Coronary Ligation-induced Arrhythmia Research Articles

Investigation on SCH00013, a novel cardiotonic agent with Ca++ sensitizing action. 4th communication: influence on experimentally induced ventricular arrhythmia in dogs.

Influence of 4,5-dihydro-6-[1-[2-hydroxy-2-(4-cyanophenyl)ethyl]- 1,2,5,6,-tetrahydropyrido-4-yl]pyridazin-3(2H)-one (SCH00013) and vesnarinone (CAS 81840-15-5) on the arrhythmia experimentally induced by three different methods was investigated in dogs. In digitalis-induced arrhythmia, SCH00013 (3 mg/kg i.v.) showed a tendency to improve the arrhythmia with a decrease in the arrhythmic ratio and an increase in the conducted beats (CB), though these changes did not reach a significant level; it decreased significantly the blood pressure (BP) with no change in the total heart rate (THR) and atrial rate (AR). Vesnarinone (3 mg/kg i.v.) did not affect these parameters except for BP that was decreased significantly. In two-stage coronary ligation-induced arrhythmia, SCH00013 (1 and 3 mg/kg i.v.) did not change the arrhythmic ratio, CB, AR and BP, while the THR being slightly decreased; the arrhythmic ratio showed a tendency to decrease with SCH00013 when examined at 24 h after coronary ligation. Vesnarinone (3 mg/kg i.v.) did not affect these parameters at 24 and 48 h after ligation. In epinephrine (adrenaline)-induced arrhythmia, both SCH00013 and vesnarinone showed exacerbation of arrhythmia. SCH00013 at 1 mg/kg i.v. did not elicit ventricular fibrillation (VF) in five dogs examined, but at 3 mg/kg i.v. it elicited VF in two of three dogs. Vesnarinone at 1 mg/kg i.v. induced VF in all of three dogs examined. Incidence of VF induced by optical isomers of SCH00013 was not significantly different from each other: both isomers elicited VF in two of six dogs at 1 mg/kg i.v. and at 3 mg/kg i.v. each of them induced VF in two dogs examined. The present results indicate that SCH00013 is a cardiotonic agent that is equivalent to or less arrhythmogenic than vesnarinone in animal models of arrhythmia, such as adrenaline- and digitalis-induced arrhythmia and the two-stage coronary ligation-induced arrhythmia. Optical isomers of SCH00013 were essentially equieffective in eliciting exacerbation of adrenaline-induced arrhythmia in the dog.

Comparative Effects of Idazoxan, Prazosin, and Yohimbine on Coronary Ligation-Induced Arrhythmias in Spontaneously Hypertensive Rats

We investigated whether certain drugs with alpha-adrenergic antagonist activity display anti-arrhythmic effects in hypertensive animals subjected to acute coronary artery ligation. The left anterior descending coronary artery (LAD) was ligated in open-chest pentobarbital-anesthetized spontaneously hypertensive rats (SHR); arrhythmias were subsequently recorded for 30 min. Drugs were administered intravenously, (i.v.) 5 min before ligation. The effects of yohimbine and idazoxan were compared with those of prazosin. Prazosin (100 mu g/kg) increased the occurrence of ventricular tachycardia (VT). In contrast, yohimbine 1.6 mg/kg decreased both the occurrence and the duration of VT and the occurrence and the duration of ventricular fibrillation, (VF). The results obtained with idazoxan 1 mg/kg were similar to those with yohimbine. The ECG alterations induced by coronary artery ligation in rats treated with yohimbine and idazoxan were more pronounced than in controls and in rats treated with prazosin, suggesting that the antiarrhythmic effects observed were not mediated by antiischemic activity. The protective effects against ligation-induced arrhythmias were preceded by a hypotensive effect and a decrease in the rate-pressure product in yohimbine-treated but not in idazoxan-treated animals. In rats treated with prazosin, more arrhythmic events were observed, although hemodynamics were similar to those in rats treated with yohimbine. Our results suggest that the yohimbine-induced antiarrhythmic action is not due to an alteration of conduction or repolarization rates. In this model, yohimbine and idazoxan appear to protect against ligation-induced arrhythmias. These data suggest that drugs with alpha-adrenergic properties might influence the nervous drive to the heart in SHR with cardiac ischemia. However, further investigations are needed to ascertain whether the alpha-adrenoceptor blockade participates in this effect.

Acute antiarrhythmic effects of intravenously administered amiodarone on canine ventricular arrhythmia.

We investigated antiarrhythmic effects of intravenously (i.v.) administered amiodarone using four canine ventricular arrhythmia models. Bolus injections of amiodarone 3 mg/kg suppressed epinephrine (EPI)-induced arrhythmia and 5-mg/kg bolus injections of amiodarone suppressed digitalis- and two-stage coronary ligation-induced arrhythmia models, but the antiarrhythmic effects did not correlate with the amiodarone plasma concentrations. The infusion of amiodarone 6.67 mg/kg/h did not prolong the QTc interval or produce antiarrhythmic effects in coronary ligation and reperfusion experiments. Amiodarone significantly decreased the mean blood pressure (MAP), and this effect lasted throughout the observation period. The results indicate that the antiarrhythmic effects of intravenously administered amiodarone may not be due to its class III action, but to other actions, such as class I, II and IV actions.

Effect of KRN2391 on canine ventricular arrhythmia models

1. 1. KRN2391 (3–30 μg/kg, i.v.) produced a decrease in mean blood pressure (MBP) with concomitant increase in heart rate (HR) and change in electrocardiogram (ECG) such as the shortening of PP and PQ intervals and the prolongation of QTc and these changes in HR and ECG were attenuated by pretreatment with propranolol (1 mg/kg) in normal dogs. 2. 2. KRN2391 at 30 μg/kg induces neither suppression nor aggravation of ventricular arrhythmias caused by adrenaline and digitalis. 3. 3. In two-stage coronary ligation-induced arrhythmia, KRN2391 inhibited arrhythmia at 48 hr. 4. 4. These results suggest that KRN2391 may be effective on arrhythmia related to ischemia. In addition, it is considered that arrhythmia is not induced even by a high dose of KRN2391 in the normal condition.

Antiarrhythmic effects of combined application of class I antiarrhythmic drugs; addition of low-dose mexiletine-enhanced antiarrhythmic effects of disopyramide and aprindine in various-rate canine ventricular tachycardias.

We examined the possible beneficial effects of combined application of class I drugs using digitalis-induced and two-stage coronary ligation-induced canine ventricular arrhythmia models. Combination treatment with disopyramide (0.3 mg/kg/min for 10 min) and mexiletine (0.3 mg/kg/min for 5 min) enhanced the antiarrhythmic effect of a single treatment of disopyramide (0.3 mg/kg/min for 10 min). Combination treatment with aprindine (0.1 mg/kg/min for 10 min) and mexiletine (0.3 mg/kg/min for 5 min) enhanced antiarrhythmic effects of a single treatment of aprindine (0.1 mg/kg/min for 10 min) on digitalis and 24-h two-stage coronary ligation-induced arrhythmia models, but in the 48-h two-stage coronary ligation-induced arrhythmia model, a slow ventricular tachycardia (VT) model, addition of mexiletine to aprindine caused no enhancement of antiarrhythmic effects. The results support those of a previous electrophysiologic study of combination treatment with class I drugs in which disopyramide and mexiletine acted additively but aprindine and mexiletine did not act additively when the ventricular preparation was driven at slow rates. Total heart rate (HR) and mean blood pressure (MAP) were not influenced by additional application of mexiletine.

Antiarrhythmic effects of bisaramil in canine models of ventricular arrhythmia

The antiarrhythmic effects of bisaramil were examined in canine models of digitalis-, adrenaline- and two-stage coronary ligation- induced arrhythmia. Bisaramil (0.3–1.5 mg/kg i.v.) suppressed all the arrhythmias. The antiarrhythmic plasma concentration (IC 50) for arrhythmias induced by digitalis, adrenaline, and 24 h two-stage coronary ligation were 0.11, 0.81, and 0.75 μg/ml, respectively. Bisaramil is a potent class I agent, judging from its low antiarrhythmic plasma concentrations. Oral bisaramil (10 mg/kg) also suppressed 24-h coronary ligation-induced arrhythmia. These results indicate that bisaramil may be a useful drug for the treatment of various clinical ventricular arrhythmias.

Effects of gallopamil, a Ca 2+ channel blocker in models of ventricular arrhythmia in dogs

The antiarrhythmic effects of gallopamil on adrenaline-, digitalis- and two-stage coronary ligation-induced arrhythmias and on adrenaline-induced triggered arrhymia were investigated. Gallopamil suppressed adrenaline-induced and adrenaline-induced triggered arrhythmias, and these antiarrhythmic effects of gallopamil were similar to those of verapamil. Gallopamil also showed some antiarrhythmic effect on the 48-h coronary ligation-induced arrhythmia. The plasma concentration of gallopamil which decreased the arrhythmic ratio for adrenaline-induced arrhythmia by 50% (IC 50)_was 32 ng/ml. These results indicate that gallopamil may be a clinically useful antiarrhythmic drug.

Effects of a new class I antiarrhythmic drug bidisomide on canine ventricular arrhythmia models.

The antiarrhythmic and direct cardiovascular effects of a new antiarrhythmic agent, bidisomide, alpha-(2-[acetyl(1-methylethyl)amino]ethyl)-alpha-(2- chlorophenyl)-1-piperidinebutanamide, were investigated. To determine the anti-arrhythmic effects, spontaneously occurring adrenaline-, digitalis- and two-stage coronary ligation-induced arrhythmias were used. Bidisomide suppressed these three arrhythmia models. The antiarrhythmic plasma concentration, IC50, of bidisomide for digitalis-induced arrhythmia was 22.1 micrograms/ml, and those calculated for intravenous bidisomide in 24 h and 48 h coronary ligation-arrhythmias were 15.1 and 11.6 micrograms/ml and that calculated for oral bidisomide in 24 h coronary ligation-arrhythmia was 5.4 micrograms/ml and that for adrenaline induced arrhythmia was 58.7 micrograms/ml. In the blood perfused sinoatrial node and papillary muscle preparations, bidisomide decreased the sinoatrial rate and contractile force and increased the intraventricular conduction time and coronary blood flow. These results indicate that bidisomide is similar to other class I antiarrhythmic agents such as pirmenol and KW-3401 in its antiarrhythmic profile and is expected to become a clinically useful antiarrhythmic drug.

P-093 - Effect of combined use of class I antiarrhythmic drugs on canine digitalis-induced arrhythmia and two-stage coronary ligation-induced arrhythmia models

P-093 - Effect of combined use of class I antiarrhythmic drugs on canine digitalis-induced arrhythmia and two-stage coronary ligation-induced arrhythmia models

Effects of a New Antiarrhythmic Drug TYB-3823* on Canine Ventricular Arrhythmia Models

The antiarrhythmic and direct cardiovascular effects of a new antiarrhythmic agent, TYB-3823 [1-(2,6-dimethylphenyl)-4,4-dimethyl-aminoguanidine hydrochloride], were investigated. To determine the antiarrhythmic effects, spontaneously occurring adrenaline-, digitalis-, and two-stage coronary ligation-induced arrhythmias were used. TYB-3823 suppressed these three arrhythmia models. The antiarrhythmic plasma concentrations, IC50, of TYB-3823 for digitalis-, coronary ligation-, and adrenaline-induced arrhythmias were 7.8, 16.8, and 5.0 micrograms/ml, respectively. In the blood perfused sinoatrial (SA) node and papillary muscle (PM) preparations, TYB-3823 decreased the sinoatrial rate (SAR) and contractile force following an initial small positive inotropic effect and increased the intraventricular conduction time and coronary blood flow. These results indicate that TYB-3823 is similar to other class I antiarrhythmic agents, such as aprindine and nicainoprol, in the antiarrhythmic profile and is expected to become a clinically useful antiarrhythmic drug.

Efficacy and Plasma Concentrations of SC-36602 in Canine Models of Ventricular Arrhythmia

The antiarrhythmic effectiveness of a new class I agent, SC-36602, was evaluated in two canine models of ventricular arrhythmia. In a Harris coronary ligation-induced arrhythmia model, SC-36602 significantly reduced ectopic rate at doses of 8 mg/kg i.v. and 15, 20 and 30 mg/kg per os. In a ouabain-induced arrhythmia model, a 9 mg/kg i.v. dose of SC-36602 had a sustained (greater than or equal to 60 min) antiarrhythmic effect. The approximate plasma concentration of SC-36602 necessary for measurable antiarrhythmic activity was estimated to be 2-7 micrograms/ml after either i.v. or oral administration. No adverse cardiovascular or central nervous system effects were observed in conscious or anesthetized dogs in response to SC-36602.

Antiarrhythmic effects of the class 1c antiarrhythmic drug, flecainide, on canine ventricular arrhythmia models.

The properties of a class 1c antiarrhythmic drug, flecainide, were examined using 3 canine ventricular arrhythmia models: (1) digitalis-, (2) adrenaline- and (3) two-stage coronary ligation-induced arrhythmias. The minimum effective plasma concentration of flecainide was determined for each model. Flecainide suppressed the arrhythmias. The minimum effective plasma concentrations for arrhythmias induced by digitalis, adrenaline and 24 hr coronary ligation, were 0.9 +/- 0.2, 1.4 +/- 0.6, 1.5 +/- 0.4 mcg/ml, respectively (mean +/- SD, n = 6). These minimum effective plasma concentrations of flecainide were almost equal to the reported in vitro concentration that suppress the Na channels of isolated canine ventricular tissues. Thus, flecainide may suppress these arrhythmias by inhibiting the Na channels of cardiac cells.

Antiarrhythmic Effects of a New Drug, E-0747, on Canine Ventricular Arrhythmia Models

Antiarrhythmic effects of a new antiarrhythmic drug, E-0747, were examined using four canine ventricular arrhythmia models: digitalis-, adrenaline- and two-stage coronary ligation-induced arrhythmias and a newly developed locally-induced digitalis arrhythmia. The minimum effective plasma concentration of E-0747 was determined for the first three arrhythmia models. E-0747 suppressed those arrhythmias, and the minimum effective plasma concentrations for arrhythmias induced by digitalis, adrenaline, 24 hr coronary ligation, and 48 hr coronary ligation were 1.4±0.6, 1.8±0.4, 1.6±0.4 and 2.2±0.2 μg/ml, respectively (mean±S.D., n = 5–10). The aforementioned minimum effective plasma concentrations of E-0747 for these arrhythmias were almost equal to the reported concentration in vitro to suppress the Na channels of isolated canine ventricular tissues. The class 1 property of E-0747 was also shown in a newly developed locally-induced digitalis arrhythmia. Thus E-0747 suppresses arrhythmia by inhibiting Na channels of cardiac cells and is expected to become a clinically useful antiarrhythmic drug.

Antiarrhythmic plasma concentrations of mexiletine on canine ventricular arrhythmias.

Antiarrhythmic effects of mexiletine were examined using three canine ventricular arrhythmia models--digitalis-, adrenaline-, and two-stage coronary ligation-induced arrhythmias. The minimum effective plasma concentration for each arrhythmia model was determined. Mexiletine suppressed all the arrhythmias, and the minimum effective plasma concentrations for arrhythmias induced by digitalis, adrenaline, 24-h coronary ligation, and 48-h coronary ligation were 1.8 +/- 0.6, 3.7 +/- 0.9, 1.9 +/- 0.3, and 2.2 +/- 0.4 micrograms/ml, respectively (mean +/- SD, n = 6-7). The concentration for adrenaline-induced arrhythmias was significantly higher than those for the other types of arrhythmias. Mexiletine had a hypotensive effect when it was given intravenously, but this effect was not observed when it was given orally. Oral mexiletine was also effective in suppressing the 24-h coronary ligation-induced arrhythmia. Mexiletine induced convulsions when higher doses were given. The correlations between the mexiletine plasma concentrations and its antiarrhythmic effects were not very strong, probably indicating individual variations in sensitivity to mexiletine.

Effective Plasma Concentrations of Aprindine in Canine Ventricular Arrhythmias

Antiarrhythmic effects of aprindine were examined using three canine ventricular arrhythmia models (induced by digitalis, adrenaline, and two-stage coronary ligation), and the minimum effective plasma concentration of aprindine was determined for each arrhythmia model. Aprindine suppressed all three arrhythmias, and the minimum effective plasma concentrations for arrhythmias induced by digitalis, adrenaline, and 24-h and 48-h coronary ligation were 0.8 +/- 0.4, 1.0 +/- 0.4, 1.6 +/- 0.3, and 3.1 +/- 0.5 micrograms/ml, respectively (mean +/- SD, n = 6-7). The minimum effective plasma concentrations of aprindine for digitalis- and adrenaline-induced arrhythmias were significantly lower than those for coronary ligation-induced arrhythmias. Oral aprindine was also effective in suppressing both the 24- and 48-h coronary ligation-induced arrhythmias. Aprindine had a hypotensive effect when it was given intravenously, but this effect was not observed when it was given orally. The correlations between the aprindine plasma concentrations and the antiarrhythmic effects were not very strong and indicated individual variations in sensitivity to aprindine.

Antiarrhythmic effect of SUN 1165, N-(2,6-dimethylphenyl) -8-pyrrolizidineacetamide hydrochloride in experimental animal models

Antiarrhythmic actions of SUN 1165 in four experimental arrhythmia models were compared with those of disopyramide and lidocaine. SUN 1165 showed a potent and long - lasting antiarrhythmic activity against the two-stage coronary ligation-induced arrhythmia (Harris1 method) when administered i.v. or orally to conscious dogs. Its potency was 2 to 10 times that of disopyramide. The effect of i.v. or intraduodenally administered SUN 1165 was also superior to that of disopyramide in suppressing the other ventricular arrhythmia models such as ouabain-induced arrhythmia in pentobarbital anesthetized dogs and epinephrine-induced arrhythmia in halothane anesthetized dogs. Intraduodenal antiarrhythmic doses of SUN 1165 caused no block of atrio-ventricular conduction in anesthetized open-chest dogs. SUN 1165 at an orally active dose of 10 mg/kg produced slight and short-lasting decrease in the maximum rate of rise of left ventricular pressure (dP/dt max.), which was recorded as an index of cardiac contractile activity in five filaria-free healthy conscious dogs. From these results, it is concluded that SUN 1165 is a potent Class I antiarrhythmic agent with less liability to cause block of atrio-ventricular conduction and depression of cardiac contractility.