[Alindine reduces decreased ventricular conduction induced by large doses of bupivacaine in the anesthetized dog].
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Biomedical subjects
Publications and source records attributed to A Sassine.
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The use of diazepam has been suggested for the treatment of convulsions resulting from accidental high plasma levels of local anaesthetics. However, it has been reported that this drug may increase the cardiac effects of bupivacaine in dogs. The present study aimed to assess the effects of diazepam on the electrophysiological signs of a high-dose intravenous bolus of bupivacaine in fourteen dogs, divided into two groups, and anaesthetized with thiopentone and ventilated. All the animals were given a bolus dose of 4 mg.kg-1 bupivacaine. Immediately afterwards, group I (n = 7) received 0.8 ml.kg-1 normal saline solution and group II (n = 7) was given 4 mg.kg-1 diazepam over 1 min. The parameters measured on lead II of the electrocardiogram were: cycle length (R-R interval), QRS length (QRS) and QT interval corrected for heart rate (cQT). Intranodal (AH) and His-Purkinje (HV) conduction times were measured with recording bipolar stimulation electrodes (USCI 6F). Mean aortic pressure (Pao) was measured via a femoral arterial line. In the two groups, the parameters were recorded before and 2, 5, 10 and 15 min after the bupivacaine bolus. Arterial blood samples for measurement of bupivacaine and diazepam serum levels were obtained before and 3, 15 and 30 min after the bupivacaine bolus. There was no significant difference between the two groups in the electrophysiological or haemodynamic parameters at any time. However, the increase in HV and QRS length was a little higher in group I than in group II.(ABSTRACT TRUNCATED AT 250 WORDS)
The cardiac electrophysiological effects of CERM 4205, a new cardioactive agent, were studied by means of intracardiac electrodes in man and in anaesthetized dogs. The results show that CERM 4205 is a cardioactive drug with a main inhibitory effect on slow-response structures (sinus and atrioventricular node) with an associated effect on fast-response structures (atrial, His-Purkinje and ventricular tissues). No qualitative differences were observed between the effects observed in man and dogs. In conclusion, the present study confirms that CERM 4205 is a compound with combined class IV and class I electrophysiological effects in dogs and man. The anaesthetized dog appears to be a satisfactory model for the evaluation of the electrophysiological effects of cardioactive drugs.
The possibility that an asynchronous increase in the ventricular monophasic action potential duration is the basis of the quinidine-induced torsade de pointes, has led us to study the electrophysiological effects of increasing doses of intravenous quinidine. We measured the monophasic action potential duration and the ventricular effective refractory period at several right ventricular myocardial sites in the anaesthetized dog. Our results showed that quinidine induces a dose-dependent prolongation in ventricular effective refractory period and in ventricular monophasic action potential duration. These increases were uniform throughout the right ventricle. No variations in repolarization or in refractoriness were observed between the four ventricular sites studied. The results suggest that quinidine does not have a direct effect on dispersion of repolarization, and that mechanisms other than its direct electrophysiological action are involved in the development of torsade de pointes.
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The cardiac electrophysiological effects of Penticainide, a new antiarrhythmic agent, were studied by means of intracardiac electrodes in the anaesthetized dog. Intravenous administration of 5 mg/kg of Penticainide reduced the sinus rate and prolonged the sinus node recovery time. Atrial refractory periods increased. Anterograde intranodal conduction slowed and nodal refractoriness increased. Conduction time in the His-Purkinje tissue and ventricle increased, as did the ventricular refractory periods. Monophasic action potential duration was not altered by the drug in the atrium or the ventricle. The mechanism of action of Penticainide as an antiarrhythmic drug seems to be correlated to its membrane effects: inhibition of the fast-inward current, responsible for the marked effects on His-Purkinje and ventricular tissues; and inhibition of the slow-inward current, suggested by its effects on sinus node and atrio-ventricular node.
In anesthetized dogs, it has already been shown that cibenzoline (4 mg/kg i.v.) possesses class 1 anti-arrhythmic properties. In this work, the cardiac electrophysiologic effects of cibenzoline (1 mg/kg i.v.) were studied before and after propranolol (0.2 mg/kg i.v.) treatment. Cibenzoline caused a slight tachycardia, a reduction of conduction velocity in the His-Purkinje system and in the ventricle, but no significant effects in the atria and the atrioventricular node were detected. On the contrary, when dogs were given the beta-adrenoceptor blocking agent propranolol, cibenzoline produced major effects in the slow response structures, especially in the sinus node and the atrioventricular node (bradycardia and depression of the atrioventricular nodal conduction). No further effects were observed on the His-Purkinje system and ventricle as compared to administration of cibenzoline alone. In dogs, cibenzoline given i.v., had no effects on the slow response systems, probably because of sympathetic nervous system intervention since the class 4 effects of cibenzoline appeared after beta-adrenoceptor blockade.
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The effects of three purine derivatives of adenine, adenosine triphosphate (Striadyne), purified adenosine triphosphate and adenosine, on conduction tissue, were studied in closed chest dogs with endocavitary recording catheters. The dogs were anaesthetised with pentobarbital and ventilated, then three bipolar catheters were positioned to allow atrial pacing and recordings of atrial and His bundle potentials. The purines studied were administered by rapid bolus intravenous injection. The dosage was identical based on a predetermined dose-response curve (dose of 2 mg/kg). The study of the effects on atrioventricular conduction was carried out before and after administration of antagonists: atropine, 0.08 mg/kg and aminophylline, 10 mg/kg. Twelve dogs were studied for each purine: 6 with initial premedication with atropine and then aminophylline, and 6 with the inverse sequence. Lengthening of AV conduction was due exclusively to nodal depression. No variation in the HV interval was observed (HV = 35 +/- 4 ms). Lengthening of AH interval was observed very soon after injection of the drugs (5 to 10 seconds) with a peak effect between 20 and 40 seconds. Reversion to the initial value always occurred in under 2 minutes. In the model studied, Striadyne and purified adenosine triphosphate were much more powerful than adenosine, both in intensity and duration; high degree AV block was obtained in 10 out of 12 cases with Striadyne and in 8 out of 12 cases with purified adenosine triphosphate, but in only 2 out of 12 cases with adenosine. The use of specific antagonists demonstrated the different modes of action of the three purines.(ABSTRACT TRUNCATED AT 250 WORDS)
The electrophysiologic effects of bepridil in the anesthetized closed-chest dog were studied with intracardiac electrodes using the extrastimulus technique to measure the refractory periods of atria, atrioventricular (AV) junction and ventricles. Intravenous administration of 5 mg/kg of bepridil caused a reduction in sinus node rate and prolonged the sinus node recovery time. Refractory periods in the atrium, especially the effective refractory period, increased. Anterograde AV nodal conduction was slowed and refractoriness increased, often resulting in AV nodal Wenckebach periods, during atrial pacing, and retrograde conduction was always completely abolished. Refractory periods of the AV junction were altered in a comparable fashion to conduction through the AV node. No significant actions on conduction or the refractory period were noticed in the His-Purkinje system or the ventricle. The mechanism of action of bepridil seems to be correlated to its membrane effects, namely, inhibition of pathways responsible for the slow inward current, which explains its selective action on myocardial sites where this current is particularly involved.
Intravenous adenosine proved effective in eight out of ten episodes of acute spontaneous supraventricular tachycardia. AV node blockade induced by adenosine occurred 20 s after injection, and disappeared very quickly. Side-effects were transient and never serious. Therefore, it is thought that adenosine can be proposed safely for the short-term treatment of supraventricular tachycardia. Because of the different mechanisms of action, the specific side-effects observed after ATP administration are unlikely to be encountered.
The electrophysiological effects of cibenzoline on the myocardium of the anesthetized dog were studied by the endocavitary catheter method. Plasma cibenzoline levels were measured throughout. The cibenzoline effects on the sinus rate were negligible. The corrected sinus recovery time was significantly prolonged only following chronic oral administration. Atrial refractory periods were significantly increased only at the fifth minute following acute intravenous administration and after chronic oral treatment. The intranodal conduction time (AH) and the refractory periods in atrio-ventricular node were slightly modified or not at all. On the other hand, intraventricular and His-Purkinje (HV) conduction times, ventricular refractory periods and QRS duration were strongly increased following acute or chronic administration. This would imply a principal effect on the rapid kinetics sodium entry current. Nevertheless, the very marked effect upon this current could, under the experimental conditions adopted, have masked a lesser action upon other membrane permeabilities, involved in other myocardial structures.
The mechanisms of action of cibenzoline upon the electrical activity of the cardiac membrane in vitro, were studied using frog auricular preparations. Action potentials and transmembrane currents were examined using the double sucrose gap technique. Cibenzoline 2.6 X 10(-6) M reduced the amplitude and rate of depolarization of the action potential, slightly prolonged its duration and increased the refractory period. Voltage clamp analysis revealed a notable decrease in the amplitude of sodium rapid inward current, accompanied by a decrease in the kinetics of activation and inactivation, time to peak of the current was increased, as was the inactivation time constant. Cibenzoline delayed recovery from inactivation, reactivation time constants were increased. Cibenzoline also reduced the slow kinetic current due to calcium and sodium ions. The calcium portion of this current was less affected. These data lead to the conclusion that cibenzoline has the characteristics of class I and some class IV anti-arrhythmic action, but cibenzoline is not another quinidine because it would not appear to influence outward potassium current.
A study of plasma and cardiac concentrations of amiodarone during the course of long-term oral therapy was made possible by the improvement of analytical high performance liquid chromatography of plasma and tissue extracts. The plasma level was found to increase linearly with the daily dose of the drug, above a threshold value of c. 1 . 9 mg kg-1 day-1. Similarly, the cardiac content increased linearly with the daily dose, with no threshold, showing that the drug is taken up and accumulated in the cardiac tissue, with no obvious difference between atrial and ventricular samples (P greater than 0 . 05). Both plasma and heart showed no saturation at high drug intake, a justification for increasing the oral intake in severe cases. The linear relationship between tissue and blood concentrations allows a prediction of the cardiac level from a simple and routine blood analysis.
Electrophysiological effects of butoprozine (L 9394 Labaz) were investigated on the anaesthetized dog by programmed electrical stimulation of the heart and simultaneous recording of the His bundle electrogram and monophasic action potentials from the auricular and ventricular endocardial wall. Butoprozine injected intravenously depressed sino-atrial node function, lengthened A-V nodal conduction time and the A-V nodal refractory period, and prolonged the atrial refractory period. Thus butoprozine acted preferentially on parts of the myocardial tissue where the slow inward current seems to be particularly involved. In this respect, butoprozine was more active than amiodarone, but in contrast to this drug, butoprozine did neither prolong the ventricular monophasic action potential duration nor the ventricular refractory period. In the anaesthetized dog both drugs have practically analogous actions except at the ventricular level, which suggests that their effect on ionic currents at this level may be different.
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The existence of a cardiac phase of supernormal excitability is not fully proved at the cellular level. As far as the whole heart is concerned, the phenomenon of supernormal conduction is still under discussion. Intracardiac conduction has been studied both in the right atrium (13 dogs) and in the right ventricle (14 dogs) by programmed stimulation (extrastimulus technique), while monophasic action potential (MAP) was recorded. The phenomenon of supernormal conduction was noted in 67.7% of cases, starting at 59.0% and ending at 78.0% of the basic cycle, hence occuring shortly after phase 3 of the MAP. In the ventricle, a phase of supernormal conduction was present in 52.4% of cases, starting at 66.1% and ending at 77.9% of the basic cycle. After ajmaline, the supernormal conduction was moved towards the end of the cycle. The mechanism of supernormal conduction, and its implications in the study of arrhythmias are discussed.