Antiarrhythmic effects of optical isomers of cibenzoline 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 micrograms/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 micrograms/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.     

Antiarrhythmic plasma concentrations of cibenzoline on canine ventricular arrhythmias

Using two-stage coronary ligation-, digitalis-, and adrenaline-induced canine ventricular arrhythmias, antiarrhythmic effects of cibenzoline were examined and the minimum effective plasma concentration for each arrhythmia model was determined. Cibenzoline suppressed all the arrhythmias, and the minimum effective plasma concentrations for arrhythmias induced by 24-h coronary ligation, 48-h coronary ligation, digitalis, and adrenaline were 1.9 +/- 0.9 (by 8 mg/kg i.v.), 1.6 +/- 0.5 (by 8 mg/kg i.v.), 0.6 +/- 0.2 (by 2 mg/kg i.v.), and 3.5 +/- 1.3 (by 5 mg/kg i.v.) micrograms/ml, respectively (mean +/- SDM, n = 6-7). The concentration for adrenaline-induced arrhythmia was significantly higher than those for the other types of arrhythmias. This pharmacological profile is similar to those of mexiletine and tocainide, and all three drugs have central nervous system (CNS) stimulant action. Because cibenzoline had only weak hypotensive and sinus node depressive effects and was found to be orally active when given to coronary ligation arrhythmia dogs, its clinical usefulness is expected.     

Antiarrhythmic effect of a new class 1 antiarrhythmic drug, nicainoprol, on canine ventricular arrhythmias

Using two-stage coronary ligation-, digitalis- and adrenaline-induced canine ventricular arrhythmias, antiarrhythmic effects of nicainoprol were examined in dogs, and the minimum effective plasma concentration for each arrhythmia model was determined. Nicainoprol suppressed the arrhythmias, and the minimum effective plasma concentrations for arrhythmias induced by 48 hr coronary ligation, digitalis and adrenaline were 8.9 micrograms/ml (by 5 mg/kg, i.v.), 3.0 micrograms/ml (by 3 mg/kg, i.v.) and 2.7 micrograms/ml (by 3 mg/kg, i.v.), respectively. The concentration for coronary ligation arrhythmia was higher than those for the digitalis and adrenaline arrhythmias. This pharmacological profile is similar to those of aprindine and propafenone. Nicainoprol induced some central nervous system effect including vomiting in conscious coronary ligated dogs. Though intravenous nicainoprol (5 mg/kg) was not effective on 24 hr coronary ligation arrhythmia, an oral dose of 30 to 40 mg/kg was effective. These results indicate that it may become a clinically useful antiarrhythmic drug.     

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 micrograms/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.     

Effects of zatebradine and propranolol on canine ischemia and reperfusion-induced arrhythmias

1,3,4,5-Tetrahydro-7,8-dimethoxy-3[3-[[2-(3, 4-dimethoxyphenyl)-ethyl]methylamino]propyl]-2H-3-benzazepin-2-one -hy drochloride (Zatebradine) is a specific bradycardiac agent, blocking the hyperpolarization-activated pacemaker current (I(f)), and thus has no negative inotropic effect. The purpose of this study was to examine whether zatebradine is effective against ischemia and reperfusion-induced arrhythmias in dogs compared to propranolol. Arrhythmia was induced by ligation of the left anterior descending coronary artery followed by reperfusion. Ischemia-induced biphasic arrhythmias were suppressed in both zatebradine and propranolol groups. During ischemia, fatal ventricular fibrillation occurred in four dogs in the control group, 0 in the zatebradine group, and two dogs in the propranolol group. Of the 31 dogs subjected to reperfusion, mortality rates in the zatebradine, propranolol, and control groups were 56%, 75%, and 86%, respectively, and there were no significant differences. In the heart beating 10 beats/min faster than the predrug heart rate by atrial pacing, both zatebradine and propranolol attenuated ischemia-induced arrhythmias but did not affect reperfusion arrhythmias. Our results suggest that I(f) and/or beta-adrenoceptors rather than the bradycardiac action might be related to the antiarrhythmic effects during ischemia, but that they do not play a role in the generation of the reperfusion-induced ventricular arrhythmias.     

Effects of KT-362, a new Na and Ca influx and Ca release inhibitor, on canine ventricular arrhythmias

Antiarrhythmic effects of the new drug KT-362, which was reported to suppress Na and Ca currents of cardiac cells and also to suppress intracellular Ca release in isolated smooth muscle preparations, were examined using two-stage coronary ligation-, digitalis- and adrenaline-induced ventricular arrhythmias in the dog. Intravenous KT-362 at 10 mg/kg suppressed coronary ligation arrhythmia both at 24 and 48 hr after ligation, and the minimum effective plasma concentrations for arrhythmias induced by 24 hr coronary ligation and 48 hr coronary ligation were 6.1 +/- 1.7 and 8.6 +/- 2.7 micrograms/ml, respectively. Antiarrhythmic effects were accompanied by transient hypotension. Oral administration of 70-100 mg/kg was also effective on 24 hr coronary ligation arrhythmia. However, there was no prominent hypotension in these experiments. Intravenous KT-362 at 3 mg/kg suppressed digitalis arrhythmia; and the minimum effective plasma concentration was 3.3 +/- 1.2 micrograms/ml, which was lower than the effective plasma concentrations for coronary ligation arrhythmias. Intravenous KT-362 at 1 mg/kg also suppressed adrenaline arrhythmia; and the minimum effective plasma concentration was 1.0 +/- 0.1 microgram/ml, the lowest among the effective plasma concentrations. These pharmacological profiles of KT-362 are quite different from those of class 4 Ca antagonists, but similar to those of class 1 drugs such as propafenone. Though KT-362 has a hypotensive effect, it is effective on canine ventricular arrhythmias; thus its clinical usefulness for supraventricular and ventricular arrhythmias is expected.     

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.     

Effects of nizofenone on experimental arrhythmia in dogs

The effects of nizofenone, a new compound with cerebral protective properties, were compared with those of quinidine on various types of experimental arrhythmia in dogs. Pretreatment with nizofenone (3 and 10 mg/kg, i.v.) markedly increased the amount of ouabain needed to cause cardiac toxicity in pentobarbital-anesthetized dogs, to the same degree as quinidine (10 mg/kg, i.v.). Nizofenone (1, 3 and 10 mg/kg, i.v.) was effective in reversing established ouabain-induced ventricular tachycardia in pentobarbital-anesthetized dogs. In contrast quinidine (3 and 10 mg/kg, i.v.) showed only weak activity in this test. Nizofenone (3 and 10 mg/kg, i.v.) significantly reduced the ectopic ventricular rate in pentobarbital-anesthetized dogs 24 hr after a two-stage ligation of the anterior descending coronary artery. Quinidine (10 mg/kg, i.v.), however, was more potent in this test. In addition, nizofenone, like quinidine, caused hypotension and bradycardia and prolonged the electrocardiogram QTc interval. On the other hand, nizofenone (1 and 10 mg/kg, i.v.) was inactive against epinephrine-induced arrhythmias in halothane-anesthetized dogs. Quinidine (10 mg/kg, i.v.) was effective in this test and also antagonized the pressor response induced by epinephrine. The effects of quinidine on adrenergically-induced arrhythmias are considered to be mediated through a blocking of the adrenergic alpha-receptors. Nizofenone did not show the adrenergic alpha-receptor blocking effect. Accordingly, the above findings suggest that the antiarrhythmic action of nizofenone may result from depressant effects on the cardiovascular system and from a membrane-stabilizing effect.     

Arrhythmia models for drug research: classification of antiarrhythmic drugs

The aim of this study was to classify antiarrhythmic drugs based on their effectiveness on 6 in vivo arrhythmia models, mainly using dogs. The models were produced by two-stage coronary ligation, digitalis, halothane-adrenaline, programmed electrical stimulation in old myocardial infarction dogs, coronary artery occlusion/reperfusion, or chronic atrioventricular block. Na(+)-channel-blocking drugs suppressed two-stage coronary ligation and digitalis arrhythmias. Ca(2+)-channel blockers and beta-blockers suppressed halothane-adrenaline arrhythmia. Positive inotropic drugs aggravated halothane-adrenaline arrhythmia, but did not aggravate digitalis arrhythmia. K(+)-channel blockers suppressed programmed electrical stimulation induced arrhythmia, but induced torsades de pointes type arrhythmia in chronic atrioventricular block dogs and aggravated halothane-adrenaline arrhythmia. Na(+)/H(+)-exchange blockers suppressed coronary artery occlusion/reperfusion arrhythmias. This classification may be useful for predicting the clinical effectiveness in the preclinical stage of drug development.     

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

To determine whether a hyperpolarization-activated current (I_f) 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 SEA0400, a Na+/Ca2+ exchange inhibitor, on ventricular arrhythmias in the in vivo dogs

SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline), a novel and selective inhibitor of Na+/Ca2+ exchanger, was investigated for its possible antiarrhythmic effects on arrhythmias of Ca2+ overload induced by coronary ligation/reperfusion and by digitalis in the dog. SEA0400 (1.0 mg/kg) did not change the hemodynamics but slightly prolonged the QRS duration (P<0.05). Pre-ischemic administration (10 min before coronary occlusion) of SEA0400 (1.0 mg/kg) and post-ischemic administration (1 min before reperfusion) of SEA0400 (0.3, 1.0 and 3.0 mg/kg) had no effects on the incidence of ventricular fibrillation induced by coronary ligation/reperfusion. On the other hand, SEA0400 (3.0 mg/kg) decreased the arrhythmic ratio in the digitalis arrhythmias (P<0.01). However, atrioventricular block and cardiac standstill were induced in two digitalized dogs. In conclusion, SEA0400 has no significant antiarrhythmic effect on arrhythmias induced by coronary ligation/reperfusion, but has an obvious suppressing effect on tachyarrhythmias induced by digitalis in in vivo canine models.     

Effects of cariporide (HOE642) on myocardial infarct size and ventricular arrhythmias in a rat ischemia/reperfusion model: comparison with other drugs

The effects of pretreatment with cariporide on myocardial infarction and ventricular arrhythmias in a rat model of ischemia/reperfusion were compared with those of nicorandil, propranolol, and nifedipine. Each drug was administered intravenously before coronary occlusion. Cariporide at 0.1, 0.3, and 1 mg/kg significantly reduced the infarct size (infarct mass/risk mass) from 28 +/- 4% (vehicle control value) to 9 +/- 3, 9 +/- 3, and 5 +/- 2%, respectively. Propranolol at 2.5 mg/kg also significantly reduced the infarct size to 11 +/- 1%. Neither nicorandil nor nifedipine was effective when given at 0.1 mg/kg. Cariporide dose dependently decreased the number of ischemia-induced ventricular premature beats (VPB), incidence and duration of ventricular tachycardia, and the number of reperfusion-induced VPB. Nicorandil was effective against only VPB after reperfusion, and propranolol reduced only postischemic arrhythmias, but nifedipine had no effect on either type of arrhythmia. In summary, cariporide reduced the infarct size and dose dependently suppressed arrhythmias induced by ischemia/reperfusion in rats. In contrast, in the present rat model, the doses of the other three drugs used in this study did not show comparable effects.     

Antiarrhythmic properties of a prior oral loading of amiodarone in in vivo canine coronary ligation/reperfusion-induced arrhythmia model: comparison with other class III antiarrhythmic drugs

Amiodarone, which is generally classified as class III antiarrhythmic drug in the Vaughan Williams classification, is widely used for the treatments of refractory arrhythmias. However, we previously reported that intravenous infusion of amiodarone (6.67 mg/kg per hour) did not suppress arrhythmias induced by coronary ligation/reperfusion in dogs. In this study, we examined effects of a prior oral loading of amiodarone on arrhythmias induced by coronary ligation/reperfusion. Sixteen female beagle dogs (8.5 - 12.5 kg) were divided into two groups; one group was given amiodarone (40 mg/kg, orally, n = 8), and the other was given empty gelatin capsules (n = 8) 2 h before the operation. Dogs were anesthetized with pentobarbital and artificially ventilated. The left chest was opened, and the left anterior descending coronary artery was ligated for 30 min and then reperfused. The mean plasma concentration of amiodarone was over 1.3 mug/ml. Although the prior oral loading of amiodarone did not change the QT interval, amiodarone suppressed the number of ectopic beats during coronary ligation and the incidence of ventricular fibrillation during coronary ligation and reperfusion periods (P<0.05 vs control group). In conclusion, a prior oral loading of amiodarone suppressed arrhythmias induced by coronary ligation/reperfusion with a dose that did not prolong the QT interval. This antiarrhythmic property of amiodarone is different from those of the other class III drugs in that antiarrhythmic effects were accompanied by QT prolongation in our all previous studies.     

Antiarrhythmic plasma concentrations of NIK-244 on canine ventricular arrhythmias

Using two-stage coronary ligation-, digitalis-, and epinephrine (EPI)-induced canine ventricular arrhythmias, we examined antiarrhythmic effects of NIK-244 and determined the minimum effective plasma concentration for each arrhythmia model. NIK-244 suppressed coronary ligation- and digitalis-induced arrhythmias, and the minimum effective plasma concentrations for arrhythmias induced by 24-h and 48-h coronary ligation and digitalis were 0.41 +/- 0.10 (by 1 mg/kg i.v.), 0.70 +/- 0.13 (by 1 mg/kg i.v.), and 0.21 +/- 0.08 (by 0.5 mg/kg i.v.) microgram/ml, respectively (mean +/- SD of the mean, n = 6). The concentration for digitalis-induced arrhythmia was significantly lower than those for coronary ligation arrhythmias. NIK-244 was not effective on EPI arrhythmia, and 1 mg/kg worsened the arrhythmia to ventricular fibrillation in three of six dogs. This pharmacologic profile is similar to those of disopyramide, procainamide, and SUN 1165. Since NIK-244 had no deleterious effects on blood pressure and sinus node activity, its clinical usefulness is expected.     

Electrophysiological actions of amrinone in dogs with cardiac lesions

We examined the actions of amrinone in five models using dogs to determine under what circumstances intravenous amrinone might exert arrhythmogenic or antiarrhythmic properties. In dogs with 24-h post-coronary artery ligation arrhythmias, amrinone, given at incrementally increasing doses of 1.5, 3.0, and 6.0 mg/kg at 30-min intervals, produced significant increases of cardiac contractility without altering the severity of the arrhythmia. In dogs with 2- to 6-day-old ischemic lesions and 90-100% sinus beats, a bolus dose of 3.0 mg/kg amrinone was followed by an increased incidence of abnormal beats (p = 0.013); neither 1.5 nor 6.0 mg/kg caused a significant incidence of arrhythmias. Acute occlusion of the left anterior descending coronary artery followed by reperfusion caused fibrillation in nine of 15 control dogs and two of 14 dogs treated with 2.3 mg/kg amrinone. This difference was significant at the level p less than 0.05. In ouabain-intoxicated dogs, amrinone at 1.0 and 3.0 mg/kg neither worsened nor improved the arrhythmias. In the atrial circus flutter arrhythmia, amrinone increased ventricular heart rate by a significantly greater amount than it increased atrial rate, suggesting that amrinone facilitates atrioventricular conduction.     

Effects of angiotensin II type 1 receptor antagonist (candesartan) in preventing fatal ventricular arrhythmias in dogs during acute myocardial ischemia and reperfusion

Fatal arrhythmias may be prevented by long-term oral administration of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II type 1 (AT 1 ) receptor antagonists. However, there have been no studies evaluating the electrophysiologic changes that occur with the acute administration of AT 1 receptor antagonists during acute myocardial ischemia and reperfusion. This study aimed to evaluate the ability of candesartan to prevent fatal arrhythmias during acute myocardial ischemia and reperfusion. The left anterior descending (LAD) coronary artery was ligated for 10 min and then reperfused for 10 min in 45 adult mongrel dogs. Candesartan (1 mg/kg) or saline was administered intravenously 10 min before ligation of the LAD coronary artery (candesartan group [n = 20] and control group [n = 25], respectively). Changes in ventricular effective refractory period (ERP) and intramyocardial conduction time (ICT) in the risk area were compared during LAD occlusion and reperfusion. Ischemia-induced shortening of ERP was inhibited in the candesartan group compared with the control. There was a 4.7 +/- 5.8% increase in ERP in the candesartan group, compared with a 11.5 +/- 6.3% shortening in the control group (p < 0.01). Prolongation of ICT was inhibited in the candesartan group compared with the control group during both ischemia and reperfusion (maximal prolongation of ICT: 0.1 +/- 3.0% vs. 37.7 +/- 9.6%, respectively; p < 0.01). Incidence of ventricular fibrillation was lower in the candesartan group than in the control group (25% [5/20] vs. 72% [18/25], respectively; p < 0.01). Candesartan suppresses changes in ERP and ICT during acute myocardial ischemia and reperfusion, suggesting that candesartan can prevent the development of fatal arrhythmias.     

QT-prolonging class I drug, disopyramide, does not aggravate but suppresses adrenaline-induced arrhythmias. Comparison with cibenzoline and pilsicainide

We investigated the effects of class I antiarrhythmic drugs on corrected QT (QTc) interval and adrenaline-induced arrhythmias in halothane-anaesthetized, closed-chest dogs. For this purpose, we plotted a dose–response curve for adrenaline by calculating the arrhythmic ratio, which is the number of ventricular ectopic beats induced by adrenaline divided by the total heart rate, and observed the changes in the arrhythmic ratio–adrenaline dose relation before and after administration of class I drugs. Disopyramide and cibenzoline decreased the arrhythmic ratio induced by adrenaline. Disopyramide prolonged the QTc interval by 20% (P<0.01), but cibenzoline did not. Pilsicainide prolonged the QTc interval (12%), but this drug did not change the arrhythmic ratio. These results indicate that in contrast to the class III drugs which we have reported earlier, i.e. 1,3-dimethyl-6-{2-[N-(2-hydroxyethyl)-3-(4-nitrophenyl)-propylamino]ethylamino}-2,4 (1H,3H)-pyrimidinedione hydrochloride (MS-551), 1-(2-amino-4-methanesulfonamidophenoxy)2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane hydrochloride (KCB-328) and E-1-{[(5-(4-chlorophenyl)-2-furanyl)methylene]amino}-3-[4-(4-methyl-1-piperazinyl)butyl]-2,4-imidazolidinedione dihydrochloride (azimilide), class I drugs do not aggravate adrenaline-induced arrhythmias even though some drugs prolong the QTc interval.     

Actions of a newly synthesized compound (711389-S) on various types of experimentally induced arrhythmias in mammalian species in situ

We examined effects of 711389-S, a new antiarrhythmic agent, on ouabain-induced arrhythmias in dogs and guinea-pigs, aconitine-induced arrhythmias in dogs and mice, adrenaline-induced arrhythmias in dogs under an anesthetized condition, and arrhythmias induced by coronary artery ligation and occlusion by a glass bead in dogs under conscious and un-restrained conditions. 711389-S (1-3 mg/kg, i.v.) decreased the number of ventricular extrasystoles induced by ouabain in dogs, and the doses of ouabain required to induce various types of arrhythmias were increased by pretreatment of guinea-pigs with intraduodenal application of 711389-S (5-10 mg/kg). In mice, 711389-S (3 mg/kg, i.v. or 10 mg/kg, p.o.) significantly prolonged the time to onset of arrhythmias induced by aconitine infusion. Atrial fibrillation induced by a topical application of aconitine on the atrium was blocked by 711389-S (1 mg/kg, i.v.) in dogs. 711389-S (1-3 mg/kg, i.v.) depressed arrhythmias induced by adrenaline and restored the sinus rhythm by significantly decreasing the number of ventricular ectopic beats induced by coronary ligation or occlusion in dogs. Oral administration of 711389-S (10-30 mg/kg) in dogs markedly depressed the ventricular ectopic beats induced by coronary ligation. The half decay time of 711389-S after a single bolus injection of 711389-S ranged from 60 to 80 min. Results indicate that 711389-S has similar antiarrhythmic effects to those of other Class I antiarrhythmic agents in situ, and they suggest that this compound might have potential usefulness as a new type of antiarrhythmic agent for clinical use.     

Alpha-human atrial natriuretic peptide, carperitide, reduces infarct size but not arrhythmias after coronary occlusion/reperfusion in dogs

Carperitide, a recombinant form of alpha-hANP, possesses potent diuretic, natriuretic, and vasodilatory activity, and inhibits the renin-aldosterone system and sympathetic nervous activity. However, its beneficial effects on ischemic myocardium have not been studied fully. We examined carperitide's effects on infarct size, hemodynamics, and arrhythmia frequency in anesthetized dogs (n = 20) subjected to a 90-min coronary artery occlusion/6-h reperfusion protocol. Intravenous infusion of carperitide (0.2 microg/kg/min) commenced 15 min after occlusion and continued during occlusion/reperfusion. Ventricular fibrillation developed in two of 10 control versus three of 10 treated dogs (p = NS). Hemodynamics, collateral blood flow to the ischemic wall measured 10 min after occlusion, and extent of area at risk were comparable for the two groups. Infarct size/area at risk was smaller in treated than in control dogs (4.5 +/- 2.1% vs. 27.8 +/- 7.8%, respectively; p < 0.05). During occlusion, carperitide tended to increase collateral blood flow (+39%) and significantly decreased left ventricular systolic pressure (-13%) and end-diastolic pressure (-40%) compared with baseline. In control dogs, collateral blood flow tended to decrease (-8.3%), whereas most hemodynamic parameters did not change significantly with respect to baseline. The number of arrhythmias recorded during occlusion/reperfusion was similar in the two groups. Intravenous administration of carperitide limited infarct size, but did not reduce incidence of ventricular arrhythmias after 90-min coronary occlusion/6-h reperfusion in anesthetized dogs. Although the beneficial effects of carperitide may be attributable to concomitant changes in hemodynamics and collateral blood flow, the precise mechanisms require further investigation.