Gerald J. Kelliher

A study of the antiarrhythmic action of certain beta-blocking agents☆☆☆

Abstract The effects of the beta-blocking agents, MJ-1999 (sotalol) and practolol, against ouabain and digoxin-induced ventricular rhythm disturbances were studied to evaluate the nature of the action which is involved in the antiarrhythmic action of these beta-blocking agents. Sotalol and practolol, in doses that have been reported to have little effect on cardiac excitability, protected against digoxin-induced arrhythmias. Practolol, but not the low dose of sotalol, protected against ouabain-induced cardiotoxicity. The dose of sotalol necessary to protect against ouabain-induced arrhythmias was five times greater than that necessary to protect against digoxin-induced arrhythmia and has been reported to directly depress cardiac excitability. The maximum rate of ventricular tachycardia produced by ouabain or digoxin was slower in the animals pretreated with practolol but not in those pretreated with sotalol. The slowing in heart rate produced by beta-blocking agents could not be correlated with the protection afforded against either digoxin or ouabain-induced arrhythmia. The data suggest that the capacity of beta-receptor blocking agents to reduce cardiac excitability may not be the only mechanism responsible for their antiarrhythmic action. Both practolol and sotalol protected against digoxin-induced arrhythmias and the only action common to both agents is beta blockade. Therefore, it is suggested that the beta blocking action is responsible for the antiarrhythmic action against digoxin-induced arrhythmias. However, since only practolol protected against ouabain-induced rhythm disturbances in doses which do not depress cardiac excitability and since it differs from sotalol in that it has the capacity to depress adrenergic nervous activity in these doses, it is suggested that the neural depressant action of practolol is responsible, at least in part, for its antiarrhythmic action against ouabain-induced cardiotoxicity.

Effect of prostaglandin E1 on ouabain-induced arrhythmia

Abstract Prostaglandin E 1 (PGE 1 ) was infused i.v. to a total dose of 50 μg/kg to cats anesthetized with pentobarbital. PGE 1 increased significantly the dose of ouabain necessary to produce premature ventricular complexes, ventricular tachycardia and death. All of the animals in both the control and PGE 1 -treated group died in ventricular fibrillation. PGE 1 did not produce any significant change in blood pressure or heart rate nor did it affect the cardiac slowing prior to ventricular tachycardia produced by ouabain. In addition, the maximum rate of ventricular tachycardia produced by ouabain was not different in either the control or PGE 1 -treated animals.

The effect of d(+)- and l(-)-practolol on ouabain-induced arrhythmia

Abstract The l(-)-isomer of practolol significantly increased the i.v. dose of ouabain necessary to produce premature ventricular contractions, ventricular tachycardia and ventricular fibrillation in dial-urethane anesthetized cats while the d(+)-isomer failed to influence the dose of ouabain necessary to produce these ventricular rhythm disturbances. Both isomers of practolol reduced the heart rate but did not influence the reduction in heart rate produced by ouabain. Levo practocol significantly reduced that the maximum rate of ventricular tachycardia by ouabain whereas dextro practolol was ineffective in this regard.

The effect of bretylium and clofilium on dispersion of refractoriness and vulnerability to ventricular fibrillation in the ischemic feline heart

Bretylium has been shown to have a pronounced antifibrillatory effect. The purpose of this study was to examine the effects of bretylium on changes in vulnerability to ventricular fibrillation (VF) and refractoriness which occur during acute myocardial infarction. Right ventricular VF thresholds and effective refractory periods (ERP) at six left ventricular sites were measured before and serially after left anterior descending coronary occlusion in chloralose-anesthetized cats. In eight untreated animals, there was a decrease in VF thresholds of 73% (p less than 0.01) immediately after occlusion and dispersion of refractoriness (DR) (maximum difference in ERP between normal and ischemic left ventricular sites) increased from 18 +/- 4 to 50 +/- 6 msec (p less than 0.01). Five of eight animals manifested spontaneous VF within the first minutes of occlusion but none had nonsustained VF. Pretreatment with bretylium (10 to 20 mg/kg intravenously) increased resting ERP from 181 +/- 9 to 201 +/- 9 msec (p less than 0.05) and VF threshold from 32 +/- 5 to 85 +/- 7 mA (p less than 0.001). Bretylium also prevented spontaneous VF in all eight animals and abolished occlusion-related changes in VF and DR. Fourteen animals were similarly studied using clofilium, a bretylium congener which is devoid of sympatholytic effect (no effect on blood pressure response to bilateral carotid artery occlusion). Clofilium increased resting ERP and VF thresholds at both low (0.5 mg/kg intravenously) and high doses (5 mg/kg intravenously). High-but not low-dose clofilium blunted the fall in VF threshold after coronary occlusion. In addition, DR correlated with VF threshold changes at both doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of thromboxane synthetase inhibition on vulnerability to ventricular arrhythmia following coronary occlusion.

Release of thromboxane (TXA2) during acute myocardial infarction may be an important contributing factor in the genesis of ventricular fibrillation (VF). We assessed the effect of selective TXA2 inhibition on vulnerability to VF after total occlusion of the anterior descending coronary artery in chloralose-anesthetized cats. Animals were pretreated with vehicle or with CGS-13080, a TXA2 synthetase inhibitor, 3.0 or 9.0 mg/kg intravenously. There was an apparent dose-dependent protective effect following CGS-13080 administration, in which the decrease in VF threshold following coronary occlusion was attenuated. Also, the incidence of spontaneous ventricular arrhythmia in the first 30 minutes after occlusion was reduced by two thirds in the 9.0 mg/kg CGS-13080 group compared to the vehicle-treated animals. This protective effect does not appear to be due to a change in hemodynamics, effective refractory periods, or extent of ischemia. TXA2 released during coronary occlusion appears to be arrhythmogenic, and inhibiting its synthesis may be protective.

A comparison of the effects of sotalol and of the isomers of practolol on adrenergic nervous activity

Abstract Spontaneous activity was recorded from postganglionic cardioaccelerator fibers in cats anesthetized with α-chloralose. The effects of sotalol and the d(+)− and 1(−)− isomers of practolol were examined in these experiments. The 1(−)− isomer of practolol caused a dose- related depression of adrenergic nervous activity while d(+)− practolol had no effect. Sotalol had no influence on nervous discharge. The results suggest that 1(−)− practolol depresses adrenergic nervous activity and that this effect may be important in the antiarrhythmic action of this agent.

The action of reserpine, 6-hydroxydopamine, and bretylium on digitalis-induced cardiotoxicity.

This study determined whether the protective effect of reserpine against ouabain-induced ventricular arrhythmias in the cat is due to an action of the drug on the adrenergic nerve terminal. Reserpine (5 mg/kg i.p.) administered 24 h prior to ouabain (2 micrograms/kg per min i.v., until death) increased the dose of ouabain to produce premature ventricular contractions, ventricular tachycardia, and death from 77.3 +/- 5.2 to 105.0 +/- 6.0; 84.9 +/- 5.2 to 132.7 +/- 9.1; and 108.8 +/- 4.0 to 165.7 +/- 10.4 micrograms/kg, respectively (P less than 0.05). When 6-hydroxydopamine (6OHDA; 20 mg/kg i.v.) was given 3 days prior to the experiment, the protective effect of reserpine was not evident. When bretylium (20 mg/kg i.v., 2 h prior to ouabain) was administered to animals previously treated with reserpine, the dose of ouabain which produced premature ventricular contractions, ventricular tachycardia, and death was increased to 109.0 +/- 7.2; 146.1 +/- 12.6; and 165.8 +/- 7.6 micrograms/kg, respectively (P less than 0.05). However, the magnitude of this protective action was similar to that produced by reserpine alone. Lathers et al. (Fed. Proc. 40, 672, 1981) reported that bretylium alone provides protection of a similar order of magnitude as reserpine. Thus, the effects of reserpine and bretylium were not additive; this indicates that the two agents may be acting on the same locus or they may be acting at different sites with the action of one drug masking or blocking the action of the other. Since 6OHDA prevented the action of reserpine on ouabain-induced ventricular arrhythmia and since 6OHDA only produces degeneration of adrenergic nerve terminals, it is probable that the protective effect of both reserpine and bretylium is due to an action at the adrenergic nerve terminal. The heart rate and blood pressure were not involved in the antiarrhythmic effects of reserpine.

Arrhythmia inducibility and ventricular vulnerability in a chronic feline infarction model

Ventricular tachyarrhythmias are the cause of sudden cardiac death in ischemic heart disease. Reliable animal models are necessary to study techniques for identifying individuals at risk and to develop effective modes of therapy. The purpose of the present study was to evaluate the inducibility of ventricular tachyarrhythmias and vulnerability to ventricular fibrillation and to correlate these findings with changes in ventricular refractoriness in a chronic feline model. Twelve conditioned cats were randomly divided into two groups: group A, sham-operated controls (n = 5); or group B, permanent occlusion of the left anterior descending coronary artery (n = 7). Two weeks later, the following measurements were made: (1) assessment of refractory periods at several ventricular sites; (2) inducibility to ventricular tachyarrhythmias; and (3) determination of ventricular fibrillation threshold. After electrophysiologic testing, the animals were killed and the hearts were studied histologically. Ventricular fibrillation thresholds were significantly lower in group B compared with group A (13 +/- 3 vs 46 +/- 9 mA; p less than 0.01). One of the sham-operated controls had induction of nonsustained ventricular tachycardia, while six of the group B animals had reproducible, inducible ventricular tachyarrhythmias (p less than 0.01). There was a significant dispersion in effective refractory periods between normal and infarcted sites in group B (46 +/- 6 msec) not seen in group A (12 +/- 2 msec, p less than 0.01). The group A cats demonstrated minimal damage to the myocardium or cardiac architecture. Group B cats demonstrated extensive, transmural, homogeneous infarcts of approximately 30% of the anterior wall of the left ventricle.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of site of stimulation on measurement of ventricular vulnerability in the normal and ischemic feline heart

Site of stimulation is an important variable in the inducibility of ventricular tachycardia in both non-human animal infarction models and in humans; that is, proximity of the stimulating electrode to the site of reentry facilitates the induction of sustained arrhythmia. Whether site of stimulation is decisive in measurement of vulnerability to ventricular fibrillation (VF) during acute coronary occlusion has not been fully evaluated. We measured VF thresholds in 9 chloralose-anesthetized cats at 2 right ventricular and 3 left ventricular sites (2 endocardial, 3 intramural) before and after abrupt occlusion of the anterior descending coronary artery. VF thresholds were measured using a single stimulus of increasing intensity delivered during ventricular drive. Although VF thresholds were lower at endocardial sites, there were no significant differences in VF threshold among any of the sites tested at control. After occlusion, VF thresholds fell to a similar extent at all 5 sites tested. The percent reduction in VF threshold at any site was not influenced by the sequence of testing. VF may be precipitated from multiple sites and, unlike ventricular tachycardia, does not represent an isolated focus of arrhythmogenicity.

Modulation of arachidonic acid metabolites and vulnerability to ventricular fibrillation during myocardial ischemia in the cat

To determine the relative importance of arachidonic acid pathway products on vulnerability to ventricular fibrillation (VF), we examined the effects of synthesis inhibitors and a receptor blocker acting in the cyclooxygenase (C) and lipoxygenase (L) pathways on VF thresholds in a feline model of coronary occlusion. Thresholds for the induction of VF wer measured before and after a 5-minute coronary occlusion in drug-treated animals and control subjects. Animals were treated with BW755c, a dual L and C inhibitor, CGS-8515, and L inhibitor, FPL-55712, a leukotriene receptor blocker, or sulfinpyrazone, a C inhibitor. BW755c, CGS-8515, and FPL-55712 all prevented an otherwise significant fall in VF threshold during coronary occlusion (p less than 0.01) independent of an effect on effective refractory period, heart rate, or blood pressure. In contrast, sulfinpyrazone, the only compound devoid of an effect on the L pathway, did not protect against an occlusion-related fall in VF threshold. BW755c and CGS-8515 inhibited the synthesis of L and C metabolites coincident with their protection against VF (p less than 0.01). We conclude that agents that antagonize the effects of L products protect against enhanced ventricular vulnerability during acute ischemia, whereas C inhibition alone may not afford this protection.