic effect like that of other class III drugs, but was different in antiarrhythmic profiles from those of other class III agents such as D-sotalol, E-4031, and MS-551 in that it did not prevent the occurrence of ventricular fibrillation (VF) immediately after coronary reperfusion and had some antiarrhythmic effects on digitalis arrhythmia.

MS‐551 and KCB‐328, two class III drugs aggravated adrenaline‐induced arrhythmias

We investigated the proarrhythmic effects of MS‐551 and KCB‐328, class III antiarrhythmic drugs using adrenaline‐induced arrhythmia models in halothane anaesthetized, closed‐chest dogs. In the control period, adrenaline, starting from a low dose of 0.25 to up to 1.0 μg/kg/50 s i.v., was injected to determine the arrhythmia inducing dose and the non‐inducing dose. After MS‐551 or KCB‐328 administration, the adrenaline injection was repeated and the interval between the injection and the occurrence of arrhythmia (latent interval), the changes in arrhythmic ratio (as calculated by dividing the number of ventricular premature contraction by the number of the total heart rate) and the severity of arrhythmia were observed. MS‐551 infusion, 1 mg/kg/30 min, decreased the heart rate (HR) by 16% (P<0.01) and prolonged the QTc interval by 20% (P<0.01). During the 30 min of MS‐551 infusion, arrhythmias occurred in three out of seven dogs (torsades de pointes (TdP) type VT in one dog). After these arrhythmias disappeared, MS‐551 decreased the latent interval of the adrenaline arrhythmias produced by the inducing dose (30±2 s compared with 43±3 s of the control interval, P<0.05), increased the arrhythmic ratio (P<0.05) and induced arrhythmias by non‐inducing adrenaline doses (P<0.05). Effect of a new class III drug KCB‐328 infusion, 0.3 mg/kg/30 min, was compared witih MS‐551 using the same model. KCB‐328 decreased the HR by 21% (P<0.01) and prolonged the QTc interval by 25% (P<0.01). During the 30 min of infusion, arrhythmias occurred in five out of seven dogs (TdP in two dogs). KCB‐328 also decreased the latent interval of the adrenaline arrhythmias produced by the inducing doses (31±3 s compared with 49±7 s of the control period, P<0.05), but did not significantly alter the arrhythmic ratio. Adrenaline induced TdP only after MS‐551 or KCB‐328 was administered, i.e. after MS‐551, 1 mg/kg/30 min, 3/7 versus 0/7 in the control; KCB, 0.3 mg/kg/30 min, 3/7 versus 0/7 in the control. To examine the direct arrhythmogenic effect of MS‐551 and whether an adrenergic mechanism plays some role on this arrhythmogenesis, a bolus injection of MS‐551, 3 mg/kg, was injected either without pre‐treatment or after pre‐treatment with propranolol 0.3 mg/kg. MS‐551 induced arrhythmias in five out of seven dogs (TdP in one dog). Also in the propranolol pre‐treated dogs, MS‐551 induced arrhythmias in five out of seven dogs (TdP in 1 dog). In conclusion, these observations indicate that MS‐551 and KCB‐328 induced arrhythmias and intensified proarrhythmic effects of adrenaline, MS‐551 being stronger than KCB‐328 at the same QTc prolonging doses. The direct arrhythmogenic effect of MS‐551 was not influenced by β‐blocker treatment.

Antiarrhythmic effects of a novel class III drug, KCB-328, on canine ventricular arrhythmia models

KCB-328 is a newly synthesized class III drug. To determine whether this drug has antiarrhythmic or proarrhythmic effects, we used canine ventricular arrhythmia models induced by coronary ligation and reperfusion, programmed electrical stimulation (PES), two-stage coronary ligation, digitalis, or epinephrine. KCB-328, in an intravenous infusion of 0.5 mg/kg/30 min, prolonged the QTc interval only 11%, but had antiarrhythmic effects on the reentry arrhythmias induced by PES (12 of 12 dogs with old myocardial infarction; p < 0.05). KCB-328, in an infusion of 1 mg/kg/h, suppressed the occurrence of fatal ventricular fibrillation (VF) induced by coronary ligation and reperfusion under either halothane anesthesia (p < 0.05) or pentobarbital anesthesia (p < 0.05). Under the halothane anesthesia, KCB-328 alone showed proarrhythmic effects [i.e., induction of ventricular premature contractions (VPCs)], but it did not induce a more severe effect such as torsades de pointes-type ventricular tachycardia (VT). In addition, KCB-328 had weak antiarrhythmic effects on the automaticity arrhythmias induced by 24-h coronary ligation but was effective neither on 48-h coronary ligation arrhythmias nor on the digitalis- and epinephrine-induced arrhythmias. Our results indicate that KCB-328 has powerful antiarrhythmic effects with fewer proarrhythmic potencies.

Effects of zatebradine on ouabain-, two-stage coronary ligation- and epinephrine-induced ventricular tachyarrhythmias

To determine whether a hyperpolarization-activated current (If) participates in ventricular tachyarrhythmias, we investigated the effects of zatebradine, an I(f) inhibitor, on the ventricular tachyarrhythmias induced by ouabain, two-stage coronary ligation and epinephrine infusion in the dog heart. We determined atrial rate, ectopic ventricular rate, total heart rate and arrhythmic ratio (the number of ectopic ventricular beats divided by total heart beats). Zatebradine (0.15, 0.5 and 1.5 mg/kg, i.v.) dose dependently decreased the arrhythmic ratio, ectopic ventricular rate and atrial rate of the ouabain-induced ventricular tachyarrhythmias in pentobarbital-anesthetized dogs. The inhibition by zatebradine of the ventricular arrhythmias needed larger doses than the inhibition of the atrial rate. Zatebradine weakly depressed the ectopic ventricular rate but not the arrhythmic ratio of the ventricular arrhythmias induced by two-stage coronary ligation 24 h after the ligation in conscious dogs. Although neither the ectopic ventricular rate nor the arrhythmic ratio of the epinephrine-induced ventricular arrhythmias was affected by zatebradine, after treatment with zatebradine, the arrhythmias elicited by epinephrine developed more slowly. Together with the previously reported spectra of the effects of the antiarrhythmic agents in three ventricular tachyarrhythmia models, our results suggest that zatebradine may improve automaticity-related ventricular tachyarrhythmias due to I(f) inhibition or to other undetermined mechanisms in the heart.

Effects of azimilide, a KV(r) and KV(s) blocker, on canine ventricular arrhythmia models.

Using canine coronary artery ligation/reperfusion and adrenaline arrhythmia models, we determined the effects of azimilide, a class III antiarrhythmic agent, E-1-[[(5-(4-chlorophenyl)-2-furanyl) methylene]-amino]-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidi nedione dihydrochloride. The coronary ligation/reperfusion arrhythmia experiments were divided into two groups, one using low heart rate halothane-anesthetized and the other using high heart rate pentobarbital-anesthetized dogs. Azimilide (6 mg kg(-1) + 0.1 mg kg(-1) min(-1) i.v.) prolonged the corrected QT interval (QTc), decreased the heart rate and suppressed the premature ventricular complexes during ligation (35 +/- 17 beats/30 min as compared with 909 +/- 246 in the control group), and also suppressed ventricular fibrillation induced by coronary ligation/reperfusion in the two groups (1/8 halothane-anesthetized dogs as compared with 7/8 dogs in the control group and 2/8 pentobarbital-anesthetized dogs as compared with 8/8 dogs in the control group). In adrenaline arrhythmia, azimilide hastened the onset of adrenaline arrhythmias and also aggravated the arrhythmias, showing proarrhythmic effects.

Antiarrhythmic effects of optical isomers of disopyramide on canine ventricular arrhythmias.

Antiarrhythmic effects of (+)-cibenzoline and (-)-cibenzoline were examined using two canine ventricular arrhythmia models. Digitalis arrhythmia, which is suppressed by Na channel blockers, was induced by intermittent intravenous (i.v.) injection of ouabain in pentobarbital-anesthetized dogs. Adrenaline arrhythmia, which is suppressed by Ca channel blockers, was induced by adrenaline infusion in halothane-anesthetized dogs. Ten and 5 mg/kg i.v. (+)-cibenzoline suppressed digitalis-and adrenaline-induced arrhythmias, respectively. The minimum effective plasma concentrations of (+)-cibenzoline for digitalis- and adrenaline-induced arrhythmias were 1.4 ± 0.4 and 2.0 ± 0.6 μg/ml, respectively (mean ± SD, n = 6). A lower dose of 1 mg/kg i.v. of (-)-cibenzoline suppressed the digitalis-induced arrhythmia, whereas 5 mg/kg i.v. was needed to suppress adrenaline-induced arrhythmias. The minimum effective plasma concentrations of (-)-cibenzoline for digitalis-and adrenaline-induced arrhythmia were 0.06 ± 0.04 and 0.7 ± 0.1 μg/ml, respectively (mean ± SD, n = 6). The stronger antiarrhythmic effect of (-)-cibenzoline indicates that (-)-isomer may have an effect nearly 5–20 times stronger in suppressing Na channels, but effects of both drugs on Ca channels may be almost equipotent.

Effects of an antiarrhythmic drug A-2545 on canine ventricular arrhythmia models; comparison with mexiletine and flecainide

We investigated effects of a new Na+ channel blocking antiarrhythmic drug, A-2545, N-3 (2,2,5,5-tetramethyl-3-pyrroline-3-carboxamido)-propyl-phthalimide-hydrochloride, on various canine ventricular automaticity arrhythmias induced by two-stage coronary ligation, digitalis and adrenaline, and compared them with those of mexiletine. A-2545 showed antiarrhythmic effects, significantly decreasing the arrhythmic ratio of 24-h and 48-h coronary ligation-, digitalis- and adrenaline-induced automaticity arrhythmias. The antiarrhythmic plasma concentrations (IC50) of A-2545, 2 mg kg–1 10 min–1, i.v., for 24-h and 48-h coronary ligation-, digitalis- and adrenaline-induced arrhythmias were 1.8, 1.3, 5.8 and 3.7 µg ml–1, respectively, and that calculated for oral A-2545 (25 mg kg–1) in 24-h coronary ligation-induced arrhythmia was 1.8 µg ml–1. A-2545 is specifically potent in suppressing coronary ligation-induced arrhythmias, i.e., decreasing the arrhythmic ratio nearly to zero by oral administration, and among the intravenously given experiments A-2545 was effective at lower concentrations than other arrhythmia models; A-2545, 2 mg kg–1 10 min–1, was equipotent to 5 mg kg–1 10 min–1 mexiletine in suppressing 24-h coronary ligation-induced arrhythmia, indicating that A-2545 is more potent than mexiletine. In order to determine whether A-2545 has arrhythmogenic effects, we used programmed electrical stimulation (PES)-induced reentry arrhythmias in dogs with old myocardial infarction and compared effects of A-2545 and flecainide. A-2545, 2 and 5 mg kg–1 10 min–1, significantly suppressed the PES-induced arrhythmias in all six dogs without aggravating them. These arrhythmias were not markedly suppressed by flecainide either with 1 or 3 mg kg–1 10 min–1; moreover even in one out of six dogs aggravation of arrhythmia was noted after 1 mg kg–1 10 min–1. In conclusion, A-2545 suppressed various canine ventricular arrhythmias, and the antiarrhythmic effect of A-2545 was more potent than that of mexiletine, and A-2545 did not show arrhythmogenic effects compared to flecainide.

DHA-ascorbic acidのラットおよびイヌの心室性不整脈モデルにおける抗不整脈作用

DHA-Ascorbic acid (DHA-As), a new derivative of docosahexaenoic acid (DHA) was tested for its possible antiarrhythmic effects on coronary artery ligation/reperfusion arrhythmias in rat hearts, and adrenaline-induced arrhythmias in canine hearts. DHA-As (3 mg/kg i.v.) did not change the total duration of VT, and tended to suppress the incidence of VT, VF and mortality of reperfusion in rat hearts. The heart rate, QT90 and systolic blood pressure did not change, and the diastolic blood pressure was decreased by DHA-As in the rat hearts. DHA-As significantly decreased the arrhythmic ratio only at two time points (14 and 15 min after injection), and also decreased the heart rate and mean blood pressure in canine hearts. In conclusion, DHA-As tended to suppress the reperfusion-induced arrhythmias in rat hearts. However, the change was not statistically significant. In addition, DHA-As has a weak suppressing effect on adrenaline-induced arrhythmia.