Ventricular fibrillation (VF) is one of the most life threatening events. Although in humans VF is generally sustained (SVF) requiring artificial defibrillation, in various mammals and in some cases in humans VF terminates by itself, reverting spontaneously into sinus rhythm. Since VF is one of the main causes of sudden death, one of the important clinical problems today is if and how we can transform the fatal SVF into a self limited transient one (TVF). From electrophysiological studies carried out on anaesthetized open chest animals, we have found that TVF requires a high degree of intercellular coupling and synchronization. Cardiac myocytes are electrically coupled with adjacent cells. The intercellular coupling is a focus of low electrical resistance which allows rapid transmission of electrical impulses between cells. Any decrease in intercellular coupling decreases the ability of the heart for self defibrillation. The cell-to-cell coupling decreases with age, ischemia, VF and variations in physiological conditions probably due to an increase in intercellular resistance (Ri), widening in the internexal gaps, decrease in electrotonic space constant (lambda) etc. All of these factors are known to be affected by intracellular concentration of free Ca++ ([Ca++]). On the basis of studies carried out on various mammals at different ages, we hypothesized that the ability of the heart to defibrillate depends on the cardiac catecholamine level [CA], during VF. This hypothesis is supported by the facts, known from the literature, that increase in [CA] decreases intracellular free Ca++ concentration, decreases Ri and increases lambda.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

The influence of cardiac cholinergic activation on the induction and maintenance of ventricular fibrillation.

The influence of cardiac cholinergic activation was studied in rats and cats on the induction and maintenance of ventricular fibrillation (VF). Acetylcholine (ACH 2-25 micrograms/kg), in doses which did not cause bradycardia or hypotension, induced appearance of spontaneous VF (duration 2-60 sec.) in 9/20 rats which have a high sympathetic autoregulation and in 3/6 cats only, 20-40 secs after the latter had been given adrenaline. ACh (10-45 micrograms/kg) and methacholine (10-40 micrograms/kg) also significantly prolonged the fibrillatory period induced electrically in cats and rats with and without atrial or ventricular pacing. The induction or prolongation of VF did not occur when higher doses of ACh (50-100 micrograms/kg) were given to rats. The influence of moderate amounts of cholinergic agents on the heart may be due to localised effects resulting in asynchronous activity. Alternatively, they may produce a discharge of multiple ectopic pacemakers or a disturbance in impulse conduction. Higher doses of ACh depress the S-A and ventricular ectopic activity node thereby decreasing the probability of inducing VF. It is concluded that under conditions of raised cardiac adrenergic activity, a moderate increase in cholinergic influence can both induce and prolong VF. The relevance of these findings to the "sudden infant death" syndrome is discussed.

Acetylcholine↗

PubMedDate not supplied

A self-protecting servo-model for explanation of the mechanism involved in spontaneous ventricular defibrillation.

Ventricular fibrillation (VF) is the most life-threatening arrhythmia. It has been suggested that VF in humans is always sustained. Recent publications indicated that VF can be either sustained (SVF) or transient (TVF), reverting spontaneously into sinus rhythm. In previous studies we have hypothesized that TVF requires, during VF, a high cardiac catecholamine level ([CA]). Since during VF sympathetic activity is enhanced, the question arises of why VF is sustained in the majority of cases. Looking on the living body as a self-protecting servo-mechanism, we propose a servo-model that on the one hand describes the mechanism involved in TVF and on the other proposes a therapeutic procedure which can help the heart in its effort to transform VF into TVF. Our model has been examined by various experimental studies. The results obtained strongly support our hypothesis.

Catecholamines↗

PubMedDate not supplied

Ultrastructural-functional basis for spontaneous termination of ventricular fibrillation in mammals.

Ventricular fibrillation in humans is generally sustained (SVF), but it can be also transient (TVF), reverting spontaneously to sinus rhythm. In previous studies we have shown that: a) TVF appears in all young mammals and varies according to age and species; b) it requires synchronization of myocardial cell activity; c) infusion of certain drugs may change the type of ventricular fibrillation from sustained into transient. We hypothesize that the synchronization required for TVF depends on the electrical conductivity of intercellular structures. These intercellular couplings differ among species and decrease with age. Comparison between the inter- and intra-specific variations of intercellular connective structure described in the literature with the type of ventricular fibrillation found in our previous studies on various animals of different ages showed a clear relationship between these histological variations and the changes in the type of ventricular fibrillation. In this study we examined intercellular connective structures ultrastructurally in 3 groups of cats: a. control, untreated cats exhibiting sustained ventricular fibrillation; b. untreated cats exhibiting transient ventricular fibrillation; c. treated cats exhibiting sustained ventricular fibrillation before infusion of a defibrillating drug and transient ventricular fibrillation thereafter. It was found that the intercellular connective structure in cats exhibiting sustained ventricular fibrillation differs significantly from that in cats exhibiting transient fibrillation. In hearts exhibiting sustained ventricular fibrillation, many intercellular connective structures are widened and the degree of widening is pronounced, forming a continuous line, while in hearts exhibiting transient ventricular fibrillation the widened junctions are rare and isolated and the widening is relatively small. These preliminary results strongly support our above-mentioned hypothesis, providing an explanation for the origin of transient ventricular fibrillation and a tool for the development of new defibrillating drugs.

Animals↗

PubMedDate not supplied

The defibrillating effect of catecholamine reuptake inhibitors.

In previous studies we hypothesized that spontaneous termination of ventricular fibrillation (TVF) requires a high cardiac catecholamine level ([CA]) during VF. During VF, sympathetic activity is enhanced but in the majority of cases [CA] does not reach the level required for self-defibrillation, most likely due to their relatively high reuptake by sympathetic nerve terminals. One possibility of obtaining TVF is by elevation of the [CA] during VF, either by catecholamine intracoronary injection or by treatment with compounds that inhibit catecholamine reuptake. To examine this assumption, we studied the effect of VF on 3 closely related compounds: talopram, talsupram and citalopram, with norepinephrine uptake inhibition (IC50NE) of 2.9, 0.79 and 8800 and dopamine (DA) uptake inhibition (IC50DA) of 44000, 9300 and 41000, respectively, as well as 2 enantiomers of a cis-1-piperazino-3-phenylindan derivative (Lu20-037 and Lu20-036) with IC50NE of 2.5 and 910 and IC50DA of 2.3 and 1700, respectively. The results support our hypothesis relating the defibrillating effect of a compound to its IC50NE, while its inhibitory effect on DA uptake seems to conteract the NE effect.

Animals↗

PubMedDate not supplied

Ethmozine and ethacizine--new antiarrhythmic drugs with defibrillating properties.

Ventricular fibrillation (VF) is a life-threatening arrhythmia that leads to death unless electrical defibrillation is applied in time. Recent publications indicate that VF can be either sustained (SVF), requiring electrical defibrillation, or transient (TVF), reverting spontaneously into sinus rhythm. Since VF cannot be totally prevented by drugs, a new antiarrhythmic therapeutic approach has been proposed: drug-induced enhancement of the ability of the heart to defibrillate by itself. In this study we examined the defibrillating potency of two antiarrhythmic phenothiazines, ethmozine (ETM) and ethacizine (ETA), as well as their effects on catecholamine uptake and on the electrophysiological properties of the myocardial cell membrane. The antiarrhythmic-defibrillatory activity was examined in cats; the inhibitory effect on [3H]-norepinephrine (NE) uptake was examined in rat brain synaptosomes, and the electrophysiological membrane effects were examined by microelectrode recordings in perfused strips of heart ventricle from guinea-pigs. The results indicate that: 1. ETA exhibits similar but stronger antiarrhythmic-defibrillating and NE reuptake inhibitory effects than ETM; 2. ETA at 10-6 M decreases ventricular conduction time and increases Vmax while ETM at this concentration does not change them; 3. The defibrillating ability of the drugs can be related to their inhibitory potency on NE reuptake. We suggest that the risk of sympathomimetic arrhythmogenicity is prevented by the previously described, membrane stabilizing Class 1 antiarrhythmic properties of these drugs.

Action Potentials↗