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)     

Electrophysiology and antiarrhythmic actions of E-4031 in the experimental animal model of sudden coronary death.

The Class III agent E-4031 was evaluated for its antiarrhythmic and antifibrillatory actions in conscious dogs 3-5 days after anterior myocardial infarction that were responsive to the induction of tachyarrhythmia by programmed electrical stimulation. The administration of E-4031 as an intravenous loading dose (100 micrograms/kg) followed by an infusion for 90 min (10 micrograms/kg/min) suppressed the induction of ventricular tachycardia by programmed electrical stimulation in 6 of 12 dogs and prolonged the cycle length of the induced arrhythmia in 5 of the 6 remaining animals. Continued administration of E-4031 in a dose regimen of 1,000 microgram/kg every 2 h provided significant protection (8 of 10 dogs) against the development of ventricular fibrillation (sudden coronary death) within the first hour after the onset of myocardial ischemia in a region of the ventricle remote from the infarct-related vessel. The incidence of sudden coronary death was 80% in a comparable control group of electrically inducible postinfarcted dogs. Increases in ventricular myocardial refractoriness in the paced QT and QTc intervals suggest that Class III electrophysiologic actions contribute to the antiarrhythmic and antifibrillatory actions of E-4031. The findings suggest that E-4031 may be of clinical utility in the prevention of life-threatening arrhythmias in the setting of myocardial ischemia in the postinfarcted heart.     

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.     

Antiarrhythmic actions of left stellectomy in digitalis-mediated malignant ventricular arrhythmias in the postinfarcted canine heart

Recently, this laboratory has demonstrated an enhanced susceptibility toward the development of ischemia-related lethal ventricular arrhythmias in the presence of therapeutic serum concentrations of digoxin in conscious dogs after myocardial infarction. The present study was performed to assess the effect of the interruption of cardiac sympathetic influences, via subacute left stellate ganglionectomy (LSGX), on digitalis-mediated ischemic ventricular arrhythmias. Commencing 4-5 days after anterior myocardial infarction, 11 dogs with LSGX and 14 sham controls were administered digoxin (0.0125 mg/kg/day i.v.) for 5-7 consecutive days. At baseline testing, programmed ventricular stimulation failed to initiate ventricular tachycardia in any postinfarction dog entered into this evaluation. After treatment, 11/11 digoxin + LSGX (1.33 +/- 0.10 ng/ml serum digoxin) and 14/14 digoxin-treated sham (1.23 +/- 0.14 ng/ml serum digoxin) dogs remained nonresponsive to programmed stimulation testing. The incidence of arrhythmic mortality in response to subsequent ischemia at a site remote from the infarcted anterior region was greater in the digoxin-treated sham group (1.22 +/- 0.21 ng/ml serum digoxin) than in the digoxin + LSGX group (1.33 +/- 0.10 ng/ml serum digoxin); mortality was 6/10 (60%) digoxin sham vs. 1/10 (10%) digoxin + LSGX, p less than 0.005. The underlying anterior myocardial infarct sizes (% of left ventricle: 6.8 +/- 2.3 vs. 6.6 +/- 1.1) did not differ between the digoxin sham and digoxin + LSGX groups. However, the digoxin sham controls developed larger posterolateral myocardial infarctions than did the digoxin + LSGX animals (% of left ventricle: 27.4 +/- 3.0 vs. 16.7 +/- 2.7, p less than 0.05). Norepinephrine concentrations in posterolateral through posteroseptal ventricular sections were not altered by LSGX in a separate group of digoxin-treated postinfarct dogs. The results suggest that left stellate ganglionectomy may reduce the incidence of digitalis-mediated malignant ventricular arrhythmias during ischemia, possibly due to a reduction in the severity of ischemic injury.     

Effects of the positive inotropic agents milrinone and pimobendan on the development of lethal ischemic arrhythmias in conscious dogs with recent myocardial infarction

The effects of milrinone and pimobendan upon the initiation of programmed ventricular stimulation-induced ventricular tachycardia (VT) and the incidence of lethal ischemic ventricular arrhythmias were assessed in conscious dogs with recent anterior myocardial infarctions. Based upon the results of previous studies, the animals which were entered into this investigation were nonresponsive to baseline programmed stimulation and, therefore, considered to be at "low risk" toward the development of subsequent lethal ischemic arrhythmias. Milrinone (200 micrograms/kg/h continuous i.v. infusion) and pimobendan (300 micrograms/kg i.v.) were administered in dosing regimens shown to produce equivalent and sustained increases in left ventricular (LV) + dP/dt. At the time of repeat electrophysiologic testing, 9 of 9 pimobendan-, 9 of 10 milrinone-, and 12 of 12 concurrent vehicle-treated animals remained nonresponsive to programmed ventricular stimulation. Compared to a total control population of 39 "low risk" postinfarction dogs; however, both milrinone and pimobendan administration increased the incidence of sudden ventricular fibrillation occurring in response to the development of acute posterolateral ischemia (milrinone 4 of 10 [40%] and pimobendan 4 of 10 [40%] versus "low risk" control population 4 of 39 [10.3%]; p = 0.038). The incidence of ischemic mortality at 24 h after the development of posterolateral myocardial ischemia was increased in the milrinone-treated group (6 of 10 [60%]) compared to the "low risk" control population (6 of 39 [15.2%]; p = 0.007), whereas the incidence of 24-h ischemic mortality in the pimobendan-treated group (4 of 10 [40%]) was only of borderline statistical significance when compared to that of the "low risk" control population (p = 0.083). Milrinone, but not pimobendan, delayed the onset of acute posterolateral myocardial ischemia in the postinfarction dogs. The predominant electrophysiologic effects of both milrinone and pimobendan were decreases in ventricular refractoriness in both non-infarct (NZ) and in infarct zones (IZ), as well as reductions in electrocardiographic QTc or QT intervals. These findings suggest that with both positive inotropic agents, including milrinone which may possess protective antithrombotic action, sudden death may be increased via a reduction in ventricular refractoriness in the ischemically injured heart. The enhanced susceptibility toward the development of ischemic ventricular arrhythmias in the presence of the inotropic interventions is not predicted by programmed ventricular stimulation testing prior to the ischemic event.     

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.     

Effects of flecainide acetate on ventricular tachyarrhythmia and fibrillation in dogs with recent myocardial infarction

The antiarrhythmic and antifibrillatory actions of the class IC antiarrhythmic agent flecainide acetate were examined in urethane-anesthetized dogs with recent myocardial infarction. The intravenous administration of flecainide in a loading dose of 1.0 mg/kg (n = 7) or 2.0 mg/kg (n = 6), followed by a maintenance infusion of 1.0 mg/kg/h to achieve plasma drug concentrations considered clinically therapeutic, failed to significantly elevate the electrical threshold current required to provoke ventricular fibrillation at infarct zone, border zone and non-infarct zone stimulation sites in postinfarction dogs. In 8 dogs which responded to baseline programmed stimulation with inducible sustained ventricular tachycardia, flecainide administered as 1.0 or 2.0 mg/kg loading doses followed by a 1.0 mg/kg/h maintenance infusion failed to prevent ventricular tachycardia initiation in any animal tested, although the post-treatment ventricular tachycardia cycle lengths were prolonged compared to baseline values (pre: 178 +/- 11 ms vs post: 202 +/- 17 ms, p less than 0.05). Flecainide administration apparently facilitated the induction of newly sustained ventricular tachycardia in 3 previously noninducible postinfarction dogs. The development of acute posterolateral ischemia at a site remote from previous anterior myocardial infarction resulted in the development of ventricular fibrillation in 4 of 11 (36%) saline-treated postinfarction dogs vs a cumulative 10 of 12 (83%) flecainide-treated, baseline noninducible postinfarction dogs (p less than 0.05 vs saline-treated). The incidence of sudden ischemic ventricular fibrillation was 7 of 7 (100%) among flecainide-treated baseline inducible postinfarction dogs. These data suggest that flecainide acetate may have only limited efficacy in preventing ventricular tachycardia or ventricular fibrillation soon after myocardial infarction.     

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)     

Effect of E-4031, a class III antiarrhythmic agent, on experimental infarct size in a canine model of myocardial ischemia-reperfusion injury.

Class III antiarrhythmic agents such as E-4031 have demonstrated efficacy in preventing and/or terminating malignant ventricular arrhythmias in experimental models. It has recently been suggested that Class III agents might possess additional antiischemic properties that may translate into a reduction in the frequency or severity of arrhythmia. The potential for the Class III antiarrhythmic agent E-4031 to limit the extent of developing myocardial infarction was assessed in a barbiturate-anesthetized canine model of ischemic-reperfusion injury. Untreated control (n = 13) and E-4031-treated animals (n = 8, 300 micrograms/kg, i.v., immediately preceding myocardial ischemia) were subjected to a 90-min period of left circumflex coronary artery occlusion followed by a 5-h period of reperfusion. The predominant hemodynamic effect displayed by E-4031 was a reduction in heart rate throughout the period of coronary artery occlusion and early reperfusion. Areas at risk of infarction, expressed as percentages of left ventricle, were equivalent in the control and E-4031 treatment groups (38.5 +/- 1.0 and 34.6 +/- 1.9%, respectively). Posterolateral myocardial infarct sizes, expressed either as percentages of risk area or of total left ventricle, were reduced slightly but not significantly in the E-4031 treatment group compared to the control group (35.2 +/- 5.6 and 45.4 +/- 3.0% of risk area, respectively; 12.7 +/- 2.4 and 17.6 +/- 1.4% of left ventricle, respectively). Regional myocardial blood flows in nonischemic and central ischemic zones of myocardium did not differ significantly between the control and E-4031 treatment groups before and during the period of coronary artery occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiac electrophysiologic and inotropic actions of new and potent methanesulfonanilide class III antiarrhythmic agents in anesthetized dogs.

The effects of cumulative intravenous (i.v.) administration of potent and selective methanesulfonanilide class III antiarrhythmic agents on cardiac electrophysiologic and hemodynamic parameters were compared with those of D-sotalol in chloralose-anesthetized dogs. The new class III agents tested were E-4031 [1-(2-(6-methyl-2-pyridyl)ethyl)-(4-methanesulfonamidobenzoyl)pipe ridine]; UK-66,914 [N-(4-(1-hydroxy-2-(4-(4-pyridinyl)-1-piperazinyl)ethyl)phenyl) methanesulfonamide], and UK-68,798 [1-(4-methanesulfonamidophenoxy)-2-(N- (4-methanesulfonamidophenethyl)-N-methylamino)ethane]. The class III agents produced significant and dose-dependent increases in ventricular refractoriness, with effective doses required to increase ventricular relative refractory period 20 ms above baseline (ED20, micrograms/kg i.v., with 95% confidence limits) of 5.2 (4.2-6.6) for UK-68,798, 17 (13-23) for E-4031, 75 (58-99) for UK-66,914, and 3,700 (2,600-5,800) for D-sotalol. Significant increases in the electrocardiographic QT and QTc intervals paralleled the increases in ventricular refractoriness for the four class III agents. Significant increases in left ventricular (LV) + dP/dt also paralleled increases in ventricular refractoriness and QT intervals for E-4031 (10-1,000 micrograms/kg i.v.), UK-66,914 (100-1,000 micrograms/kg i.v.), and UK-68,798 (30-1,000 micrograms/kg i.v.), but not for D-sotalol. No concomitant alterations in LV-dP/dt were observed for the new and potent methanesulfonanilide class III agents, resulting in significant increases in the ratio of LV + dP/dt/-dP/dt for E-4031, UK-66,914, and UK-68,798. Potent and selective methanesulfonanilide class III agents therefore may augment cardiac contractility in addition to prolonging ventricular refractoriness.     

Myocardial contractile behavior of a new sotalol derivative.

The effects of E4031, a new class III antiarrhythmic agent similar to sotalol, were tested in isometrically contracting rabbit papillary muscles and in anesthetized, open-chest dogs. In papillary muscles, E4031 caused a modest dose-dependent increase of 26 +/- 8% in developed tension and 38 +/- 8% in its maximal rate of rise. Since there was no significant change in the maximal rate of relaxation, the ratio between both maximal velocities increased from 0.92 +/- 0.03 to 1.19 +/- 0.10. Time to peak tension did not change significantly, whereas time to half relaxation increased from 72 +/- 3 to 85 +/- 4 ms. The effective refractory period in the rabbit papillary muscles increased from 179 +/- 10 to 414 +/- 45 ms. In the open-chest dog, the i.v. administration of E4031 did not induce significant changes in heart rate, mean arterial pressure, or left ventricular end diastolic pressure. +dP/dt increased from 1,839 +/- 162 to 2,470 +/- 247 mm Hg/s with no significant change in -dP/dt after 100 micrograms/kg of E4031. Consequently, (+dP/dt)/(-dP/dt) increased from 0.97 +/- 0.07 to 1.18 +/- 0.08. To further evaluate the effects of E4031 on myocardial relaxation, the time constant of isovolumic left ventricular pressure decay was measured by two different methods (tau 1 and tau 2) before and after administering 10 micrograms/kg E4031. Tau 1 increased from 27 +/- 1.8 to 33 +/- 1.6 ms and tau 2 increased from 30 +/- 2.3 to 41 +/- 3.3 ms.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Acute electrophysiologic effects and antiarrhythmic/antifibrillatory activity of intravenous amiodarone in a chronic feline infarction model

In animal studies, amiodarone has substantial and immediate antiarrhythmic/antifibrillatory action during acute myocardial ischemia. The magnitude of this effect is discordant with the minor degree of prolongation of ventricular action potential duration (APD) and refractoriness which occurs immediately after acute drug administration. However, amiodarone's early onset of antiadrenergic activity and inhibition of inward slow calcium channel currents may be important when arrhythmogenesis is dependent on increased sympathetic tone. Because ventricular arrhythmia substrate may differ in acute and chronic ischemic heart disease, we investigated the acute electrophysiologic and antiarrhythmic/antifibrillatory effects of intravenously (i.v.) administered amiodarone in nine chronically infarcted cats. Amiodarone caused significant decreases (-17%) in mean heart rate (HR) and increases (+10%) in mean ventricular effective refractory period (ERP), which occurred promptly after drug administration. Increases in mean ventricular fibrillation (VF) threshold also occurred (11 +/- 3.4 and 12.5 +/- 2.4 mA for right and left ventricular sites before drug as compared with 45.5 +/- 13.2 and 42 +/- 13.9 mA after drug). Despite these changes, no significant reduction in the incidence of malignant ventricular arrhythmias induced by programmed stimulation was noted (63% of animals with arrhythmia induced before drug were still inducible after drug). In addition, no change in the increased degree of mean dispersion of refractoriness between infarcted and normal myocardial sites occurred following amiodarone (22.8 +/- 3.9 ms before vs. 30.2 +/- 2.5 ms after drug). In chronic myocardial infarction without superimposed acute ischemia, early onset of amiodarone's antiadrenergic and calcium channel blocking activities may play only a minor role in preventing ventricular arrhythmias inducible by programmed stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alpha-adrenergic influences in canine ischemic sudden death: effects of alpha 1-adrenoceptor blockade with prazosin

The antiarrhythmic and antifibrillatory actions of the alpha 1-adrenoceptor antagonist prazosin were evaluated in conscious dogs 4-7 days after anterior myocardial infarction. Both the intravenous (i.v.) low single dose administration of 100 micrograms/kg and the higher multiple dose administration of 500 micrograms/kg every 6 h for 24 h failed to alter electrocardiographic intervals, ventricular effective refractory periods, or the induction of ventricular tachycardia (VT) by programmed ventricular stimulation. During the first 30 min of a subsequent episode of acute posterolateral ischemia, the incidence of ventricular fibrillation (VF) was reduced from 13 of 16 (81%) in vehicle-pretreated control animals to 2 of 8 (25%, p less than 0.05) in animals pretreated with 100 micrograms/kg prazosin and 3 of 8 (37%, p less than 0.05) in animals pretreated with 500 micrograms/kg prazosin every 6 h for 24 h. The continued administration of prazosin in the higher dose regimen, every 6 h for 24 h, significantly enhanced survival at 24 h after the onset of posterolateral ischemia in postinfarction dogs relative to the vehicle group [24-h survival: 1 of 16 (6%) vehicle v 4 of 8 (50%) in higher dose prazosin group, p less than 0.05]. These findings suggest that the blockade of alpha 1-adrenoceptor stimulation may be efficacious in preventing lethal ventricular arrhythmias associated with acute ischemia, despite the lack of effect on electrophysiologic parameters and induction of VT in the postinfarction setting.     

Antiarrhythmic and antifibrillatory actions of the levo- and dextrorotatory isomers of sotalol

The electrocardiographic responses to programmed ventricular stimulation and acute posterolateral myocardial ischemia were studied in conscious dogs treated with the resolved optical isomers of sotalol. Studies were conducted 3-7 days after anterior myocardial infarction to determine the relative contributions of beta-adrenergic receptor blockade and direct Class III electrophysiologic actions in the antiarrhythmic and antifibrillatory actions of the isomers. With cumulative i.v. administration of up to 8 mg/kg, both the beta-blocking levorotatory isomer and the dextrorotatory isomer suppressed the induction of ventricular tachyarrhythmias by programmed stimulation in at least 50% of dogs tested. Both isomers produced equivalent 15-20% increases in normal zone ventricular refractoriness, thereby preventing propagation of programmed ventricular extrastimuli of sufficient prematurity to elicit tachyarrhythmias. The levorotatory isomer of sotalol prolonged the PR interval; the administration of the dextrorotatory isomer increased QTc and, in several dogs, was associated with the development of ventricular ectopy. The prior administration of 8 mg/kg of either optical isomer of sotalol prevented the immediate spontaneous development of ventricular fibrillation in response to ischemia at a distance from the previous site of infarction. These results suggest that alterations in ventricular refractoriness may underlie the antiarrhythmic and antifibrillatory actions of the optical isomers of sotalol and of racemic sotalol.     

Antiarrhythmic and arrhythmogenic actions of methyl lidocaine during the recovery phase after canine myocardial infarction

Programmed electrical stimulation was used to evaluate the electrophysiologic and antiarrhythmic actions of methyl lidocaine in both conscious and anesthetized dogs, 4-7 days after myocardial infarction. When administered to animals demonstrating sustained ventricular tachycardia (n = 6), methyl lidocaine (5 and 10 mg/kg i.v.) prevented the induction of the original ventricular tachycardia in 2 dogs, and in the remaining 4 dogs slowed the tachycardia (cycle length 163 +/- 18 ms vs. 198 +/- 11 and 219 +/- 11 ms, respectively, p less than 0.05). New morphologic forms of sustained tachycardia were observed after drug administration in 4 of 6 experiments. When administered to animals developing only nonsustained ventricular tachycardia or no arrhythmias with programmed stimulation, methyl lidocaine administration enabled programmed stimulation to produce monomorphic sustained ventricular tachycardia in 10 of 13 experiments. The drug increased activation delays in both normal and ischemically injured epicardium, with larger activation delays always observed in ischemically injured tissue. The drug increased refractoriness in ischemically injured myocardium without altering refractoriness in normal tissue. The data suggest that the depression of conduction and prolonged refractoriness produced by methyl lidocaine in ischemically injured tissue may extinguish or slow some forms of ventricular arrhythmia while promoting the formation of new reentry pathways.     

Electrophysiologic actions of lidocaine in a canine model of chronic myocardial ischemic damage--arrhythmogenic actions of lidocaine

Lidocaine facilitated the induction of ventricular arrhythmias by programmed electrical stimulation in 16 dogs, 5 to 14 days after a temporary (90-min) occlusion of the left anterior descending coronary artery. In these 16 animals, programmed stimulation failed to produce ventricular tachyarrhythmias in any animal before lidocaine administration (3 mg/kg), while after lidocaine administration, programmed stimulation produced nonsustained ventricular tachycardia in four animals (25%), sustained ventricular tachycardia in nine animals (56%), and ventricular fibrillation in one animal (6%). Delayed electrical activity in ischemically injured ventricular myocardium produced by premature ventricular stimuli (mean +/- SD = 179 +/- 34 ms) was delayed further by the administration of lidocaine (237 +/- 42 ms, p less than 0.01), resulting in continuous local electrical activity between the final premature ventricular stimulus and the initial beat of the resultant ventricular tachycardia. Lidocaine administration did not alter myocardial refractoriness in normal ventricular tissue, but it prolonged refractoriness in ischemically injured ventricular myocardium. These results show that lidocaine can have arrhythmogenic actions when administered in the presence of existing ischemic injury, possibly the result of increased delay in activation of ischemically injured ventricular myocardium with localized reentry of myocardial electrical activity.     

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.     

Antiarrhythmic evaluation of naloxone against acute coronary occlusion-induced arrhythmias in pigs

Naloxone pretreatment (1.0, 3.0 and 10.0 mg/kg i.v.) failed to protect anesthized pigs from cardiac arrhythmias including ventricular fibrillation (VF) and death following acute occlusion (20 min) or reperfusion of the left anterior descending coronary artery. These findings suggest that opiate-like substances possibly released by the ischemic myocardium do not contribute significantly to the etiology of cardiac arrhythmias, or sudden death associated with the early stages of myocardial infarction in pigs. The effectiveness of naloxone in preventing acute ischemia-induced arrhythmias in rats my be due to mechanisms other than opiate-receptor blockade.