Antifibrillatory actions of bepridil and butyl-MDI, two intracellular calcium antagonists

The antifibrillatory and electrophysiologic actions of bepridil and butyl-methylenedioxyindene (BU-MDI), two intracellular calcium antagonists, were examined in anesthetized dogs. The administration of bepridil (1.0-10.0 mg/kg i.v.) significantly increased the electrical threshold for ventricular fibrillation determined during unobstructed coronary flow, and was associated with a significant decrease in ventricular excitability and a progressive depression in ventricular myocardial conduction. BU-MDI (3.0-30.0 mg/kg i.v.) did not significantly alter ventricular fibrillation thresholds during unobstructed coronary flow, nor did it significantly alter electrophysiologic properties such as ventricular excitability, conduction or refractoriness. The administration of either bepridil (10 mg/kg i.v.) or BU-MDI (30 mg/kg i.v.), however, resulted in significant increases in the ventricular fibrillation thresholds determined during transient myocardial ischemia, restoring the threshold values to corresponding non-ischemic levels. These results suggest that an inhibition of the action and/or availability of intracellular calcium may play a role in the antifibrillatory actions of BU-MDI and bepridil during transient ischemia.     

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.     

Haemodynamic effects of sulphinpyrazone in experimental myocardial ischaemia.

The effect of sulphinpyrazone (30 mg/kg i.v.) on heart rate, blood pressure and ventricular arrhythmias was studied in open-chested anaesthetized dogs during sequential 10 min occlusions of the left anterior descending coronary artery. An increased duration of occlusion without ventricular fibrillation and reduction in epicardial activation delay in the central ischaemic region were observed after intravenous sulphinpyrazone (n = 7). These effects were associated with a progressive and significant reduction in intrinsic heart rate (up to 15 beats/min) but no change in blood pressure. These findings suggest that heart rate changes alone may account for the observed protective effect of sulphinpyrazone against early ventricular fibrillation during acute experimental myocardial ischaemia.     

Cardiovascular effects of ranitidine and cimetidine during acute myocardial ischaemia in anaesthetized dogs

The effects of ranitidine and cimetidine on ventricular fibrillation threshold and haemodynamics were studied in pentobarbitone-anaesthetized dogs subjected to acute coronary artery ligation. These drugs did not significantly change the ventricular fibrillation threshold nor haemodynamics before coronary artery ligation, except for remarkable haemodynamic depression by ranitidine 1 mg/kg. Ligation of the left anterior descending coronary artery reduced the ventricular fibrillation threshold, decreased systemic and left ventricular pressures and myocardial contractility, and slightly increased heart rate. Pretreatment with ranitidine 0.25 or 1 mg/kg, or with cimetidine 2 mg/kg, significantly abolished the reductions in ventricular fibrillation threshold, but did not noticeably alter the haemodynamic changes. These findings further support the hypothesis that histamine release may contribute to the increased ventricular vulnerability resulting from acute myocardial ischaemia. However, the role of histamine in the haemodynamic responses to coronary artery ligation remains obscure.     

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.     

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.     

Digitalis drugs and vulnerability to ventricular fibrillation.

The effect of acetylstrophanthidine (AS), a rapid-acting digitalis-like agent, on the ventricular fibrillation (VF) threshold was examined in normal and denervated chloralose-anesthetized dogs. In neurally intact dogs an intravenous bolus of AS (0.075 mg/kg) increased the VF threshold up to a maximum 50% (P less than 0.01) within 30 min after injection. The augmented VF threshold following intravenous administration of AS was not altered by vagotomy. Bilateral stellectomy in vagotomized dogs, as well as carotid sinus and aortic arch denervations, however, prevented the AS induced increase in VF threshold. In neurally intact dogs beta-adrenergic blockade with propranolol (0.25 mg/kg) precluded AS effects. These data suggest that the increase in the VF threshold resulting from AS administration in the normal canine ventricle is due to withdrawal of sympathetic tone mediated via the baroreceptor reflex. The direct effect of AS on the myocardium is to decrease the VF threshold.     

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.     

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)     

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.     

A comparison of the antifibrillatory effect of midazolam and flunitrazepam in acute myocardial ischaemia in the dog

Summary

A study was carried out using a model of myocardial ischaemia in the dog after ligation of the left coronary artery to determine the effects of the benzodiazepines, flunitrazepam and midazolam, on the ventricular fibrillation threshold. The fibrillation threshold was measured twice within 15?min and 8?min after ligation. Fifteen minutes after the onset ofischaemic heart attack, 1.2?mg midazolam/kg or 0.25?mg flunitrazepam and midazolam, on the ventricular fibrillation threshold. The fibrillation threshold was measured twice within 15?min and 8?min after ligation. Fifteen minutes after the onset ofischaemic heart attack, 1.2?mg midazolam/kg or 0.25?mg of ischaemia. Their effects on haemodynamics were negligible. It is suggested that both benzodiazepines can be used for increasing electrical stability of the heart in patients with acute myocardial infarction and to inhibit the psychic stress response. Because of its short biological half-life and water solubility, allowing painless intravenous administration, midazolam offers a more flexible approach to pharmacotherapy immediately after acute heart attack according to the patient's current clinical status.     

Electromechanical dissociation after ventricular fibrillation: prevention with calcium-entry blockers

Calcium-entry blockers were administered in an attempt to protect myocardium during cardiac arrest due to ventricular fibrillation in mechanically ventilated dogs. An intravenous injection of verapamil, nifedipine, or lidoflazine was administered prior to successively prolonged episodes of ventricular fibrillation, during which no thoracic compression was performed. It is of interest that ventricular defibrillation was more easily obtained after treatment with the three drugs. As previously observed in this model, nine control dogs developed electromechanical dissociation (EMD) after 120 seconds of ventricular fibrillation. In contrast, six of the 11 dogs treated with 0.3 mg/kg of verapamil recovered mechanical systole after 120 seconds of ventricular fibrillation (p less than 0.05). Nifedipine administration also postponed the onset of EMD in three of four dogs. However, lidoflazine postponed the onset of EMD in only one of the eight dogs. The later onset of EMD after administration of verapamil or nifedipine in this model was attributed to myocardial protection by calcium-entry blockers during ventricular fibrillation. Decreased energy utilization during cardiac arrest was considered to be the principal protective mechanism. These observations indicate calcium-entry blockers, and especially verapamil and nifedipine, can be valuable drugs during cardiac resuscitation for ventricular fibrillation.     

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.     

Ischemia-induced conduction delay and ventricular arrhythmias: comparative electropharmacology of bethanidine sulfate and bretylium tosylate

Bretylium tosylate and bethanidine sulfate were studied in two models of experimental myocardial ischemia. In anesthetized dogs, left anterior descending coronary artery occlusion during rapid atrial pacing (180-200 min-1) produced ventricular tachycardia and fibrillation within 5 min in 9 of 11 dogs studied. In all cases, arrhythmias were preceded by and appeared to be temporally related to progressive fractionation and delay of electrograms recorded from the ischemic zone. In four dogs, bretylium (10 mg/kg) did not alter the time course of electrogram changes nor the time to onset of arrhythmia. However, in five dogs bethanidine (10 mg/kg) markedly exacerbated conduction changes in the ischemic zone and decreased the time to onset of ventricular arrhythmias (173 +/- 35 vs. 262 +/- 34 s control, mean +/- SEM, p less than 0.05). Bethanidine administration also facilitated ischemia-induced ventricular tachycardia and fibrillation in two dogs that did not exhibit ischemia-induced arrhythmias before receiving the drug. In isolated perfused rabbit hearts, global ischemia produced conduction slowing, depolarization of resting membrane potential, and decreases in amplitude and Vmax that were reproducible in serial 10 min ischemic episodes. Bretylium (10 mg/L) did not affect these parameters under either perfused or ischemic conditions. Although bethanidine (10 mg/L) also did not affect these parameters during perfusion, conduction slowing and depression of Vmax during ischemia were accelerated without affecting the time course of change in resting membrane potential. Both bretylium and bethanidine prolonged action potential duration under perfused conditions, but after 10 min of ischemia this effect was no longer evident. The results demonstrate that differences in the electrophysiologic effects of bretylium and bethanidine are markedly accentuated in the setting of acute ischemia. Although both these agents have been demonstrated to have antifibrillatory effects in other experimental settings, under the conditions of this study, bretylium failed to protect against ischemia-induced arrhythmias and acute bethanidine administration produced a proarrhythmic effect in association with an exacerbation of ischemia-induced conduction changes.     

Effects of clonidine on vulnerability to fibrillation in the normal and ischemic canine ventricle

Clonidine infusion (10 microgram/kg, i.v.) elicited a 30% increase in repetitive extrasystole (RE) threshold in 6 chloralose-anesthetized dogs. A reduction in heart rate and arterial blood pressure accompanied the increased threshold. Intracisternal injection of clonidine (2 microgram/kg) in 6 dogs caused similar alterations in these parameters. Bilateral vagotomy, performed in 6 dogs prior to intravenous clonidine, prevented the increase in RE threshold but did not prevent the drug-induced bradycardia. Atropine (0.2 and 0.6 mg/kg), however, did not attenuate the effect of clonidine on RE threshold. Clonidine administration did not prevent the reduction in ventricular fibrillation threshold associated with a 10 min occlusion of the left anterior descending coronary artery or following reperfusion. We conclude that: (1) clonidine reduces ventricular vulnerability in the normal but not the ischemic heart, and (2) its protective effect is mediated by enhanced afferent vagal input to midbrain cardiovascular regulatory centers. This central nervous system action causes a reduction in sympathetic tone to the heart.     

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.     

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 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.     

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.     

Antiarrhythmic vs. antifibrillatory activity of the basic diphenylhydantoin derivative 3-[3-(4-phenyl-1-piperidyl)propyl]-5-(4-methoxyphenyl)-5-phenylhydantoin hydrochloride

The effects of 3-[3-(4-phenyl-1-piperidyl)propyl]-5-(4-methoxyphenyl)-5-phenylhydantoin hydrochloride (TR 2985), a basic diphenylhydantoin derivative, were studied in four canine models of experimental cardiac dysrhythmias. In conscious dogs, 48 h after myocardial infarction, TR 2985 significantly reduced the frequency of spontaneous ventricular arrhythmias. However, in anesthetized dogs, TR 2985 produced only a slight and insignificant increase in the ventricular fibrillation threshold. In conscious dogs, 4 to 7 days after myocardial infarction, TR 2985 failed to prevent the electrical induction of reentrant ventricular tachycardia, and failed to protect against the development of ventricular fibrillation in response to ischemia at a site distant from the previous infarction. These results indicate that TR 2985 may be effective in preventing arrhythmias of a non-reentrant nature, but may be relatively ineffective in preventing reentrant ventricular tachycardia or ventricular fibrillation.