Failure of lidocaine to suppress lethal ischemic ventricular arrhythmias in a canine model of previous myocardial infarction.

The antiarrhythmic actions of high-dose intravenous (i.v.) lidocaine infusions were assessed in conscious dogs with spontaneous ventricular ectopy subacutely (48 h) after anterior myocardial infarction and in anesthetized dogs with ventricular tachyarrhythmias inducible by programmed ventricular stimulation at 4-11 days after anterior myocardial infarction. In conscious dogs administered cumulative doses of lidocaine at 48 h after myocardial infarction, a significant reduction in the frequency of spontaneous ventricular ectopic complexes (from 61 +/- 12 to 11 +/- 9% of total complexes) occurred only after administration of 10 mg/kg i.v. lidocaine. In anesthetized postinfarction dogs responding to baseline programmed stimulation with ventricular tachyarrhythmias, lidocaine administration (6 mg/kg i.v. loading dose + 100 micrograms/kg/min i.v. maintenance infusion) resulted in a selective increase in infarct zone conduction time (53.0 +/- 5.6 to 60.5 +/- 6.2 msec; p less than 0.05), increases in infarct zone relative refractory periods (RRPs 182 +/- 5 to 193 +/- 5 ms; p less than 0.05), and effective refractory periods (ERPs 156 +/- 4 to 165 +/- 3 ms; p less than 0.05), and an increase in noninfarct zone ERP (154 +/- 5 to 166 +/- 8 ms; p less than 0.05). The induction of ventricular arrhythmias by programmed stimulation was suppressed by lidocaine (6 mg/kg + 100 micrograms/kg/min i.v.) in 5 of 10 postinfarction animals tested, with an additional 3 animals displaying favorable stabilizations of induced arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of pimobendan (UD-CG 115 BS), a new positive inotropic agent, on ventricular tachycardia and ischemic ventricular fibrillation in a conscious canine model of recent myocardial infarction

Pimobendan (UD-CG 115 BS; 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl- 3(2H)- pyridazinone) is a newly developed, structurally novel compound with positive inotropic as well as coronary and peripheral vasodilator activities. In vitro, pimobendan has been reported to prolong the duration of the cardiac action potential of ventricular myocardial tissue, suggesting the potential for this agent to increase myocardial refractoriness and possibly exert antiarrhythmic activity in vivo. In the present study, the effects of pimobendan upon cardiac electrophysiologic parameters, the induction of ventricular tachycardia by programmed ventricular stimulation, and upon the development of ischemic ventricular fibrillation were assessed in 16 conscious dogs 3 to 5 days after experimental anterior myocardial infarction. The intravenous administration of 0.3 mg/kg pimobendan to postinfarction dogs significantly reduced the rate-corrected QTc and paced QT intervals, and reduced the relative and effective refractory periods in normal noninjured ventricular myocardium. Electrophysiologic parameters in infarcted ventricular myocardium were not altered by pimobendan. Ventricular tachycardia remained inducible early after anterior myocardial infarction in eight of eight pimobendan-treated postinfarction dogs tested. Six of the eight pimobendan-treated animals that had nonsustained tachyarrhythmias elicited as initial responses to baseline programmed stimulation testing had sustained tachycardias induced at postdrug testing, with a reduction in the number of programmed extrastimuli required to induce the postpimobendan tachyarrhythmias occurring in three animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of concordance between the antiarrhythmic and antifibrillatory actions of UM-424, a quaternary ammonium analogue of propranolol

UM-424, 1-dimethyl isopropylamino-3-(2-phenylphenoxy)-propan-2-ol chloride, is a quaternary ammonium derivative of propranolol. Previous studies have demonstrated UM-424 to suppress the development of ventricular arrhythmias in a variety of experimental canine models, while lacking significant beta-adrenergic blocking and cardiodepressant actions. In the present studies, slight and transient reductions in heart rate, coronary flow, and indices of cardiac force and pressure developed only after the intravenous administration of 10.0 mg/kg UM-424. The positive inotropic response to intravenous isoproterenol was not altered significantly by 1.0-10.0 mg/kg UM-424. In conscious dogs 4-7 days after anterior myocardial infarction, UM-424 administered intravenously in a single (5.0 mg/kg) or multiple (5.0 mg/kg q 6 h for 24 h) dose schedule increased the ventricular refractory period from 146 +/- 4 to 180 +/- 3 ms (p less than 0.01), and suppressed the initiation of ventricular tachycardia by programmed ventricular stimulation in six of nine postinfarction dogs tested. However, the incidence of subsequent ventricular fibrillation developing in response to acute ischemia at a site remote from previous myocardial infarction was 100% in both UM-424 (n = 8)- and vehicle (n = 8)-treated postinfarction dogs. These findings suggest UM-424 is ineffective in preventing the development of ischemic ventricular fibrillation in the presence of previous myocardial injury, despite the efficacy of this agent in suppressing other experimentally induced ventricular arrhythmias.     

Effects of flecainide on occlusion and reperfusion arrhythmias in dogs

To assess flecainide's ability to suppress ventricular fibrillation during reperfusion, we compared flecainide acetate (2 mg/kg i.v.) with saline placebo in 50 pentobarbital-anesthetized dogs undergoing proximal anterior descending coronary artery occlusion for 20 min followed by sudden release. Treatment selection was blinded and randomized. Flecainide (1 mg/kg) was given for 5 min before ligation and 1 mg/kg over the 20 min occlusion period. Heart rate, blood pressure, myocardium at risk, and QRS duration before drug infusion were similar between treatment groups. Flecainide prolonged the QRS duration 12% with no effect on heart rate or blood pressure. Dogs successfully cardioverted from ventricular fibrillation during occlusion were subjected to reperfusion. One of the 25 dogs treated with placebo fibrillated during occlusion, whereas 13 of the 25 dogs treated with flecainide fibrillated during occlusion and 10 of these 13 could not be resuscitated. Thirteen of the 25 dogs in the placebo group fibrillated during reperfusion, whereas 3 of the remaining 15 dogs in the flecainide treatment group fibrillated during reperfusion. The proarrhythmic effects of flecainide during occlusion confound interpretation of its antiarrhythmic activity during reperfusion. Thus, although flecainide may have prevented ventricular fibrillation during reperfusion, it clearly caused ventricular fibrillation during occlusion in this preparation of acute myocardial ischemia.     

Effects of ibutilide on spontaneous and induced ventricular arrhythmias in 24-hour canine myocardial infarction: a comparative study with sotalol and encainide.

The electrophysiologic and antiarrhythmic effects of ibutilide, sotalol, and encainide were compared in dogs 24 h after myocardial infarction. Ibutilide (0.03 to 0.3 mg/kg i.v.) prevented the induction of ventricular arrhythmias in 100% of the dogs that had demonstrated inducible ventricular arrhythmias prior to treatment. This antiarrhythmic action was associated with significant increases in ventricular refractoriness and monophasic action potential duration. Sotalol (1.0 to 10.0 mg/kg i.v.) increased the ventricular refractory period and monophasic action potential duration and prevented the induction of ventricular arrhythmias in 75% of the dogs that demonstrated inducible ventricular tachyarrhythmias at baseline. Although 10 mg/kg of sotalol was required to prevent the initiation of ventricular tachycardia, this dose produced marked cardiovascular depression and hypotension in 50% of the dogs tested. Neither ibutilide nor sotalol significantly decreased the incidence of spontaneous ventricular arrhythmias. The class IC agent encainide (0.3 to 3.0 mg/kg i.v.) was successful in preventing the induction of ventricular arrhythmias in only 20% of the dogs tested. However, in contrast to ibutilide and sotalol, encainide significantly reduced spontaneous arrhythmias. Atrial and ventricular refractoriness were significantly increased only after the highest dose of encainide tested (3.0 mg/kg). Over the dose ranges studied, the relative efficacy for prevention of pacing-induced ventricular arrhythmias was ibutilide greater than sotalol much greater than encainide. For suppression of spontaneous ventricular arrhythmias, the relative efficacy was encainide much greater than ibutilide = sotalol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of the effects of intravenous LNC-834, a new antiarrhythmic agent, and quinidine in canine models of arrhythmia.

The effects of intravenous LNC-834, a new antiarrhythmic agent, and quinidine sulfate were evaluated and compared in 24-h infarction, programmed electrical stimulation (PES), and ventricular fibrillation threshold (VFT) canine models of cardiac arrhythmias. In the 24-h infarction model (24 h after myocardial infarction), animals averaged 85% arrhythmic beats before treatment. LNC-834 gave greater suppression of these spontaneous arrhythmias (97%) and had a longer duration of action (150 min) than did quinidine (70% and 85 min, respectively) at 10 mg of base/kg, although plasma levels were comparable (1.82 +/- 0.19 and 1.50 +/- 0.27 micrograms/ml of plasma for LNC-834 and quinidine, respectively). At 10 mg of base/kg, LNC-834 and quinidine increased effective refractory periods by 9 and 7%, respectively. In the PES model, LNC-834 (3 mg of base/kg) suppressed ventricular tachycardia (VT) in 33% (2/6) of the dogs tested: none of the six quinidine-treated animals displayed suppression of VT at cumulative doses of 0.3 to 30 mg of base/kg. In PES dogs, inducible and noninducible, mortality was less with LNC-834 treatment than with quinidine [9% (1/11) and 36% (4/11), respectively]. Neither LNC-834 nor quinidine elevated VFT in naive, anesthetized dogs. Although no treatment significantly affected the intrinsic heart rate in VFT dogs, both LNC-834 and quinidine produced significant hypotension; however, LNC-834 caused less hypotension than did quinidine at equal doses. This study demonstrates that LNC-834 may be a useful antiarrhythmic agent with efficacy comparable to and hemodynamic advantages over quinidine.     

Antiarrhythmic effects of MS-551, a new class III antiarrhythmic agent, on canine models of ventricular arrhythmia.

The antiarrhythmic effects of MS-551, which prolongs cardiac action potential duration without affecting the maximum upstroke velocity of the action potential, were assessed in three different canine ventricular arrhythmia models: 1) ventricular tachycardia (VT) induced by electrical stimuli 3-5 days after myocardial infarction, 2) spontaneous ventricular tachyarrhythmias 24-48 hr after two-stage coronary ligation and 3) ventricular tachyarrhythmias induced by digitalis. Intravenous administration of MS-551 (0.1-1 mg/kg) decreased the susceptibility in 10 dogs out of 13 to VT or ventricular fibrillation evoked by programmed electrical stimulation (PES) delivered to the ventricular septum 3-5 days after myocardial infarction. Oral administration of MS-551 (3 mg/kg) also decreased the susceptibility to VT evoked by PES in 7 out of 10 conscious postinfarction dogs. Concurrently, intravenous (0.1-1 mg/kg) or oral (3 mg/kg) administration of MS-551 produced increases in the ventricular effective refractory periods (ERP) by 7 +/- 1% - 17 +/- 3% or 13 +/- 2%, respectively. Similarly, d-sotalol (0.3-3 mg/kg, i.v. and 10 mg/kg, p.o.) decreased the susceptibility to VT with increased ERP. However, MS-551 (1 and 10 mg/kg, i.v.) failed to inhibit both canine two-stage coronary ligation arrhythmia and digitalis arrhythmia. These results suggest that MS-551 is a pure class III antiarrhythmic drug which may be effective in the treatment of life-threatening reentrant tachyarrhythmias, but not in automaticity arrhythmias.     

Antiarrhythmic effects of desethylamiodarone in dogs with subacute myocardial infarction and inducible ventricular arrhythmias

To determine if desethylamiodarone (DA), the principal metabolite of amiodarone, has antiarrhythmic activity, DA was administered intravenously (i.v.) as a 5 mg/kg bolus followed by a 2-h infusion of 8 mg/kg/h to 12 dogs with 5-7-day-old myocardial infarction and reproducibly inducible sustained ventricular arrhythmias. Programmed electrical stimulation of the right ventricle was repeated, and plasma DA concentration was determined at 15-min intervals during DA administration. At the end of the infusion, the animals were killed and DA concentration in infarcted and noninfarcted myocardium was measured. Grading and statistical analysis of induced arrhythmias revealed significant amelioration during DA infusion, with partial or complete suppression in 9 of the 12 dogs. Apparent steady-state plasma DA concentration (range 0.8-1.0 micrograms/ml) was achieved and maintained during the final 105 min of infusion. DA concentration in noninfarcted myocardium (62.6 +/- 22.0 micrograms/g) was significantly higher (p less than 0.01) than DA concentration in infarcted myocardium (25.6 +/- 18.6 micrograms/g). We conclude that DA administered i.v. has antiarrhythmic activity in dogs with subacute myocardial infarction and reproducibly inducible sustained ventricular arrhythmias.     

Proarrhythmic effects of procainamide and tocainide in a canine infarction model.

A canine model of myocardial infarction (MI) was used to study the type and frequency of ventricular antiarrhythmic and proarrhythmic effects due to procainamide and tocainide and the risk factors associated with development of proarrhythmia. An anterior MI was created by a 2-h occlusion of the left anterior descending artery (LAD) with complete reperfusion. Programmed ventricular stimulation was performed on two occasions after MI, on days 4-6 and on days 8-10, before drug and during antiarrhythmic drug infusion at three dose levels. The antiarrhythmic drugs were given in a randomized cross-over design. Only procainamide caused a dose-dependent increase in QRS, JTc, and right ventricular effective refractory period (ERP). Neither procainamide nor tocainide made sustained ventricular tachycardia (VT) noninducible, but procainamide slowed the tachycardia rate. Both drugs successfully made ventricular fibrillation (VF) noninducible: procainamide in 78% of trials and tocainide in 50% of trials. Proarrhythmia (development of inducible VT during drug when not present before drug or inability to terminate VT during drug administration) developed in 29% of dogs that received procainamide and 25% of dogs that received tocainide. There was no apparent correlation of QRS, JTc, and right ventricular ERP after drugs and proarrhythmia due to procainamide or tocainide. There was no significant difference in the size of MI between dogs with one or more proarrhythmic response to either drug and dogs that had no proarrhythmia. In this model, procainamide and tocainide had no antiarrhythmic efficacy for VT, but had moderate proarrhythmia potential that was unpredictable.     

Development of ventricular tachyarrhythmias in the conscious canine during the recovery phase of experimental ischemic injury: effect of bethanidine administration

The antiarrhythmic and antifibrillatory actions of bethanidine were evaluated in two conscious canine models which are capable of developing ventricular tachyarrhythmias during the recovery phase of myocardial infarction. In the first model, nonsustained (n = 3) or sustained (n = 12) ventricular tachycardia (cycle length, 165 +/- 6 ms; mean +/- SD) was initiated by programmed electrical stimulation, 4-9 days after experimental myocardial infarction. Bethanidine was administered in cumulative doses of 2, 4, 8, and 16 mg/kg and programmed stimulation repeated. Bethanidine, in doses of 4, 8, and 16 mg/kg, slowed the cycle length of the tachycardia and allowed slower rates of ventricular pacing to produce equivalent delays at epicardial sites in the ischemic zone. Despite these changes, induction of sustained ventricular tachycardia was prevented in only two of 13 animals. Bethanidine (8 mg/kg i.v. every 8 h, n = 4; 16 mg/kg i.v. every 8 h, n = 5) failed to prevent the development of premature ventricular beats, ventricular tachycardia, and ventricular fibrillation which developed in response to a transient ischemic episode superimposed on the heart that had a previous acute myocardial infarction. No differences in survival at 24 h were observed between saline- (10%, n = 10) and bethanidine-treated (0%, n = 9) groups. These results suggest that bethanidine acts to increase the refractory period and depresses conduction velocity in ischemically injured tissue, slowing the rate of ventricular tachycardia. However, the drug fails to suppress the development of ventricular arrhythmias and ventricular fibrillation in both canine models.     

Antiarrhythmic and electrophysiologic actions of clofilium in experimental canine models

Clofilium was studied in three experimental models. In non-ischemic and chronically infarcted canine hearts, clofilium (0.5-2 mg/kg) produced a dose-dependent increase in electrical ventricular fibrillation threshold (VFT), but prolonged the effective refractory period (ERP) of normal myocardium in only the non-ischemic heart. When chronically infarcted hearts were subjected to programmed electrical stimulation, 1 mg/kg of clofilium inhibited the re-induction of either ventricular tachycardia or ventricular fibrillation in 5 of 6 animals and slowed the rate of the induced tachycardia in the sixth. Clofilium, however, failed to alter ventricular refractory periods of normal myocardium at either twice diastolic threshold current (176 +/- 5 ms control vs. 187 +/- 9 ms post-clofilium, P greater than 0.05) or at 10 mA (134 +/- 6 ms control vs. 137 +/- 13 ms post-clofilium, P greater than 0.05). In addition, chronic administration of clofilium (2 mg/kg, i.v., followed by 1 mg/kg every 12 h) was ineffective in decreasing mortality in a canine model of sudden coronary death. Of 10 saline-treated conscious animals subjected to an electrically-induced intimal lesion of the left circumflex coronary artery in the presence of a previous ischemic insult, all 10 died suddenly of ventricular fibrillation within 173 +/- 45 min after current application. Under similar conditions, 7 clofilium-treated animals died suddenly within 249 +/- 88 min (P greater than 0.05) after current application while 3 animals survived (P greater than 0.10). Clofilium did, however, elevate the effective refractory period in these animals (150 +/- 3 ms saline-treated vs. 195 +/- 7 ms clofilium-treated). It is concluded from our data that there is little relationship between clofilium's electrophysiologic actions in normal myocardium and antiarrhythmic effects. Furthermore, simple prolongation of refractoriness in normal non-ischemic myocardium may be insufficient for the prevention of ventricular fibrillation which develops in response to a transient ischemic event superimposed on a chronically injured myocardium.     

Effect of digoxin on the extent of injury and the severity of arrhythmias during acute myocardial ischemia and infarction in the dog

Recently, this laboratory has demonstrated an enhanced susceptibility toward the development of lethal ventricular arrhythmias occurring in response to acute posterolateral ischemia in dogs with previous anterior myocardial infarction in the presence of therapeutic serum concentrations of digoxin. In the present study, acute posterolateral myocardial ischemia was produced in the absence of previous myocardial infarction in 15 digoxin-pretreated (1.19 +/- 0.21 ng/ml serum digoxin, 5-7 days pretreatment) and 11 vehicle-pretreated dogs. The incidences of sudden ventricular fibrillation and of 24 h arrhythmic mortality in response to posterolateral ischemia were 4/15 (27%) vs. 1/11 (9%) (p = 0.23) and 7/15 (47%) vs. 4/11 (36%) (p = 0.27) for digoxin- vs. vehicle-pretreated dogs, respectively. Ventricular ectopic activity at 24 and 48 h after the onset of posterolateral ischemia was reduced significantly by both intravenous lidocaine (1.0-5.0 mg/kg) and verapamil (50.0-500.0 micrograms/kg) in the vehicle-pretreated dogs, whereas neither antiarrhythmic agent significantly suppressed ventricular ectopy in the digoxin-pretreated dogs. The mean sizes for developing posterolateral myocardial infarctions (percentage of left ventricle) were greater for the digoxin-pretreatment group (31.9 +/- 2.8%) vs. vehicle-pretreatment group (14.8 +/- 2.0%, p less than 0.001). These findings suggest that uncomplicated acute myocardial ischemia in the presence of serum concentrations of digoxin that are considered clinically therapeutic may result in the development of larger areas of developing myocardial infarction and in the occurrence of ventricular arrhythmias that are less sensitive to suppression with conventional antiarrhythmic agents.     

Mechanism of antiarrhythmic efficacy of propafenone as assessed by programmed electrical stimulation in conscious dogs.

Programmed electrical stimulation (PES) was performed in 18 conscious, chronically instrumented mongrel dogs 6-21 days after a 4-h occlusion of the left anterior descending coronary artery (LAD). At baseline, 8 of 10 animals responded with sustained ventricular tachycardia (SVT) and 2 of 10 responded with ventricular fibrillation (VF). Cumulative administration of 2 and 4 mg/kg propafenone intravenously (i.v.) prevented induction of the baseline arrhythmia in 7 of 10 (p less than 0.05) and 5 of 10 (p = 0.1) animals, respectively. Cumulative administration of two doses of saline to 8 control animals with SVT inducible at baseline did not affect subsequent inducibility. QRS duration was only slightly prolonged after 2 mg/kg propafenone (+3.5 +/- 1.1 ms, p less than 0.05). Administration of 4 mg/kg was associated with a further increase in QRS duration (+8.0 +/- 2.3 ms, p less than 0.01) and a decrease in sinus cycle length (-60.0 +/- 17.2 ms, p less than 0.05). Propafenone consistently and significantly prolonged ventricular refractoriness only in responders. Furthermore, at both dosages, there was a negative correlation between drug-induced increases in ventricular refractoriness and baseline refractoriness (r = -0.72, p = 0.02; r = -0.81, p = 0.005 with 2 mg/kg and 4 mg/kg propafenone, respectively). Thus, the lesser antiarrhythmic efficacy of 4 mg/kg as compared with 2 mg/kg may result from excessive increases in intraventricular conduction time and/or unfavorable hemodynamic effects of this dose. Furthermore, our study confirms an association of the antiarrhythmic efficacy of propafenone with increases in ventricular refractoriness. In addition, the present investigation demonstrated that such increases in refractoriness are most likely to occur at short baseline values.     

Antiarrhythmic effect of chronic oral amiodarone treatment in dogs with myocardial infarction and reproducibly inducible sustained ventricular arrhythmias.

The antiarrhythmic effect of an 8-week oral amiodarone regimen was studied in dogs with 1-week-old myocardial infarction and reproducibly inducible sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Eighteen dogs were randomly assigned to receive either amiodarone, 40 mg/kg/day for 10 days, followed by 30 mg/kg/day for 4 days and then 20 mg/kg/day for 6 weeks (N = 9), or placebo (N = 9). Programmed electrical stimulation was conducted weekly in the two treatment groups. Plasma concentrations of amiodarone and desethylamiodarone were determined weekly, and their myocardial concentrations in the noninfarcted and infarcted regions of the left ventricle were measured at the end of the study. Suppression of inducible arrhythmias was observed at weeks 1,3-7, and 8 in the amiodarone-treated dogs, whereas no suppression occurred in the placebo-treated group. Plasma amiodarone concentration was maximal at 2.5 +/- 1.4 micrograms/ml at week 2, decreased to 1.9 +/- 1.1 micrograms/ml at week 3, and remained steady thereafter. Plasma desethylamiodarone concentrations were in the range of 0.2 +/- 0.1 to 0.4 +/- 0.2 microgram/ml from weeks 1 through 8. Myocardial amiodarone and desethylamiodarone concentrations in the noninfarcted region of the left ventricle were 34.0 +/- 15.8 and 20.8 +/- 7.8 micrograms/g, respectively, at the end of the study. The lack of antiarrhythmic effect of amiodarone at week 2 coincided with the highest plasma amiodarone concentration. The data indicate that this dog model of ventricular arrhythmias is useful for studying the antiarrhythmic action of amiodarone.     

Effects of pirmenol on electrical induction of sustained ventricular tachycardia in a seven-day-old canine myocardial infarction.

Effects of pirmenol on electrical induction of sustained ventricular tachycardia (VT) were examined in 14 dogs with 7-day-old myocardial infarctions. Before administration of the drug, sustained VT was induced in 8 of 14 dogs. After administration of 3 mg/kg pirmenol, induction of VT was suppressed in 2 dogs but remained inducible in 6 dogs. After cumulative administration of 5 mg/kg pirmenol, VT was no longer inducible in 3 dogs but in the other 3 dogs VTs were still inducible at increased cycle lengths. After 7 mg/kg pirmenol, VT was not inducible in the remaining three dogs. Arrhythmias could not be provoked in any postinfarction dogs after pirmenol administration. Plasma concentrations after sequential and cumulative administration of 3, 5, and 7 mg/kg pirmenol averaged 0.43, 0.65, and 1.15 micrograms/ml, respectively. Administration of pirmenol increased the effective refractory period (ERP) and paced QRS duration in both the normal and infarcted ventricular myocardium. In the infarcted myocardium, prolongation of the ERP for the second and third extrastimuli was greater than for the first one (p less than 0.05). Results indicate that pirmenol is effective for prevention of sustained VT owing to prolongation of both the ERP and conduction time in recent myocardial infarction.     

Electrophysiologic and antiarrhythmic actions of sulphinpyrazone and its sulfide metabolite G25671

In anesthetized dogs, the cumulative intravenous administration of 1.0-40.0 mg/kg sulphinpyrazone failed to alter the ventricular excitation threshold, ventricular refractory period and ventricular fibrillation threshold determined during nonobstructed coronary blood flow. Sulphinpyrazone, however, did attenuate the reduction in the ventricular fibrillation threshold occurring during transient myocardial ischemia. G25671, the sulfide metabolite of sulphinpyrazone, failed to alter ventricular refractoriness and 'nonischemic' ventricular fibrillation thresholds, and was minimally effective in reducing the decrease in 'ischemic' fibrillation thresholds when administered in cumulative intravenous doses of 5.0-20.0 mg/kg. In conscious dogs in the subacute phase of anterior myocardial infarction, the administration of a cumulative 10.0-40.0 mg/kg sulphinpyrazone failed to alter the mode of induction, rate or morphology of ventricular tachyarrhythmias initiated by programmed ventricular stimulation. These data suggest that neither sulphinpyrazone nor its sulfide metabolite possess primary electrophysiologic properties which might contribute directly to significant antiarrhythmic or antifibrillatory activity.     

Comparative effects of antiarrhythmic drugs on the ventricular fibrillation threshold

The purpose of this study was to compare the effects of several different antiarrhythmic drugs on the ventricular fibrillation threshold (VFT). Experiments were performed on open-chest dogs anesthetized with pentobarbital. The VFT was measured on the right ventricle by scanning the vulnerable period with a single 10-ms electrical stimulus. The following antiarrhythmic drugs were each given intravenously to eight different dogs: procainamide (25 mg/kg), lidocaine (2 mg/kg + 70 micrograms/kg/min), flecainide (3 mg/kg), timolol (0.1 mg/kg), clofilium (1 mg/kg), dl-sotalol (5 mg/kg), and bethanidine (4 mg/kg). The drugs resulted in the following increases in the VFT: procainamide, 33 +/- 13%; lidocaine, 21 +/- 5%; flecainide, 38 +/- 10%; timolol, 19 +/- 6%; clofilium, 14 +/- 6%; sotalol, 33 +/- 10%; and bethanidine, 69 +/- 15%. The changes in VFT were all significant (p less than 0.01) except for clofilium. Only procainamide and sotalol caused stimulus-induced runs of nonsustained polymorphic ventricular tachycardia that spontaneously reverted to sinus rhythm after 4 s or more. In individual experiments, the occurrence of nonsustained polymorphic tachycardia that resembled ventricular fibrillation could not be correlated with a change in the VFT. In addition, there appeared to be no relationship between a drug-induced increase of the VFT and alterations in the QRS duration, the QT interval, or the ventricular effective refractory period. Bethanidine had the greatest effect on the VFT, in spite of the fact that this drug shortened the ventricular effective refractory period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lidocaine has a narrow antiarrhythmic dose range against ventricular arrhythmias induced by programmed electrical stimulation in conscious postinfarction dogs

Summary The aim of the present study was to investigate the dose-dependent antiarrhythmic efficacy of lidocaine against electrically induced tachycardias in conscious, chronically instrumented postinfarction dogs. Programmed electrical stimulation (PES) was performed in 16 dogs 8 to 21 days after a 4 h occlusion of the left anterior descending coronary artery (LAD). Infusion of saline in 8 control animals with sustained ventricular tachycardia (SVT) inducible at baseline did not affect subsequent inducibility. In the treatment group 7 of 8 animals responded with SVT and one exhibited ventricular fibrillation at baseline. After an initial bolus of 1 mg/kg lidocaine intravenously (i.v.), the drug was infused at infusion rates of 40, 80 and 120 g/kg/min (i.v.). During 80 g/kg/min lidocaine (mean plasma level 3.5 g/ml) 7 out of 8 animals displayed an antiarrhythmic response; both the lower and the higher infusion rate were associated with a smaller antiarrhythmic efficacy (3 of 8 animals responded to 40 g/kg/min and 4 of 8 to 120 g/kg/min). Licocaine did not affect ventricular refractory periods, but induced an increase in intraventricular conduction time at all infusion rates, from 66.2 ms at baseline to 67.7 ms (p<0.05), 67.7 ms (p<0.05), 70.0 ms (p<0.01) respectively.In conclusion the present study demonstrates that lidocaine is of considerable value in the management of PES-induced ventricular arrhythmias in the postinfarction phase. However there is only a small optimal therapeutic plasma level range, where lidocaine exhibits its antiarrhythmic efficacy against this type of arrhythmia; this makes a carefully titration of the drug necessary both in the experimental and in the clinical setting. Send offprint requests to K. Krejcy at the above address     

Effects of bradykinin on inducible sustained ventricular tachycardia two weeks after myocardial infarction in pigs.

We studied the in vivo effect of bradykinin infusion on inducible sustained ventricular tachycardia (VT) 2 weeks after myocardial infarction in pigs, based on the assumption that the antiarrhythmic effect of angiotensin-converting enzyme (ACE) inhibitors may, apart from their angiotensin-II lowering effect, also be due to elevation of endogenous bradykinin levels. Of the six pigs with inducible VT in the control state, four were noninducible during subsequent bradykinin infusion (p less than 0.05). The ventricular effective refractory period (VERP) did not change during bradykinin infusion (from 237 +/- 37 to 239 +/- 42 ms), nor did intraventricular conduction change (filtered QRS duration was 45 +/- 17 ms before and 43 +/- 19 ms during infusion). Bradykinin caused both a significant systolic blood pressure (SBP) decrease (from 79 +/- 14 to 49 +/- 4 mm Hg, p less than 0.001) and diastolic BP (DBP) decrease (from 41 +/- 10 to 27 +/- 4 mm Hg, p less than 0.01). In conclusion, exogenous bradykinin reduced the inducibility of sustained VT 2 weeks after myocardial infarction. Because refractory periods or conduction velocity were not affected, the mechanism of action might be associated with the BP decrease, which can decrease wall stress. The previously reported antiarrhythmic effect of ACE inhibitors may be due in part to elevation of endogenous bradykinin levels.     

Suppression of lethal ischemic ventricular arrhythmias by the class III agent E4031 in a canine model of previous myocardial infarction.

The antiarrhythmic efficacy of a new and potent class III agent E4031 [1-[2-(6-methyl-2-pyridyl)-ethyl]-4-(4- methylsulfonylaminobenzoyl)piperidine] was evaluated in several canine models of recent myocardial infarction. In anesthetized dogs with baseline inducible ventricular arrhythmias studied 4-10 days after anterior myocardial infarction, 30-300 micrograms/kg i.v. E4031 suppressed induction of ventricular tachyarrhythmias by programmed ventricular stimulation in 7 of 10 animals tested, while significantly prolonging refractoriness in both noninfarcted and infarcted ventricular myocardium. The incidence of lethal ischemic ventricular arrhythmias developing in response to acute posterolateral myocardial ischemia in the presence of previous anterior infarction was reduced from 10 of 10 (100%) in a vehicle pretreatment group to 3 of 10 (30%, p less than 0.01) in an E4031 (300 micrograms/kg intravenously, i.v.) pretreatment group. Neither the sizes of the underlying anterior myocardial infarctions (26.9 +/- 3.7 vs. 33.2 +/- 2.1% of left ventricle) nor the times to development of acute posterolateral myocardial ischemia (43 +/- 11 vs. 40 +/- 8 min) differed significantly between the vehicle and E4031 pretreatment groups, respectively, suggesting that the reduction in the incidence of lethal ischemic arrhythmias in the E4031 pretreatment group was not due to smaller underlying, electrically unstable myocardial substrates nor to a delay in onset of the acute ischemic insult. In conscious dogs with spontaneous ventricular ectopy at 48 h after myocardial infarction and in anesthetized dogs with no baseline inducible arrhythmias at 4-10 days after myocardial infarction, E4031 (30-3,000 micrograms/kg i.v.) produced no facilitation or aggravation of spontaneous or inducible ventricular arrhythmias. These findings suggest that pharmacologic agents such as E4031 that increase ventricular refractoriness (class III electrophysiologic activity) may provide significant protection against development of malignant ischemic ventricular arrhythmias in the setting of previous myocardial infarction.