Cardiac lesions induced by neuroleptic drugs in the rabbit.

Sudden death seems to be more frequent following treatment with neuroleptic drugs in patients with pre-existing cardiac lesions, especially dilated and hypertrophic myocardiopathy. The present study was undertaken to confirm the hypothesis that myocardial lesions can be induced by neuroleptic drugs. Eight groups of 6 New-Zealand White rabbits were treated for 3 months: group I: controls (saline); group II: 15 mg/kg/day amisulpride; group III: 0.20 mg/kg/day haloperidol; group IV: 3 mg/kg/day levomepromazine; group V: 0.30 mg/kg/day olanzapine; group VI: 1.0 mg/kg risperidone, every 15 days; group VII: levomepromazine+haloperidol, same dose levels as single treatments; group VIII: levomepromazine+risperidone, same dose levels as single treatments. The hearts were immediately weighted and fixed, and paraffin sections were prepared and examined. Ventricular hypertrophy was observed following treatment with olanzapine and was still more marked with the combinations levomepromazine+haloperidol and levomepromazine+risperidone. Amisulpride and haloperidol induced necrotic lesions and levomepromazine, endocardial fibrosis. There was a lack of severe cardiac lesions following treatment with risperidone. The observed cardiac lesions can be compared to those seen in toxic myocarditis. These findings confirm the hypothesis that some neuroleptic drugs induce myocardial lesions. Further studies are warranted to demonstrate the effects of treatments of longer duration and the influence of pre-existing cardiac lesions.

[Deleterious cardiac effects of serotonin in myocardial ischemia: role of naftidrofuryl]. / Analyse des effets délétères cardiaques de la sérotonine lors de l'ischémie myocardique: place du naftidrofuryl.

It is now accepted that serotonin can either initiate or aggravate myocardial ischaemia through a vasoconstrictor action and platelet activation. It is therefore possible that substances likely to neutralize the effects of serotonin could be used, without any danger, in humans with ischaemic heart disease. This type of action may therefore be exerted by 5-HT2 antagonists, such as naftidrofuryl. A recent double-blind clinical study has in fact shown that administration of naftidrofuryl versus placebo leads to better exercise tolerance, with an increase in the maximum level and delay in ST segment shift (increase in the threshold of onset of ischaemia). The purpose of this study was therefore to evaluate, in an animal model (pig) of acute myocardial ischaemia (occlusion of the proximal section of the left anterior descending coronary artery), the action of serotonin, naftidrofuryl and a combination of both substances on the following parameters: 1) electrophysiological (sinus heart rate, ST segment shift, T-wave amplitude, duration of monophasic action potentials, intraventricular conduction time); 2) haemodynamic (systolic, diastolic and mean blood pressure, first derivative of rate of increase of left ventricular pressure with time: LV dP/dt max); and 3) biochemical (malonedialdehyde concentration as an index, cell peroxidation index, creatine phosphate and adenosine triphosphate). It was found that co-infusion of serotonin aggravated the myocardial ischemia and that naftidrofuryl exerted beneficial effects on the serotonin-mediated aggravation of myocardial ischaemia.

Opposite change with ischaemia in the antifibrillatory effects of class I and class IV antiarrhythmic drugs resulting from the alteration in ion transmembrane exchanges related to depolarization.

It is known that class I antiarrhythmic drugs lose their antifibrillatory activity with severe ischaemia, whereas class IV antiarrhythmic drugs acquire such activity. Tachycardia, which is also a depolarizing factor, has recently been shown to give rise to an alteration of ion transmembrane exchanges which is particularly marked in the case of calcium. This leads one to wonder if the change in antifibrillatory activity of antiarrhythmic drugs caused by ischaemia depends on the same process. The change in antifibrillatory activity was studied in normal conditions ranging to those of severe ischaemia with a class I antiarrhythmic drug, flecainide (1.00 mg x kg(-1) plus 0.04 mg x kg(-1)x min(-1), a sodium channel blocker, and a class IV antiarrhythmic drug, verapamil (50 microg x kg(-1) plus 2 microg x kg(-1) x min(-1)), a calcium channel blocker. The experiments were performed in anaesthetized, open-chest pigs. The resulting blockade of each of these channels was assessed at the end of ischaemic periods of increasing duration (30, 60, 120, 180, 300, and 420 s) by determining the ventricular fibrillation threshold (VFT). VFT was determined by means of trains of diastolic stimuli of 100 ms duration delivered by a subepicardial electrode introduced into the myocardium (heart rate 180 beats per min). Ischaemia was induced by completely occluding the left anterior descending coronary artery. The monophasic action potential was recorded concurrently for the measurement of ventricular conduction time (VCT). The monophasic action potential duration (MAPD) varied with membrane polarization of the fibres. The blockade of sodium channels by flecainide, which normally raises VFT (7.0 +/- 0.4 to 13.8 +/- 0.8 mA, p < 0.001) and lengthens VCT (28 +/- 3 to 44 +/- 5 ms, p < 0.001), lost its effects in the course of ischaemia. This resulted in decreased counteraction of the ischaemia-induced fall of VFT and decreased aggravation of the ischaemia-induced lengthening of VCT. The blockade of calcium channels, which normally does not alter VFT (between 7.2 +/- 0.6 and 8.4 +/- 0.7 mA, n.s.) or VCT (between 30 +/- 2 and 34 +/- 3 ms, n.s.), slowed the ischaemia-induced fall of VFT. VFT required more time to reach 0 mA, thus delaying the onset of fibrillation. Membrane depolarization itself was opposed as the shortening of MAPD and the lengthening of VCT were also delayed. Consequently there is a progressive decrease in the role played by sodium channels during ischaemia in the rhythmic systolic depolarization of the ventricular fibres. This reduces or suppresses the ability of sodium channel blockers to act on excitability or conduction, and increases the role of calcium channel blockers in attenuating ischaemia-induced disorders.

Efficacy of a beta-adrenergic receptor antagonist, propranolol, in preventing ischaemic ventricular fibrillation: dependence on heart rate and ischaemia duration.

OBJECTIVES: To investigate the prevention of ventricular fibrillation with a beta-adrenergic receptor (beta-AR) antagonist in anaesthetized, open-chest pigs in a model of ischaemia, intended to reproduce what happens either in anginal attack or in the first hour of infarction. METHODS: Ventricular fibrillation threshold (VFT) was determined with trains of diastolic stimuli of 100 ms duration delivered by a subepicardial electrode inserted in the area subjected to ischaemia. Ischaemia was obtained by the complete occlusion of the left anterior descending coronary artery, either near its origin during brief but increasing periods (30, 60, 90, 120, 150, 180, 240, 300 s), or half-way from its origin for a much longer time (more than 60 min). RESULTS: During transient proximal occlusion and isoprenaline infusion (0.25 microgram/kg/min), propranolol (50 micrograms/kg plus 2 micrograms/kg/min) attenuated both tachycardia and the fall in VFT to 0 mA. The shortening of MAP duration accompanying depolarization of the fibres was concurrently slowed down, and time to fibrillation prolonged (122 +/- 15 to 262 +/- 14 s, p < 0.001). In the absence of isoprenaline infusion, propranolol exerted similar effects, but to a lesser degree, in proportion to heart rate dependent on sympathetic activity. In contrast, it became unable to raise VFT before and during ischaemia, when heart rate was kept constant by pacing. After persistent midportion occlusion, significant differences in VFT were found only at the 5th min, depending on whether heart rate was accelerated by isoprenaline (0.8 +/- 0.2 mA), left normal (1.8 +/- 0.3 mA) or slowed down by propranolol (1.6 +/- 0.3 mA). Later on, especially after 15 and 25 min of ischaemia, VFT, which was below 1.0 mA, did not appear to be influenced by the activation or blockade of beta-ARs: spontaneous fibrillations were observed in the same number in this period with or without the administration of propranolol. Beyond 30 min after occlusion, the rise in VFT, subsequent to the first irreversible cell damage, also occurred in the same way. CONCLUSIONS: The prevention of ischaemic ventricular fibrillation by a beta-AR antagonist, judged from VFT, is easily checked experimentally when ischaemia is only transitory, especially if sympathetic activity is high. The maintenance of VFT at a relatively high level is essentially related to the depressant effect on the sinus rate. The same animal model does not give support to an effective protection in the first hour of infarction. However, the control of heart rate may also be beneficial in these circumstances by attenuating systemic haemodynamic disorders.

Possible prevention by amlodipine of ventricular fibrillation related to brief ischemia episodes.

Calcium antagonists may reduce propensity to ventricular fibrillation, by altering the balance between coronary blood flow and metabolic demand, and thus may substantially prolong time to occurrence of fibrillations. This delay in the onset of fibrillation should be sufficient to prevent sudden death in the case of transitory episodes of myocardial ischemia. Therefore, this study was based on the determination of time to onset of fibrillation in an animal model of transitory ischemia. This model was achieved by the complete, but transitory occlusion of the left anterior descending coronary artery near its origin under ventricular pacing at a constant high rate (180 beats/min), in anesthetized, open-chest pigs. Amlodipine was preferred to another calcium antagonist for this study because it is among the least negatively inotropic of these drugs. It was intravenously infused at 0.02 mg.kg-1.min-1. Time to fibrillation was prolonged from 87 +/- 10 to 146 +/- 16 s (p < 0.05) with the 0.30 mg/kg dose and to 201 +/- 22 s (p < 0.05) with the 0.60 mg/kg dose, without serious impairment of blood pressure or left ventricular dP/dtmax in the absence of ischemia. Concurrently, amlodipine significantly limited the shortening of monophasic action potential duration (200 +/- 4 vs. 172 +/- 6 ms), the lengthening of conduction time (43 +/- 2 vs. 53 +/- 2 ms), and the alterations of ST segments and T waves induced by 60 s ischemic depolarization. Consequently, amlodipine might reduce the incidence of sudden death by lengthening time to onset of fibrillation beyond the duration of the ischemia, when transitory.

[Value of calcium channel blockers in the prevention of ventricular fibrillation of ischemic etiology: experimental arguments]. / Intérêt des inhibiteurs du canal calcique dans la prévention de la fibrillation ventriculaire d'origine ischémique: arguments expérimentaux.

The prevention of ventricular fibrillation raises a special problem when related to myocardial ischaemia, since class I antiarrhythmic drugs are then ineffective and may even behave as profibrillatory agents: the usual antifibrillatory properties of these drugs which are inhibitors of sodium channel, activated at high potentials, disappear with the disappearance of the role of sodium channel caused by ischaemic depolarization. Calcium channel then replacing sodium channel, calcium channel inhibitors should tend to prevent ischaemic ventricular fibrillation. Therefore, vulnerability to ventricular fibrillation was assessed in open-chest pigs by the threshold for fibrillation electrically induced with impulses of 100 ms duration at the rate of 180 beats/min. Ischaemia was produced by total occlusion of the left anterior descending coronary artery near its origin. Electrical fibrillation threshold was measured at the end of ischaemic period of increasing duration (30, 60, 120, 180, 240, 360 s) under control conditions and after i.v. administration of verapamil (50 micrograms/kg loading dose and 2 micrograms/kg/min infusion). Unaffected by verapamil when coronary circulation was normal, fibrillation threshold was raised by the drug when lowered by ischaemia, increasingly with the prolongation of ischaemia responsible for depolarization of the fibres, up to 500%. The rise of fibrillation threshold resulted in a delay in the triggering of fibrillation which occurs when the fibrillation threshold (6-8 mA) falls down to the pacing threshold (0.3-0.4 mA). These experiments tend to confirm the positive results recently obtained in man with verapamil in the prevention of postinfarction sudden death, provided that myocardial contractility is not too much adversely affected. But, in these experiments, left ventricular dP/dt max was not reduced by more than 15%, even just after the loading dose and returned to its control values within a few minutes.