Termination of ouabain-induced ventricular tachycardia by flunarizine in conscious dogs

The ability of flunarizine to terminate ouabain-induced ventricular tachycardia was investigated in conscious dogs. These arrhythmias result from triggered activity based on delayed afterdepolarizations. Sustained ventricular tachycardia was induced by ouabain (48 +/- 6 micrograms/kg) and pacing in 13 animals with surgically induced complete atrioventricular block. Flunarizine was administered i.v. when the arrhythmia had persisted for at least 20 min. Flunarizine induced an increase of the R-R interval from 300 +/- 30 to 410 +/- 50 ms (P less than or equal to 0.001) in all dogs. Flunarizine (2 mg/kg) terminated ventricular tachycardia with long R-R intervals (330 +/- 20 ms) in seven dogs. An additional dose of flunarizine (1 mg/kg) resulted in termination of the faster tachycardias (280 +/- 15 ms). The arrhythmias were not induced again by pacing for 27 +/- 18 min. Reinitiated tachycardias could be suppressed again by flunarizine. In conclusion, flunarizine (1) slows and terminates arrhythmias resulting from delayed afterdepolarizations, and (2) prevents their reinitiation.     

Protection of CGS 10078B against ouabain-induced arrhythmia in the cat

CGS 10078B (CGS; 1-[2,3-dihydro-1,4-(2S)-benzodioxin-2-yl]-5-[2,3-dihydro-1,4-(2R)- benzodioxin-2-yl]-3-(1R,5S)-aza-1,5-pentanediol methane sulfonate) is an agent with alpha- and beta-receptor and calcium channel blocking actions. To study its antiarrhythmic activity, cats were anesthetized with alpha-chloralose, ventilated, and given atropine and gallamine. CGS (10 or 20 mg/kg, i.v.) was infused 15 min prior to ouabain. Bolus injections of ouabain (25 micrograms/kg, i.v.) were given every 15 min until death (D). Some cats were pretreated with reserpine (R; 5 mg/kg, i.p.) 24 h prior to the experiment. In other cats 6-hydroxydopamine (6-OHDA; 20 mg/kg, i.v.) was administered 3 days prior to CGS 20 mg/kg and ouabain. Data were compared with those of Lathers [Eur. J. Pharmacol. 64: 95, 1980], i.e., with 12 cats who received only ouabain and with 11 pretreated with timolol (T; 5 mg/kg, i.v.) prior to ouabain. After CGS (10 or 20 mg/kg, i.v.), but just prior to the first dose of ouabain, the blood pressure (BP) was decreased (p less than 0.05) from control (165 +/- 6 vs. 96 +/- 7, and 136 +/- 5 vs. 90 +/- 10 mm Hg, respectively). Comparable heart rate (HR) values were also decreased (p less than 0.05) from 225 +/- 17 to 166 +/- 14 and from 193 +/- 8 to 152 +/- 6 beats/min. 11 min after T, BP and HR had decreased (p less than 0.05) from 133 +/- 6 to 103 +/- 7 mm Hg and from 134 +/- 4 to 104 +/- 6 beats/min, respectively. Ouabain did not influence these decreases in BP and HR. CGS (10 or 20 mg/kg, i.v.) increased (p less than 0.05) the time to ouabain-induced arrhythmia (AR) and D. The magnitude of the protection appeared to be similar to that afforded by T. R given prior to CGS (20 mg/kg, i.v.) also increased the time to ouabain-induced AR and D while 6-OHDA increased the time to AR. The CGS protection against ouabain-induced AR was still present in animals pretreated with R or 6-OHDA. This indicates that the antiarrhythmic affect is not dependent upon adrenergic neuronal blockade.     

Investigation of electrophysiologic mechanisms for the antiarrhythmic actions of R 56865 in cardiac glycoside toxicity.

R 56865 is an experimental compound that has been shown to ameliorate the effects of cardiac glycoside toxicity and myocardial ischemia. We evaluated the direct electrophysiological effects of R 56865 and its effects on the electrophysiological sequelae of ouabain toxicity in vivo and in vitro. In normal anesthetized dogs, R 56865 alone at doses of 0.04 to 0.16 mg/kg i.v. had no effect on atrial, AV nodal, or ventricular conduction times and refractoriness, but at doses of 0.64 to 2.5 mg/kg it tended to increase these parameters. In ouabain-pretreated dogs, R 56865 (0.08 to 0.32 mg/kg i.v.) dose-relatedly reduced ouabain-induced ventricular arrhythmias. In normal isolated canine Purkinje fibers, R 56865 (1-10 microM) reduced Vmax at short pacing cycle lengths and decreased the action potential duration at concentrations of 0.1 to 10 microM. R 56865 at concentrations through 10 microM had no significant effect on normal action potentials of canine ventricular muscle and slow response action potentials in guinea pig papillary muscles. In Purkinje fibers exposed to toxic concentrations of ouabain, R 56865 (1 microM) reduced the delayed after depolarization (DAD) amplitude and inhibited triggered activity. R 56865 had no effect on normal automaticity in canine Purkinje fibers at 1 microM, but 10 microM significantly slowed it. R 56865 at 10 microM did not affect isoproterenol-enhanced automaticity and only slightly reduced barium-induced abnormal automaticity that occurred at reduced membrane potentials. These results demonstrate that R 56865 reverses cardiac glycoside-induced arrhythmias in anesthetized dogs at doses that do not significantly affect conduction or refractoriness. Suppression of ouabain-induced DAD and triggered activity in isolated Purkinje fibers, at concentrations not affecting normal or abnormal automaticity, may be the mechanism of R 56865's antiarrhythmic actions in vivo. Suppression of DAD does not appear to be associated with blockade of voltage-dependent calcium channels, but R 56865 may prevent intracellular sodium overload by limiting excessive sodium entry during ouabain intoxication.     

蝙蝠葛碱对麻醉兔体内希氏束电图的影响及与几种药物的相互作用

蝙蝠葛碱(Dau)剂量依赖性延长麻醉家兔希氏束电图(HBE)的A-H,H-V间期,使V波增宽,并延长心房和房室结不应期。利多卡因(Lid)、对HBE各间期无明显影响,但有减弱Dau延长H-V间期的作用。异丙肾上腺素(Iso)可对抗Dau延长A-H,H-V间期及增宽V波的作用。阿托品(Atr)可缩短Dau已延长的A-H间期。提示Atr和Lid可分别改善Dau抑制的房室及希—浦系统的传导,而Iso对房室传导和室内传导均有改善作用。     

Protective activity of calcium entry blockers against ouabain intoxication in anesthetized guinea pigs

Several studies have suggested a central role for calcium in the pathogenesis of digitalis-induced arrhythmias. To test this hypothesis, the effects on ouabain-induced arrhythmia of intraarterial pretreatment with the calcium entry blockers nifedipine, flunarizine, verapamil, diltiazem, and bepridil, the calcium entry promotor Bay K 8644, and CaCl2 were compared with those of the currently applied digitalis antidotes phenytoin and lidocaine in urethane-anesthetized (1.5 g/kg i.p.) guinea pigs. Pretreatment with nifedipine (0.03 and 0.1 mg/kg), flunarizine (1 and 3 mg/kg), and phenytoin (10 mg/kg) doubled the time (from 10-20 to 20-40 min) required to provoke toxic ECG changes. Verapamil, diltiazem, and bepridil caused a slight but significant reduction of ouabain toxicity. Pretreatment with CaCl2 (10 mg/kg) enhanced all toxic effects of ouabain. None of the above-mentioned pretreatments as such changed the ECG parameters. Bay k 8644 (0.03 and 0.1 mg/kg) enhanced the effects of ouabain on ventricular rhythm, but abolished the ouabain-induced impairment of AV conduction. Bay k 8644 as such increased heart rate (from 318 +/- 11 to 376 +/- 6 beats/min at 0.1 mg/kg) and shortened the PR interval. The negative inotropic effects of the calcium entry blockers were quantified in electrically paced (3 Hz) guinea pig isolated left atria 15 min after pretreatment with ouabain (3 X 10(-7) M). The rank order of potency for the negative inotropic effect was nifedipine greater than verapamil greater than bepridil greater than diltiazem greater than flunarizine. In conclusion, nifedipine, flunarizine, and phenytoin showed obvious and equally effective protection against ouabain-induced arrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of 5-HT(4) receptor agonists, cisapride and mosapride citrate on electrocardiogram in anaesthetized rats and guinea-pigs and conscious cats

The purpose of this study was to examine the arrhythmogenic potential of 5-HT4 receptor agonists, cisapride and mosapride citrate (mosapride) in vivo. In anaesthetized rats, cisapride at intravenous infusion of 10 and 30 mg/kg/hr for 1 hr prolonged the electrocardiographic RR and QT intervals, whereas at 3 mg/kg/hr, it prolonged the RR interval without affecting the QT interval. Mosapride at 30 mg/kg/hr for 1 hr slightly, but not significantly, prolonged the QT interval. In anaesthetized guinea-pigs, cisapride at intravenous infusion of 0.3, 1 and 3 mg/kg over 15 min. prolonged the RR interval (18-44%), QT interval (18-42%) and the corrected QT interval (QTc; 8-19%). Mosapride at 3, 10 and 30 mg/kg over 15 min. little affected the QTc although at 30 mg/kg, it slightly prolonged the RR and QT intervals. With repeated oral administrations of 30 mg/kg twice a day for 7 days, cisapride prolonged the QT interval (11-35%) and QTc (11-32%) at the 3rd and 7th days in conscious cats. In addition, cisapride depressed the ST segment in two out of five cats. Mosapride at 60 mg/kg twice a day for 7 days did not affect the QT interval or QTc in cats. The maximal plasma concentrations of mosapride and its main metabolite (a des-4-fluorobenzyl-mosapride) at the 7th day in cats were 9.4+/-2.8 microM and 2.5+/-0.3 microM , respectively, being 100 and 30-60 times higher than those in man given therapeutic doses (Sakashita et al. 1993a&b). These results indicate that mosapride has little arrhythmogenic potential.     

Indecainide: effects on arrhythmias, electrophysiology, and cardiovascular dynamics

The cardiovascular pharmacology of indecainide, a new class I antiarrhythmic agent, was studied in intact animals. Arrhythmias produced by ouabain were converted to sinus rhythm by indecainide (100 micrograms/kg/min, i.v.) at 0.7 +/- 0.1 mg/kg and a corresponding plasma concentration of 1.7 +/- 0.2 micrograms/ml at the time of conversion. Infusion at a slower rate (20 micrograms/kg/min) converted to sinus rhythm at 0.4 +/- 0.1 mg/kg and 0.4 +/- 0.2 micrograms/ml plasma. Arrhythmias produced by prior (24 h) coronary artery occlusion were converted to 50% sinus rhythm by indecainide (100 micrograms/kg/min, i.v.) at 1.3 mg/kg. In conscious dogs, 6 mg/kg indecainide p.o. prolonged the PR and QRS intervals by 31 +/- 5 and 13 +/- 3%, respectively, at a corresponding plasma concentration of 2.8 +/- 0.5 micrograms/ml. His bundle studies revealed that the PR interval prolongation was due to an increase in both A-H and H-V intervals. In anesthetized dogs, indecainide (1-5 mg/kg, i.v.) decreased cardiac contractility, however, this effect was comparable to or less than that produced by other class I agents and was likely due to the Na+-channel-blocking activity of the drug. The autonomic effects of indecainide were slight and no effects were produced on peripheral hemodynamics, the QTc interval, or the central nervous system. It was concluded that indecainide is a potent class I antiarrhythmic agent that would appear to have only minimal propensity for producing adverse side effects in humans.     

The effects of verapamil on the electrophysiology of the intact immature mammalian heart

The electrophysiologic effects of intravenous verapamil were compared in six intact neonatal puppies ages 3-15 days and in adult dogs. Utilizing standard intracardiac recording and programmed stimulation techniques, sinus and AV nodal function and atrial and ventricular refractory periods were determined following incremental intravenous doses of 0.075 mg/kg, 0.15 mg/kg, and 0.30 mg/kg of verapamil. In the neonate, intravenous verapamil resulted in a significant increase of the sinus cycle length (37 +/- 6%) but no changes occurred in either the percent sinus node recovery time or the corrected sinus node recovery time. The atrial effective refractory period was prolonged by verapamil (32 +/- 12%). Concerning atrioventricular (AV) nodal function, verapamil produced a small but significant prolongation of resting AH interval (50.5 +/- 2.4 ms (control) versus 57.3 +/- 4.7 ms post 0.30 mg/kg) and a dose-related prolongation of the paced cycle length resulting in AV nodal Wenckebach (170 +/- 12.8 ms control, 190 +/- 10.3 ms post 0.075 mg/kg, 215.8 +/- 13.0 ms post 0.15 mg/kg and 246.7 +/- 22.8 ms post 0.30 mg/kg). The effective refractory period (ERP) and functional refractory period (FRP) of the atrioventricular node (AVN) were prolonged in a dose-dependent fashion (ERP-AVN: 75 +/- 19% increase, FRP-AVN: 42 +/- 14% increase). Retrograde conduction, present in all six neonates, was completely abolished in four of six subjects and significantly prolonged in one other puppy by verapamil. No changes in ventricular refractory periods were observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

苄基四氢巴马汀对α和β等受体的影响

苄基四氢巴马汀(BTHP)使苯福林对大鼠肛尾肌和兔主动脉条作用的累积量效曲线平行右移,最大反应不压低,pA₂值分别为5.86和5.8,但对甲氧明和B-HT920升高DP作用的量效曲线无明显影响。BTHP可使异丙肾上腺素和组胺正性频率作用的量效曲线非平行右移,最大反应压低。BTHP还能明显缩短大鼠再灌流所致心律失常的持续时间。结果提示,BTHP对α₁受体的阻断及对β和H₂受体的非竞争性拮抗作用可能与该药抗心律失常作用有部分关系但并非其主要机理。     

Antiarrhythmic and hemodynamic effects of an aminosteroid (Org 3001) in the digitalized dog.

Org 6001 (3alpha-amino-5alpha-androstan-2beta-ol-17-one-hydrochloride) is an orally non-hormonal aminosteroid possessing antiarrhythmic activity. In 13 dogs the efficacy of the drug against ouabain-induced ventricular tachycardia (VT) was studied. VT was produced by a mean dose of 67.5 +/- 18.7 mug/kg ouabain, administered by continuous infusion of 25 mug/min. 20 min after the onset of VT an 0.125 mg/kg/min infusion of Org 6001 was initiated, doubling the dose every 10 min. In all dogs VT was reverted into normal sinus rhythm (NSR) by a dose of 9.72 +/- 7.07 mg/kg (0.87-20.75 mg/kg) Org 6001. The duration of VT ranged from 27-61 min (mean 47.1 +/- 11.4 min), including the 20 min waiting period. NSR persisted in 8 dogs until the experiment was terminated (90 min after onset of VT), while in 5 dogs VT returned after 3-23 min sufficient to revert VT into NSR. A bolus injection of Org 6001 (10 mg/kg) gave an immediate return to NSR in 3 dogs, in which VT was provoked again by administration of a second dose of ouabain after the 90 min period had elapsed. Though the interaction of ouabain makes a quantitative analysis of the negative inotropic effects difficult, it appeared that there uas no major hemodynamic deterioration during and after treatment with Org 6001. During digitalization there was a significant increase in the first derivative of left ventricular systolic pressure (peak LVdP/dt) from 2340 +/- 600 to 3650 +/- 1070 mm Hg/sec and in peripheral resistance, while heart rate decreased. During VT, left ventricular systolic pressure (LVSP) and mean aortic pressure (MAP) dropped by approximately 20 mm Hg, while heart rate increased significantly. After treatment with Org 6001, LVSP and MAP further decreased to 128 +/- 30 mm Hg (p less than 0.05) areased to 128 +/- 30 mm Hg (p less than 0.05) and 112 +/- 20 mm Hg respectively. Peak LVdP/dt fell from 3650 +/- 1390 to 2780 +/- 970 mm Hg/sec (p less than 0.05). Heart rate had dropped to 126 +/- 22 beats/min (p less than 0.05). During the first 30 min after Org 6001 infusion was stopped none of the parameters showed significant changes, although peak LVdP/dt rose slightly. It is shown in the present investigation that Org 6001 has effective antiarrhythmic properties in controlling ouabain-induced VT with acceptable cardiodepressant actions.