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)     

Electrophysiologic effects of bepridil in normal and infarcted canine myocardium

The electrophysiologic effects of bepridil, 10 mg/kg i.v., were determined in normal noninfarcted and in infarcted ventricular myocardium in 8 urethane-anesthetized dogs 4-6 days after anterior myocardial infarction. At drive cycle lengths of 400 and 333 ms, bepridil significantly increased relative (RRP) and effective (ERP) refractory periods in both normal ventricular tissue (mean increases, RRP 7-14%, ERP 5-6%, p less than 0.05-0.01) and in infarcted ventricular tissue (mean increases, RRP 12-15%, ERP 13-14%, p less than 0.01). Bepridil also selectively prolonged the local activation delay in infarcted ventricular myocardium (mean increases 37.5-45.1%, p less than 0.01), while ventricular excitation thresholds were not altered by bepridil in either normal or infarcted myocardium. Before bepridil administration, programmed ventricular stimulation initiated sustained ventricular tachycardias in 6 of the 8 postinfarction dogs tested. After bepridil, 2 of the 6 previously responsive animals were rendered noninducible, 3 animals responded to programmed stimulation with nonsustained tachyarrhythmias of relatively slower rates, and the one remaining dog responded with sustained ventricular tachycardia (VT). These data suggest that increases in refractoriness in both normal noninjured and in ischemically injured ventricular tissue, with a selective delay in conduction in ischemically injured tissue, contribute to the antiarrhythmic actions of bepridil in the setting of myocardial infarction.     

The antiarrhythmic actions of intravenous and oral UM424 in postinfarction canine myocardium

The electrophysiologic and antiarrhythmic effects of oral and intravenous UM424 were studied in canine models of acute and chronic myocardial injury. In the first phase of this study, reentrant ventricular tachyarrhythmias and/or ventricular fibrillation were initiated by programmed electrical stimulation techniques in seven dogs 48-120 h after myocardial infarction. The cycle length of these reentrant ventricular beats was 176 +/- 16 ms, and they were accompanied by fractionated asynchronous epicardial electrical activity in the injured region that bridged the diastolic interval, i.e., 143 +/- 37 ms. When this prolonged, diastolic electrical activity ceased, the ventricular tachyarrhythmias ceased. UM424 5 mg/kg i.v. increased the effective refractory period of the normal myocardium by 21 ms (p less than 0.05), depressed cardiac conduction in the injured, infarcted myocardium and suppressed these reentrant tachyarrhythmias. Ventricular fibrillation could not be initiated after UM424. In the second phase of this study, a canine model of coronary artery thrombosis was used to produce spontaneous ventricular arrhythmias. UM424 60 mg/kg p.o. converted these ventricular arrhythmias to normal sinus rhythm. This pharmacologic action was not associated with deleterious hemodynamic side effects and lasted for 3 h, the duration of each experiment. These results demonstrate that after oral or intravenous administration, UM424 possess antiarrhythmic and antifibrillatory actions in canine models of acute and chronic myocardial injury.     

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 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.     

Proarrhythmic potential of halofantrine, terfenadine and clofilium in a modified in vivo model of torsade de pointes

1. This study was designed to compare the proarrhythmic activity of the antimalarial drug, halofantrine and the antihistamine, terfenadine, with that of clofilium a K(+) channel blocking drug that can induce torsade de pointes. 2. Experiments were performed in pentobarbitone-anaesthetized, open-chest rabbits. Each rabbit received intermittent, rising dose i.v. infusions of the alpha-adrenoceptor agonist phenylephrine. During these infusions rabbits also received increasing i.v. doses of clofilium (20, 60 and 200 nmol kg(-1) min(-1)), terfenadine (75, 250 and 750 nmol kg(-1) min(-1)), halofantrine (6, 20 and 60 micromol kg(-1)) or vehicle. 3. Clofilium and halofantrine caused dose-dependent increases in the rate-corrected QT interval (QTc), whereas terfenadine prolonged PR and QRS intervals rather than prolonging cardiac repolarization. Progressive bradycardia occurred in all groups. After administration of the highest dose of each drug halofantrine caused a modest decrease in blood pressure, but terfenadine had profound hypotensive effects resulting in death of most rabbits. 4. The total number of ventricular premature beats was highest in the clofilium group. Torsade de pointes occurred in 6 out of 8 clofilium-treated rabbits and 4 out of 6 of those which received halofantrine, but was not seen in any of the seven terfenadine-treated rabbits. 5. These results show that, like clofilium, halofantrine can cause torsade de pointes in a modified anaesthetized rabbit model whereas the primary adverse effect of terfenadine was cardiac contractile failure.     

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.     

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)     

Cellular electrophysiological effects of the class III antiarrhythmic agents sematilide and clofilium on rabbit atrial tissues.

Sematilide (N-[2-(diethylamino)ethyl]-4- [(methylsulfonyl)amino]benzamide HCl) is a new class III antiarrhythmic agent that has been shown to be effective in preventing reentrant ventricular arrhythmias in experimental animals and humans. In this study, we examined the in vitro effects of sematilide (1-100 microM) on isolated sinoatrial (SA) node, atrioventricular (AV) node, and atrial muscle. These results were then compared to another class III agent, clofilium (1-30 microM). In SA nodal tissue, sematilide increased the action potential duration (APD) and spontaneous cycle length (SCL) in a concentration-dependent manner (EC20% = 15 +/- 3 and 54 +/- 13 microM, respectively). In addition, there was a slight reduction in maximum diastolic potential at 100 microM. Clofilium had similar class III effects, but was approximately 3 to 18 times more potent (EC20% = 6 +/- 2 and 3 +/- 1 microM for the APD and SCL, respectively). Neither agent had a significant effect on the slope of phase 4 nor on other action potential parameters. Results in AV nodal preparations were similar. Both sematilide and clofilium increased the APD and SCL in a concentration-dependent manner, with clofilium being approximately four to six times more potent than sematilide (EC20% for the APD and SCL for sematilide = 12 +/- 4 and 12 +/- 8 microM, respectively, and for clofilium = 2 +/- 1 and 3 +/- 2 microM, respectively). No significant effects were observed on other action potential parameters. Sematilide and clofilium increased the APD and effective refractory period (ERP) in atrial trabeculae in a concentration-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)     

Monophasic action potentials during reentrant atrial flutter in the dog: effects of clofilium and acetylcholine

Monophasic action potentials (MAP) were recorded from canine atrium during reentrant flutter resulting from circus movement in atrial tissue above the tricuspid ring. A catheter and plaque contact electrodes were developed to record MAP from the epicardium or endocardium during sinus rhythm, paced rhythms, and flutter. The transmembrane action potential duration of tricuspid ring tissue also was studied in vitro. During flutter at cycle lengths of 140-160 ms, MAP showed incomplete repolarization. Pacing at comparable cycle lengths had a similar effect. Acetylcholine (10 micrograms/kg, i.v.) shortened MAP duration during pacing and, during flutter, decreased cycle length and increased MAP amplitude. Clofilium (500 micrograms/kg, i.v.) prolonged flutter cycle length by 18% and terminated the flutter within 30-120 s. During pacing at a cycle length of 300 ms, clofilium increased MAP duration and effective refractory period (ERP) by 30%. Transmembrane action potentials showed that clofilium (0.2 mg/L) modified only action potential duration. Conduction velocity was significantly decreased by clofilium during flutter but not during pacing at a cycle length of 300 ms. These data support the conclusion that in this model of flutter, the circus movement occurs in partially repolarized tissue. The circus movement can be accelerated by agents (acetylcholine) that reduce ADP, and slowed and terminated by agents (clofilium) that increase it.     

Profibrillatory actions of pinacidil in a conscious canine model of sudden coronary death.

Pinacidil is one of a number of new antihypertensive agents possessing an action that involves an enhanced potassium efflux in cardiac and vascular smooth muscle. An associated feature of pinacidil is a shortening of the cardiac action potential duration, which may constitute a potentially proarrhythmic effect. The present study evaluated pinacidil (0.3 mg/kg/h i.v. for 6 h) on the postinfarcted canine heart in a subset of dogs unresponsive to programmed electrical stimulation during the subacute phase of anterior myocardial infarction, and known to be at low risk of ventricular fibrillation in response to acute posterolateral ischemia. Results were compared with a comparable control group of vehicle-treated, noninducible animals. Nonsustained ventricular tachyarrhythmia developed in 2 of 15 pinacidil-treated animals as compared to the initiation of ventricular tachycardia in 1 of 16 postinfarcted hearts (p = 0.96) in the control group. Thus, pinacidil did not alter the responsiveness of the postinfarcted heart with respect to the electrical induction of tachyarrhythmias. The subsequent development of an acute ischemic event at a site remote from the previous myocardial infarction was associated with a greater incidence of ventricular fibrillation within 1 h from the onset of ischemia in the pinacidil-treated animals (9/15; 60%) as compared to the control group (1/15; 6.7%; p = 0.007). The 24-h cumulative mortality, likewise, was greater in the pinacidil-treated group [13/15 (87%)] as compared to the vehicle-treated control group 3/15; 20%; p = 0.001. Significant cardiovascular and electrophysiologic effects of pinacidil included an increase in heart rate (124 +/- 6-143 +/- 10 beats/min, p less than 0.05) and reductions in the refractory periods of normal (178 +/- 2-166 +/- 4 ms, p less than 0.05) and peri-infarcted (170 +/- 5-185 +/- 5 ms, p less than 0.01) myocardial regions. It is concluded that pinacidil does not alter the responsiveness of the postinfarcted heart to programmed electrical stimulation. However, in the presence of a superimposed acute ischemic event, pinacidil increases the potential for the development of ventricular fibrillation in a subset of postinfarcted animals that otherwise show a low risk with respect to the development of lethal arrhythmias. It is hypothesized that the increased tendency to develop ventricular fibrillation is associated with the pinacidil-induced reduction in the ventricular refractory period. This conclusion is consistent with the known ability of pinacidil to enhance potassium efflux during myocardial repolarization and to decrease the duration of the action potential.     

Block of gating currents related to K+ channels as a mechanism of action of clofilium and d-sotalol in isolated guinea-pig ventricular heart cells.

1 The possibility that the class III antiarrhythmic drugs clofilium and d-sotalol might affect delayed rectifier potassium channels at the level of their gating currents was assessed with the whole-cell patch-clamp technique in guinea-pig isolated ventricular heart cells. 2 Clofilium (up to 20 microM) and d-sotalol (1 microM) did not decrease the Na current, the L-type Ca current or the background K current iKl, but significantly depressed the time-dependent delayed outward K current iK. 3 Clofilium partially decreased in a dose-dependent manner (1-20 microM) QON of intramembrane charge movements (ICM) elicited by a depolarizing pulse applied from a holding potential of -110 mV or following a 100 ms inactivating prepulse to -50 mV. D-sotalol (1 microM) also decreased QON. Channel density estimated from the clofilium-sensitive ICM closely matched that of the delayed rectifier channels. 4 Clofilium and d-sotalol decreased QOFF seen on repolarization in a dose- and voltage-dependent manner. The kinetics of the decay of the OFF gating currents were not affected, and only the fast phase was depressed. 5 In control conditions, QON availability with voltage was most of the time well described by two inactivating components. In the presence of clofilium and d-sotalol, a complex behaviour of QON availability was observed, unmasking additional components. The reactivation kinetics of QON after a 500 ms inactivating pulse to 0 mV was not affected. 6 We conclude that delayed rectifier K channels significantly contribute to QON and QOFF of ICM in guinea-pig ventricular heart cells, besides Na and Ca channels, and that clofilium and d-sotalol directly interact with these K channels proteins by affecting their gating properties.     

Effects of clofilium on cardiovascular tissues from normo- and hypertensive rats

1. The overall aim was to test whether clofilium has some potential as a positive inotrope for heart failure. We used Wistar Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHRs) and studied the effects of clofilium on isolated blood vessels, left ventricular action potentials and left ventricular contractility. 2. Clofilium at < or = 10(-6) M had no effect on WKY portal vein contractions and at < or = 3 x 10(-4) M had no effect on WKY or SHR quiescent mesenteric and intralobar pulmonary arteries. 3. Clofilium at 10(7) - 10(-5) M prolonged the WKY left ventricular action potentials and with 10(-6) and 10(-5)M this included after-depolarizations. 4. Clofilium at < or = 3 x 10(-5) M augmented the peak force, prolonged the contractions and did not cause arrhythmias in the absence and presence of isoprenaline on left ventricle strips from 12-month-old WKY. 5. The 12-month-old SHR has hypertrophy of the left ventricle with reduced peak force and prolongation of relaxation. The effects of clofilium on 12-month-old SHR left ventricle contractility were similar to those in the age-matched WKY. 6 In summary, clofilium has positive inotropic effects on the rat left ventricle that are maintained in hypertrophy. Clofilium does not have effects on blood vessels that would be detrimental in heart failure. Clofilium prolongs the rat left ventricle action potential and causes after-depolarizations. The pro-arrhythmic potential of clofilium, however, makes it unlikely that it could be used as a positive inotrope in the treatment of heart failure.     

A dual model for cardiac arrhythmias: coexistence of re-entry and abnormal automaticity and effects of antiarrhythmic agents.

1. We have developed a dual model for arrhythmia anaesthetized dogs. The model consists of an inducible re-entrant atrial tachycardia and spontaneous ventricular ectopies in the same heart. 2. The model for re-entrant atrial tachycardia was created by crushing the right atrium longitudinally in the intercaval region and transversely in the front free wall parallel to the atrioventricular groove. Ventricular abnormal automaticity was produced by prior (20 approximately 24 h) left anterior descending coronary artery occlusion. The ventricular arrhythmia was partially suppressed during rapid pacing-induced atrial tachycardia and resumed after atrial re-entry was terminated. 3. Mapping experiments indicate that the atrial tachycardia was due to circus movement occurring in the tissue around the tricuspid ring. This re-entrant circuit was identical to that induced in the model created by the incision method. 4. Clofilium (0.75 mg kg-1, n = 5) increased the cycle length of atrial re-entry by 14 +/- 4% from 139 +/- 12 to 159 +/- 18 ms (P less than 0.05). Flecainide (1.8 +/- 0.9 mg kg-1, n = 5) prolonged the cycle length of the tachycardia by 114 +/- 57% from 158 +/- 11 to 332 +/- 66 ms (P less than 0.05). 5. Both drugs terminated the atrial arrhythmia, but re-entry could be reinduced only in flecainide-treated dogs. Flecainide reduced ventricular ectopies by 89 +/- 19%, whereas clofilium did not change ventricular abnormal automaticity or maximum pacing cycle length that is necessary to overdrive the ventricle fully.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cellular electrophysiology of clofilium, a new antifibrillatory agent, in normal and ischemic canine Purkinje fibers

Intracellular electrophysiological studies were performed on isolated canine cardiac tissues to investigate further the reported ability of clofilium (3 X 10(-8)--10(-6) M) to selectively increase action potential duration (APD) and refractoriness. In Purkinje fibers from normal dogs, clofilium did not influence (1) the rate of rise of the action potential (Vmax) elicited from normal or depolarized (10 mM potassium) resting potentials, (2) the Vmax of premature potentials elicited during the repolarization phase of a previous action potential or (3) the rate of diastolic depolarization of spontaneously firing Purkinje fibers. The diastolic interval was altered by inserting a single premature impulse during diastole or by varying the basic cycle length. Clofilium (3 X 10(-7) M) slightly reduced the time constant for the relation between diastolic interval and APD in concentrations that caused a maximal increase in APD of nonpremature impulses. In dogs subjected to occlusion of the left anterior descending coronary artery 48 hr before study, the APD of surviving Purkinje fibers was longer in the infarcted zone than in the normal zone. Clofilium (3 X 10(-8) M) increased APD in both zones but more so in the normal areas, thus reducing the disparity of APD between zones. Similarly, clofilium (3 X 10(-8) and 3 X 10(-7) M) increased the effective refractory period in both zones but more so in the normal area. The increase of APD and refractoriness in normal as well as depolarized or ischemic tissues in the absence of marked changes in Vmax and conduction may decrease the likelihood of reentrant arrhythmias and underlie the antifibrillatory effects in anesthetized dogs.     

Electrophysiologic effects of bretylium tosylate on the canine heart during coronary artery occlusion and reperfusion

The electrophysiologic and antiarrhythmic actions of bretylium tosylate were studied after acute coronary artery occlusion and reperfusion in pentobarbital-anesthetized dogs. Three groups of animals were studied: Group I (n = 8) served as saline controls, Group II (n = 7) received bretylium tosylate (10 mg/kg i.v.) 60 min prior to coronary artery occlusion, and Group III (n = 5) received bretylium tosylate (30 mg/kg i.v.) in three divided doses over the 24 h prior to coronary artery occlusion. In Groups II and III the effective refractory period of the nonischemic myocardium was not altered by bretylium before or during the occlusion period, nor was it influenced by bretylium during the subsequent reperfusion period. In Group I the effective refractory period of the ischemic myocardium decreased 24 +/- 3.0% after coronary occlusion and increased 12 +/- 3% above the preocclusion level on reperfusion. In Group II the effective refractory period of the ischemic myocardium decreased 28 +/- 3.2% after coronary occlusion but did not overshoot preischemic levels on reperfusion. In Group III the effective refractory period decreased 15 +/- 3.8% following coronary occlusion and did not overshoot preocclusion levels during reperfusion. The ventricular activation times of the normal and ischemic myocardium were not affected by bretylium tosylate during occlusion or reperfusion in Group II or III. Significant reperfusion arrhythmias were observed only in Groups I and II. These data suggest that bretylium tosylate exerts its antiarrhythmic actions in ischemic myocardium by reducing the dispersion of cardiac refractoriness produced by coronary artery occlusion and, consequently, abolishing the abrupt change in cardiac refractoriness that follows coronary artery reperfusion. These antiarrhythmic actions of bretylium are pronounced in the chronically treated group, suggesting an electrophysiologic basis of the delayed antiarrhythmic actions of bretylium.     

Arrhythmias induced by myocardial ischaemia-reperfusion are sensitive to ionotropic excitatory amino acid receptor antagonists

We have investigated the effects of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK801), a non-competitive N-methyl-D-aspartate (NMDA) ionotropic excitatory amino acid receptor antagonist, and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA ionotropic excitatory amino acid receptor antagonist, ketamine and memantine, NMDA receptor channel blockers, on ventricular arrhythmias induced by myocardial ischaemia and myocardial ischaemia-reperfusion. Coronary artery occlusion caused 100 +/- 2% ventricular tachycardia, in saline treated group, and 60 +/- 3% ventricular fibrillation. 66 +/- 6% of the animals recovered from ventricular fibrillation, while in 34 +/- 4% of animals the ventricular fibrillation caused mortality. The incidence of ventricular tachycardia, ventricular fibrillation and mortality was not modified by treatment of rats with MK801 (0.3 mg/kg i.v.), CNQX (1 mg/kg i.v.), ketamine (10 mg/kg) and memantine (1.5 mg/kg), injected 5 min prior to occlusion. Reperfusion caused severe arrhythmias which started within 5 +/- 2 s. For instance, in the saline treated group, the incidence of ventricular tachycardia was 100 +/- 5%, while ventricular fibrillation occurred in 87 +/- 3% of the animals and lasted 90 +/- 12 s. The mortality was 62 +/- 6%. The incidence of ventricular tachycardia, ventricular fibrillation and mortality induced by reperfusion was greatly (P < 0.01) reduced in animals treated with MK801 (0.3 mg/kg i.v.), CNQX (1 mg/kg i.v.), ketamine (10 mg/kg) and memantine (1.5 mg/kg), injected 5 min prior to occlusion. Therefore, reperfusion-induced arrhythmias, but not ischaemia-induced arrhythmias, are sensitive to NMDA/non-NMDA ionotropic excitatory amino acid receptor antagonists.     

Blockade of delayed rectifier K+ currents in neuroblastoma x glioma hybrid (NG 108-15) cells by clofilium, a class III antidysrhythmic agent.

1. The whole-cell patch-clamp technique was used to examine the effects of the class III antidysrhythmic agent, clofilium, on voltage-activated delayed rectifier K+ currents (IKv) in undifferentiated mouse neuroblastoma x rat glioma hybrid (NG 108-15) cells. Ca(2+)-activated K+ currents also seen in these cells were abolished by bath application of 4 mM Co2+. 2. Bath application of clofilium (0.3 to 70 microM) caused dose-dependent, irreversible inhibition of IKv in these cells. Under control conditions, activated currents were sustained during 200 ms depolarizing steps, but in the presence of clofilium, or after its wash-out, currents were reduced in amplitude and showed a time-dependent decay. 3. Clofilium blockade of IKv was voltage-dependent; the degree of current inhibition increased with increasing depolarizations. The transient nature of IKv seen in the presence of clofilium was also more apparent at higher test potentials. 4. The effects of clofilium were use-dependent: when cells were left unstimulated during drug application, and then depolarizations were resumed, several pulses were required for clofilium blockade to reach a steady level. Similar results were obtained post-clofilium, when cells were unstimulated during application and then removal of clofilium, suggesting that although the blocking action of the drug was use-dependent, it bound to the closed, delayed rectifier K+ channel. 5. High concentrations (100 or 300 microM) of sotalol, another class III antidysrhythmic agent, were without discernible effects on IKv in NG 108-15 cells. 6. The effects of clofilium on a neuronal IKv described here, and its possible mechanism of action, are compared with previously reported effects of clofilium on the cardiac IKv.     

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)     

Critical role of dose in protection by propranolol against ventricular fibrillation in a pig model of acute myocardial ischemia

We hypothesized that the antiarrhythmic efficacy of propranolol during acute myocardial ischemia could be dose related. Propranolol was administered in two equally divided doses 30 min before and 10 min after ligation of the anterior descending coronary artery (CAL) in anesthetized open-chest pigs. Only the lowest dose of propranolol, i.e., 0.1 mg/kg intravenously (i.v.) (plasma level 22 +/- 2 ng/ml) decreased the incidence of ventricular fibrillation (VF), i.e. 3 of 12 versus 16 of 20 in control group (p less than 0.01). VF incidence with propranolol 0.5 or 3 mg/kg was 4 of 6 and 8 of 9, respectively (both NS vs. control group). Propranolol 0.1 mg/kg did not change left ventricular (LV) blood flow. Propranolol 3 mg/kg reduced blood flow in the peripheral ischemic myocardium to 13.2 +/- 1.2 versus 19.2 +/- 1.4 ml/100 g/min in control group (p less than 0.01), and in the midischemic zone to 4.4 +/- 0.5 versus 7.0 +/- 0.9 ml/100 g/min in control group (p less than 0.001). Propranolol 0.1 mg/kg prevented a disparity of levels of cyclic AMP from arising between ischemic and non-ischemic myocardium, whereas propranolol 3.0 mg/kg did not. Furthermore, LV mechanical function was suppressed by propranolol 3 mg/kg. Only the lowest dose of propranolol (i.e., 0.1 mg/kg) decreased the incidence of VF in this model.