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Calcium antagonists have been reported to counteract the increase by ischemia of vulnerability to ventricular fibrillation. This ability might be especially of interest in the prevention of sudden death subsequent to a major, but transitory, inadequacy between myocardial oxygen requirements and available coronary blood flow produced by exercise, emotion, etc., because death is then not related to irreversible damage of myocardial fibers. This study has been undertaken to examine the protective effect of a calcium antagonist on an animal model of this type of ischemia. This model used complete, but transient occlusion of the left anterior descending coronary artery near its origin during pacing at a constant high rate (180 beats/min) in anesthetized, open-chest pigs, most often resulting in fibrillation within 1-2 minutes after a progressive fall of the electrical fibrillation threshold. Amlodipine was the preferred calcium antagonist for this study because it is only moderately negatively inotropic. The results of the preventive administration of amlodipine was assessed by the time to onset of fibrillation. Amlodipine 0.30 mg/kg prolonged this time by 50-100% (p < 0.05) without appreciable impairment of blood pressure or myocardial contractility. Concurrently, amlodipine delayed the shortening of the monophasic action potential duration, the lengthening of conduction time, and the alterations of ST segments and T waves linked to ischemic depolarization. Consequently, when given experimentally before the occurrence of major, but transitory ischemia, amlodipine protected against fibrillation. Similarly, in clinical settings it ought to delay sudden death that may occur as a result of a major but transitory inadequacy between myocardial oxygen requirements and available coronary blood flow.

The effects of three quinidine-like drugs, disopyramide, lidocaine and flecainide were investigated in anaesthetized, open-chest pigs on vulnerability to ventricular fibrillation under normal conditions and under myocardial ischaemia conditions. Vulnerability to fibrillation was evaluated by electrical ventricular fibrillation threshold (VFT), measured with 100 ms duration diastolic impulses the intensity of which was increased by steps of 1.0 or 0.5 mA. Impulses were delivered at the rate of 180 beats · min(-1). The ventricles were subjected to pacing at the same rate before the VFT determination, particularly throughout periods of ischaemia of increasing duration (30, 60, 90, 120, 150 s), separated by appropriate intervals for reproducibility of the results. Monophasic action potential (MAP) duration and conduction time were monitored in the ischaemic area under pacing. Ischaemia was obtained by complete occlusion of the left anterior descending coronary artery near its origin. The three drugs were i.v. administered in clinical dose range (1.00 mg · kg(-1) plus 0.04 mg · kg(-1) · min(-1)). In the absence of ischaemia, they increased almost equally VFT (from about 7 to 10 mA), despite 25% prolongation of conduction time. But, none of them was able to impede the increasingly marked fall of VFT caused by ischaemia: at 30 s, they had already lost any capacity for raising VFT and, beyond this time, they even aggravated its fall which led to spontaneous fibrillation when VFT approached 0 mA. The faster fall of VFT shortened time to onset of fibrillation (20 24 fibrillations for the three drugs at 150 s as against 12 24 in control period), the ischaemia-induced reduction of MAP duration (by 20%) being also hastened and slowing of conduction enhanced, given the addition of the depressant effects of ischaemia and drugs on conduction. Consequently, the antifibrillatory properties normally manifested by the studied drugs are first suppressed, then inverted by ischaemia.

Results obtained in the prevention of ventricular fibrillation secondary to myocardial ischaemia are unexpected. Profibrillatory properties might be manifested by Class I antiarrhythmic drugs, normally antifibrillatory. Clear antifibrillatory properties might be manifested by calcium channel blockers, the antifibrillatory effects of which are normally questionable. Therefore, the action of a Class I antiarrhythmic drug, flecainide, and of a calcium channel blocker, verapamil, on the vulnerability to ischaemic ventricular fibrillation was assessed in anaesthetized, open-chest pigs by ventricular fibrillation threshold. Ventricular fibrillation threshold was determined with trains of diastolic stimuli of 100 msec duration, delivered at a rate of 180 beats/min (near that of the ventricular tachycardia), by a subepicardial electrode inserted into the area that could be subjected to ischaemia. Before determining this threshold, ventricles were paced at the same rate, particularly during the ischaemic periods. Ischaemia was produced by complete occlusion of the left anterior descending coronary artery, either at its origin or half-way from it, over increasing periods. The monophasic action potential and conduction time were recorded in the ischaemic area. Before ischaemia, flecainide was adapted to rais the ventricular fibrillation threshold, in spite of a lengthening of the conduction time. Verapamil was devoid of any influence on these parameters. The antifibrillatory effect of flecainide disappeared with ischaemia, which reduced the ventricular fibrillation threshold down to near 0 mA, with triggering of the spontaneous fibrillation at this level: this reduction was no longer counteracted and even hastened by flecainide, becomes finally profibrillatory. Verapamil, on the contrary, delayed the fall in ventricular fibrillation threshold, maintained far from 0 mA, with prevention of fibrillation, unless the occlusion was maintained over a much longer period. Verapamil similarly delayed the shortening of the monophasic action potential duration and the lengthening of the conduction time, preceding fibrillation and leading to it. Consequently, ischaemic depolarization is apparently responsible for the loss of antifibrillatory activity in a sodium blocker, such as flecainide, and the development of antifibrillatory activity in a calcium blocker, since the sodium channel is activated only at high potentials, whereas the calcium channel is activated at lower potentials.

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.

Myocardial ischemia sensitizes the cardiotoxic effects of bupivacaine, especially the propensity to ventricular fibrillation. To investigate this sensitization and to elucidate its mechanism, the influence of bupivacaine alone, or associated with ischemia, was studied on electrical fibrillation threshold in anesthetized, open chest pigs. Determination of fibrillation threshold was performed with impulses of 100 ms duration at the rate of 180 bpm, in the absence of ischemia and at the end of increasing periods of ischemia (30, 60, 120, 180 s) obtained by complete occlusion of the left anterior descending coronary artery close to its origin. The effect of bupivacaine (1.00 mg/kg initial dose plus 0.04 mg.kg-1.min-1 over 25 min) was compared to the control in the same animals. This effect corresponded to 1.4-1.8 micrograms/mL plasma concentrations likely to be observed in humans after regional anesthesia. Bupivacaine significantly increased the fibrillation threshold before coronary occlusion from approximately 7.0 to 9.5 mA. In contrast, during ischemia the fibrillation threshold was shifted to the left and down, with a hastening of spontaneous fibrillation. Recording of monophasic action potentials in the ischemic area revealed that conduction time was prolonged by more than 100% under the combined influence of ischemia and bupivacaine, whereas the major enhancement of excitability due to ischemia was not attenuated by bupivacine. Therefore, bupivacaine should be used with caution in the condition of ischemia, especially if heart rate is rapid. In the present experiments, tachycardia is another factor in the enhancement of bupivacaine effects on conduction.

In recent clinical studies, certain class I antiarrhythmic drugs (flecaïnide, lidocaïne) appeared to be responsible for an increase in mortality, when used to treat ventricular arrhythmias occurring after or during infarction. Experimentally, in pigs whose rate of ventricular beats was kept constant by pacing, all the studied class I antiarrhythmic drugs, disopyramide, lidocaïne and flecaïnide, proved to be to a variable degree capable of shortening time to onset of fibrillation (TOF) elicited by controlled myocardial ischemia. Fibrillation occurred at the end of the decline, under the influence of ischemia, of electrical fibrillation threshold (EFT) down to near 0 mA. The fall of EFT to this level was checked by ischemias of increasing duration to be hastened by the cited antiarrhythmic drugs. In other words, these drugs exert a profibrillatory effect in the ischemic heart.

A comparative evaluation of beta-blockers and calcium antagonists as protective agents against ventricular fibrillation related to myocardial ischaemia, was attempted in the pig heart in situ of anaesthetized, open-chest animals, subjected to a temporary complete occlusion of the left anterior descending coronary artery near its origin. This occlusion resulted in fibrillation occurring after a time depending on the vulnerability to the fibrillatory process. As this time to onset of fibrillation does normally not exceed a few minutes, its determination could be achieved repeatedly in the course of an experiment, in the absence and presence of drugs such as beta-blockers and calcium antagonists. When propranolol (0.05 mg/kg, i.v.) and verapamil (0.05 mg/kg, i.v.) abolished tachycardia produced by isoproterenol (0.25 micrograms/kg/min), the triggering of fibrillation was delayed in either case: in animals under atrial pacing at a rate close to the sinus rate on each determination, time to fibrillation was prolonged from about 160 to 400 sec by propranolol and from 160 to 640 sec by verapamil, with a return to control values within 60 min. Under ventricular pacing at a constant high rate (180 beats/min), no change was observed in time to fibrillation after propranolol (0.025 or 0.050 mg/kg), whereas verapamil, in the same conditions and in the same doses, multiplied this time by about 4 and 6, respectively. Consequently, propranolol and verapamil are likely to protect against fibrillation immediately after i.v. injection, but the protection due to propranolol is only indirect and a consequence of bradycardia which tends to increase the polarization of the muscular fibres, whereas verapamil adds to the same influence a direct preventive action by avoiding a cellular calcium overload in these fibres, which is responsible for the depolarization and fluctuations of their membrane potential.

A comparative study of the various classes of antiarrhythmic drugs as agents protecting against ischaemia-induced ventricular fibrillation was undertaken in the pig in situ heart, in anaesthetized animals which were subjected to complete temporary occlusion of the left anterior descending coronary artery. This occlusion resulted in fibrillation after a time which varied in inverse ratio to vulnerability to fibrillation. However, as this time did not exceed a few minutes, time to onset of fibrillation could be repeatedly measured in the course of an experiment, in the absence or in the presence of an antiarrhythmic drug. Under ventricular pacing at a constant rate, 180 beats/min, all the class I antiarrhythmic drugs, flecainide, disopyramide and lidocaine, in clinical dose range, reduced time to fibrillation to a large extent (25 to 50%) at the maximum of their action, with gradual return to control values within less than one hour. The enhancement of vulnerability to fibrillation was accompanied by reduction in intraventricular conduction velocity and fibrillation rate. With the same ventricular pacing, no change was observed in time to fibrillation under the influence of propranolol or amiodarone. As for verapamil, it lengthened this time considerably, up to 600%. However, bradycardia produced in usual circumstances ensures a real protection against ischaemic fibrillation with propranolol and amiodarone and enhances protection directly exerted by verapamil.

The effects of three antiarrhythmic drugs were investigated in anesthetized, open-chest pigs, in a left ventricular area, under pacing at a constant high rate (180 beats/min), in the absence and presence of ischemia. Ischemia was produced by transient complete occlusion of the left anterior descending coronary artery near its origin. In addition to the surface electrocardiogram, conduction time and monophasic action potential were recorded in the contractile fibers. In the absence of ischemia, intravenous flecainide and propafenone 2.5 mg/kg, and intravenous cibenzoline 2.0 mg/kg considerably lengthened conduction time (by 50-90%) but had no significant effect on the monophasic action potential duration. Consequently, the cited antiarrhythmic drugs enhance the prolongation of conduction time by 60% but do not limit the 30% shortening of the monophasic action potential caused by ischemia. Contrary to what was expected, they largely reduced the time to onset of the fibrillation due to ischemia from about 120 to 25 seconds. Thus, they manifested profibrillatory properties (more pronounced than those of other antiarrhythmic drugs of class I), which might be explained by their potent action on depolarization.

The effects of the calcium channel modulators, Bay k 8644, infused i.v. at a rate of 2.5 micrograms/kg/min, and diltiazem, injected i.v. in a dose of 0.5 mg/kg, on the susceptibility to fibrillation induced by ischaemia, were investigated in anaesthetized, open-chest pigs. Ischaemia was produced, under ventricular pacing at constant high rate (180 beats/min), by transient complete occlusion of the left anterior descending coronary artery, near its origin. It was maintained till the triggering of fibrillation. The propensity to fibrillation was judged from the time elapsing between the onset of occlusion and the onset of fibrillation (time to fibrillation). In addition to the surface electrocardiogram, conduction time and monophasic action potential were recorded in the ventricular contractile fibres, as were dP/dtmax in the left ventricle and blood pressure in the carotid artery. At the end of a 10 min infusion, Bay k 8644 lowered to a large extent (about 40%) the time to fibrillation, which returned to its control values within the following 20 min. Conversely, diltiazem increased the time to fibrillation by a factor 4 or 5 at 5 min after its administration. This time to fibrillation remained substantially increased 25 min later. These changes were not associated with alterations in conduction time or monophasic action potential duration in the absence of ischaemia, but with significant alterations in myocardial contractility and blood pressure: in the direction of an increase with Bay k 8644 and of a decrease with diltiazem. These results are in agreement with the enhancement by Bay k 8644 and the prevention by diltiazem of cell calcium overload which is at present recognized as being the essential determinant of the fibrillatory process.

Regional anesthesia with bupivacaine in pediatric patients is often accompanied by light levels of halothane general anesthesia. To determine the potential cardiotoxicity of these two drugs when used together, we defined the interaction between moderate plasma bupivacaine concentrations (1270-1760 ng/mL) and halothane (end-tidal concentrations, 0.5%-1.0%) on ventricular contractility and conduction in 22 closed-chest dogs anesthetized with chloralose. Bupivacaine alone (1-mg/kg intravenous bolus plus a 0.1-mg.kg-1.min-1 constant rate infusion) resulted in significant increases in ventricular conduction time (VCT) and effective refractory period (VERP) and nonsignificant decreases in dP/dtmax and blood pressure. The addition of halothane resulted in hypotension and in progressively increasing plasma bupivacaine levels secondary to reduced hepatic clearance, which led to further dose-related significant increases in VCT and VERP and to significant decreases in dP/dtmax and blood pressure. In other dogs given halothane but in which bupivacaine levels were held constant (1400 ng/mL), VCT remained constant and VERP lengthened slightly, whereas dP/dtmax decreased. We conclude that the combination of bupivacaine and halothane can cause adverse effects on ventricular contractility and intraventricular conduction.

The effects of three Ic antiarrhythmic drugs, flecainide, propafenone and cibenzoline, were investigated in anaesthetized, open-chest pigs, in a left ventricular area, during pacing at a constant high rate (180 beats min-1), in the absence and the presence of ischaemia. Ischaemia was produced by transient complete occlusion of the left anterior descending coronary artery 1-1.5 cm from its origin. In addition to surface electrocardiogram, conduction time and monophasic action potential were recorded in the contractile fibres. Measurement of the effective refractory period was added in the absence of ischaemia. In this event, flecainide and propafenone, each in a dose of 2.5 mg kg-1 i.v. and cibenzoline, 2.0 mg kg-1, i.v., considerably lengthened (by 50-90%) conduction time, but did not affect or hardly affected the duration of the monophasic action potential or the effective refractory period. Thus, it seems that these Ic antiarrhythmic drugs enhance the prolongation of conduction time by 60% and do not prevent the 30% shortening of monophasic action potential caused by ischaemia: contrary to expectation, they produced a large reduction (from about 120 to 25 s) in the onset time of fibrillation due to ischaemia. Thus, they manifested profibrillatory properties (more pronounced than those of other class I antiarrhythmic drugs), which might be explained by their potent action on depolarization with almost total absence of action on repolarization.

The effects of three Ic antiarrhythmic drugs were investigated in anaesthetized, open-chest pigs, in a left ventricular area under pacing at constant high (180/min) rate, outside and during an ischaemia produced by temporary complete occlusion of the left anterior descending coronary artery, 1-1.5 cm from its origin. In addition to surface ECG, conduction time and monophasic action potential were recorded in the contractile fibres. Measurement of effective refractory period was added outside the periods of ischaemia. In this event, flecainide and propafenone, in 2.5 mg/kg dose, and cibenzoline, in 2.0 mg/kg dose, i.v. injected, lengthened considerably (50 to 90%) conduction time, but did not affect or hardly affected monophasic action potential and effective refractory period. During ischaemia, they did not hinder the abbreviation of monophasic action potential (30%) and reduced to a large extent (about 120 to 25 s) the onset time of fibrillation. The profibrillatory effect of Ic antiarrhythmic drugs, certainly more pronounced than those of other antiarrhythmic drugs, might be explained by their potent action on depolarization of the contractile fibres coincident with an almost total absence of action on repolarization.

Clinically, bupivacaine has depressant effects on intraventricular conduction that may lead to serious atrioventricular blocks or reentrant arrhythmias at plasma levels below those required to produce these effects experimentally (2-3 micrograms/ml instead of 8-10 micrograms/ml). The difference could be due to drugs present in the blood at the time of regional anesthesia that similarly inhibit conduction. This hypothesis was examined in 30 anesthesized, closed-chest dogs by measuring conduction time in the ventricular contractile fibers as well as effective refractory period under pacing at a constant, relatively high (180 beats/minute) rate. Changes in sinus rate were limited, as well as changes in ventricular effective refractory period and blood pressure regardless of the drug tested. In contrast, cibenzoline, disopyramide, and propranolol increased conduction time and lengthened QRS duration. Clomipramine appeared to prolong conduction time and widen QRS only moderately in therapeutic doses, whereas verapamil did not manifest noticeable effects on conduction. Caution is therefore recommended in regional anesthesia with bupivacaine in subjects being treated with cardiovascular drugs, such as cibenzoline, disopyramide, and propranolol and their congeners, or even by tricyclic antidepressants.

Intraventricular conduction disorders and reentrant arrhythmias in dogs can be produced by high plasma bupivacaine concentrations. The authors' aim was to determine if these conduction disturbances also occurred at moderate plasma bupivacaine concentrations (2.2-3.7 micrograms/ml) when in association with other factors which affect intracardiac conduction, such as hyponatremia and hyperkalemia. Thus, duration of the QRS complex, ventricular conduction time, and effective refractory period (ERP) was measured during ventricular pacing at 180 beats per min in 46 anesthetized, closed-chest dogs separated into five treatment groups as follows: group I, an iv bolus of 4 mg/kg of bupivacaine plus an infusion of 0.1 mg.kg-1.min-1 of bupivacaine followed in 50-60 min by 10 ml.kg-1.min-1 of 1.5% glycine iv to produce dilutional hyponatremia; group II, 1.5% glycine alone, as above; group III, bupivacaine, as above, followed in 50-60 min by 0.05 mmol.kg-1.min-1 of KCl iv to produce hyperkalemia; group IV, KCl alone, as above; and group V, bupivacaine, as above, except that the duration of infusion was 90 min. QRS duration and ventricular conduction time, which were prolonged approximately 33% and 61%, respectively, by bupivacaine alone were additionally prolonged 29% and 44%, respectively, when serum sodium concentration was lowered to 114 mmol/l and potassium concentration was raised to 7.7 mmol/l. The combinations of bupivacaine and hyponatremia, and bupivacaine and hyperkalemia tended to increase ERP more than did bupivacaine alone, although these changes were not statistically significant. Wave burst arrhythmias and episodes of ventricular tachycardia occurred spontaneously or were triggered by pacing in those dogs in which conduction time was most prolonged.(ABSTRACT TRUNCATED AT 250 WORDS)

High concentrations of bupivacaine and profound hypothermia individually cause intraventricular conduction disturbances and reentrant arrhythmias. The effects of the combination of relatively low concentrations of bupivacaine and mild hypothermia are unknown and are the subject of this study. Three groups (n = 10-12) of dogs anesthetized with thiopental-chloralose were treated as follows: group 1, bupivacaine + hypothermia; group 2, bupivacaine alone; group 3, hypothermia alone. Bupivacaine was administered as a 4 mg/kg iv bolus followed by an iv infusion of 0.1 mg.kg-1.min-1. Hypothermia, i.e., a 4 degrees C reduction in core temperature, was produced by cooling the blood with an extracorporeal circuit. The peripheral ECG was recorded to determine the duration of QRS complexes and the QT interval. Conduction time and effective refractory period (ERP) of ventricular contractile tissue were measured with right ventricular endocavitary electrodes. Measurements were made with the heart paced at 180 beats/min and without pacing. In group 1 dogs, bupivacaine (plasma level, 2.8 +/- 0.3 microgram/ml) initially caused a prolongation of conduction time and QRS duration, which were further lengthened (approximately doubled) by a temperature decrease of 4 degrees C from baseline. The QT interval and ERP also were increased but to a lesser degree. In dogs in which the effects were most pronounced, rhythm disorders, such as wave burst arrhythmias (most common), premature systoles, ventricular tachycardia, and even ventricular fibrillation, occurred either spontaneously or during pacing. Bupivacaine alone (group 2) increased QRS duration and conduction time significantly, whereas hypothermia alone (Group 3) did not cause changes in any conduction variables. In neither group were dysrhythmias observed.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of cibenzoline, rightly known as a sodium channel inhibitor (class IC antiarrhythmic drug), were investigated in anaesthetized, closed-chest dogs, on conduction in the contractile fibres, ventricular and atrial, the His-Purkinje system and the atrioventricular node. In ventricular muscle, conduction time was measured between base and apex by two endocavitary electrodes. The other conduction times were obtained from the recording of the His bundle potentials. In addition, effective refractory period was determined by the extrastimulus method in ventricular and atrial muscle and in the atrioventricular node, and sinus rate monitored in the intervals of pacing periods. In the absence of vagal tone, cibenzoline in 4 mg.kg-1 dose prolonged conduction times in the ventricular contractile tissue, His-Purkinje system and atrial contractile tissue to a large extent, but decreasingly from the former to the latter. This prolongation was antagonized by hypernatremia (174 mmol.l-1). In contrast, conduction time in the atrioventricular node, effective refractory periods and sinus rate were very little influenced. In the presence of vagal tone, the prolongation of conduction times in the ventricular contractile tissue. His-Purkinje system and atrial contractile tissue did not differ substantially from previously. It was the same for ventricular effective refractory period. But atrial effective refractory period was then considerably lengthened, while conduction time and effective refractory period in the atrioventricular node were greatly shortened and sinus rate notably accelerated.(ABSTRACT TRUNCATED AT 250 WORDS)

The risk of toxic effects on the heart of bupivacaine following several kinds of locoregional anaesthesia has been investigated in the dog in situ heart by determining conduction time and effective refractory period in the various parts of the conduction system and the ventricular muscle, as well as the discharge rate of the sinus node. Bupivacaine, i.v. infused at 3 rates, 0.2, 0.3 and 0.4 mg X kg-1 X min-1, proved to have depressant effects on conduction, automatism and excitability. It slows down conduction in all the parts of the myocardium, considerably at high stimulation frequencies, but always much more in the His-Purkinje system and the ventricular contractile fibres than in the atrioventricular node, because it tends to block the sodium rather than the calcium or potassium channel. Its effect remain more moderate, indeed, on sinus automatism and atrial and mainly ventricular refractoriness. Its danger lies, therefore, in the inhibition of conduction, with atrioventricular or His bundle branch block, but more frequently reentrant arrhythmias, likely to result in ventricular fibrillation. However: these alterations are observed with very high plasma levels (about 4 to 9 micrograms X ml-1), much higher than usual peak concentrations following spinal anaesthesia (0.10 micrograms X ml-1) or even epidural anaesthesia or brachial plexus block (1.20 micrograms X ml-1); reversal of these alterations occurs rapidly (reduction by 50% within 30 min for instance), when they have not led to ventricular fibrillation or they have not been associated with circulatory collapse.

The effects of two novel antiarrhythmic drugs, cibenzoline and flecainide, known to exert potent inhibitory effects on sodium channel, were investigated on intraventricular conduction in anaesthetized, closed-chest dogs. During this study, in which the heart was electrically stimulated, the pacing period was gradually reduced in the 500-200 msec range, and the pacing rate was abruptly altered (2 sec) or sustained (8 to 10 sec) in order to study the possible frequency- and time-dependency of the depression of conduction. In addition to the electrocardiogram, the conduction time was recorded in the ventricular contractile tissue between an electrode advanced to the apex and the pacing electrode positioned near the base. Effective refractory period (ERP) was concurrently measured according to the extrastimulus method, and the monophasic action potential (MAP) recorded. The drugs were infused at a rate of 0.2 mg/kg/min over a 10 min period after a 4.0 mg/kg loading dose. Conduction time was lengthened by approximately 50% at low frequencies and 100% at high frequencies. Widening of the ORS complexes paralleled this lengthening, whereas the drugs tended only to prolong ERP, without preventing its shortening induced by acceleration. Cardiac disorders were aggravated when high pacing rates were maintained for 8 to 10 sec.

Three hours after the intravenous infusion of doxorubicin (3 mg/kg over 15 min) to anesthetized dogs, the drug concentration was found much higher in the myocardium than in the plasma (about 4,000 ng/g, i.e., 50 times higher). After the intravenous infusion of doxorubicin (1.5 mg/kg over 15 min) to conscious dogs, the drug concentration appeared to decline very slowly in the myocardium, since it was close to 200 ng/g at the 7th day, whereas the plasma concentration had fallen to zero, and the drug was still detected in the cardiac tissue 21 days after the administration. As myocardial concentrations of doxorubicin persist long after plasma clearance is complete, the hazards of repeated administration, based on plasma kinetic patterns, must be emphasized.

The effects of a calcium channel blocker, verapamil, on the atrioventricular (AV) node, are antagonized by calcium, intravenously infused, so long as plasma calcium concentration does not reach 5.0 or 5.5 mmol.l-1, as previously shown. Beyond this, the antagonistic effects decrease progressively, so that there is a bell-shaped relationship between dose (or concentration) and response. The purpose of the present experiments has been to investigate a possible similar dose-response curve with a calcium channel activator, Bay k 8644. The study was carried out in anaesthetized, atropinized dogs, with cardiac pacing. The His bundle potentials were recorded by endocavitary electrodes and the AV nodal effective refractory period was measured by the extrastimulus method. Verapamil impaired AV nodal conduction and additional infusion of Bay k 8644 at a rate of 1 microgram.kg-1.min-1 partly antagonized this effect. Increasing the infusion rate of Bay k 8644 to 5 micrograms.kg-1.min-1 did not further increase but reduced the antagonism. In other experiments where infusion of calcium had partly antagonized the effect of verapamil, Bay k 8644 infused after cessation of calcium infusion did not further antagonize the effect of verapamil which even became again increasingly marked. Consequently, in the AV node depressed by a calcium channel blocker, Bay k 8644 gives rise to a bell-shaped dose-response relationship of its verapamil-antagonistic action and the reversal of this action by high doses of Bay k 8644 can be observed after both administration of either calcium or Bay k 8644 in moderate doses.

The threshold concentrations responsible for circulatory collapse were experimentally investigated by intravenously infusing the drug at high rates (0.2 and 0.3 mg kg-1 min-1 over 20 min, and 0.4 mg kg-1 over 10 min) to 11 anaesthetized and ventilated dogs. Bupivacaine plasma concentrations at the time of haemodynamic measurements were, respectively, 4303 +/- 46, 5829 +/- 615, and 8930 +/- 689 ng ml-1 (means +/- SEM). Cardiac output appeared to be the first and the most affected of the haemodynamic variables studied. Its reduction was already significant with the 0.2 mg kg-1 min-1 bupivacaine infusion, whereas mean systolic blood pressure remained unchanged because of the compensatory increase in vascular resistance. The fall of cardiac output was enhanced by the rise in bupivacaine infusion rate, with simultaneous substantial decreases in left ventricular pressure and LV dP/dt max. At this stage, the increase in systemic vascular resistance was less marked than at low infusion rates, and was not sufficient to prevent hypotension. The variations of mean pulmonary blood pressure and pulmonary capillary wedge pressure did not reach statistical significance, and the absence of significant change in mean pulmonary blood pressure at the time cardiac output was reduced reflected the increase in pulmonary vascular resistance. These results suggest that high plasma concentrations of bupivacaine exert a depressant effect on cardiac contractions earlier than on arteriolar tone.