Negative inotropic and arrhythmic effects of high doses of ciguatoxin on guinea-pig atria and papillary muscles

Ciguatoxin, the toxin present in fish responsible for ciguatera, at doses equal or above the maximum positive inotropic dose in atria (greater than 0.15 mouse units/ml) induced arrhythmias in atria and papillary muscles stimulated at 1 Hz and dose-dependent negative inotropy in atria. Negative inotropy was enhanced by ouabain or by an increase in stimulation to 3 Hz, little affected by procaine or increasing Ringer [Ca2+] and reversed by lidocaine and tetrodotoxin (TTX). Ciguatoxin caused negative inotropy associated with cell depolarisation in 1.2 mM Ca2+-Ringer and additionally caused signs of Ca overload in 3.2 mM Ca2+-Ringer. Ciguatoxin induced transient after-contractions and contracture in atria which were common in 3.2 mM but not 1.2 mM Ca2+-Ringer and which were enhanced by ouabain. TTX and lidocaine abolished after-contractions and contracture while procaine was less effective. Extrasystoles consisting of short bursts of 1-2 extra contractions per sec were seen in atria and papillary muscles within 45 min of ciguatoxin being added. The effect was observed in 3.2 mM but seldom in 1.2 mM Ca2+-Ringer and was absent when low doses of propranolol or TTX were added prior to ciguatoxin. Flutter was observed in a few papillary muscles after ciguatoxin. These results suggest that the toxic effects of ciguatoxin stem from its direct action of opening myocardial Na+ channels. Extrasystoles appeared to result mainly from its effect on neural Na+ channels causing an increased release of noradrenaline from the nerves associated with the myocardium.     

原发性高血压与心律失常相关性分析

目的探讨原发性高血压（EH）与心律失常相关性。方法对164例EH患者,进行心电图（ECG）、Horlter、超声心电图（UCG）检查,测定心律失常、左室肥厚、左房内径。结果心律失常占90.2%,其中房性心律失常占88.4%,室性心律失常占56.5%,复杂性房性心律失常占29.6%,复杂性室性心律失常占40.9%,AVB占1.8%,左室肥厚（Left Ventricnlorhypeitrophy LVH）组复杂性房性心律失常及复杂性室性心律失常明显高于无LVH组,差异有统计学意义（P〈0.05）。左房扩大组（LAD）复杂性房性心律失常与左房正常组比较,差异有统计学意义（P〈0.05）。结论 EH患者房性心律失常高于室性心律失常,高级别心律失常与LVH、LA扩大相关。     

Pharmacology of scorpion toxin II in the skeletal muscle

1. Scorpion toxin II is potent in inducing contracture and spontaneous contractions of the chick biventer cervicis muscle. In addition, this toxin induces membrane depolarization and blockade of neuromuscular transmission in this muscle preparation. The purpose of the present study is to explore the possible mechanism of actions of toxin II. 2. The muscle contracture induced by toxin II is moderately accelerated by Ca2+-free Krebs solution, delayed by high Ca2+ (10 mM), high Mg2+ (10 mM) and low Na+ (60mM) Krebs solution. Moreover, this action is inhibited slightly by d-tubocurarine and completely by either procaine or tetrodotoxin, but unaffected by beta-bungarotoxin. All these findings suggest that toxin II induces contracture mainly by increasing the Na+ permeability of the muscle membrane. 3. Spontaneous contractions induced by toxin II are abolished by Ca2+-free Krebs solution, inhibited partially by either d-tubocurarine or beta-bungarotoxin and completely by tetrodotoxin or procaine. These results suggest that toxin II induces spontaneous contractions partially by releasing acetylcholine from nerve endings and partially by increasing the Na+ permeability of the muscle membrane.     

Relationship between an arrhythmogenic action of lidocaine and its effects on excitation patterns in acutely ischemic porcine myocardium

To investigate the relationship between the effects of lidocaine on excitation patterns and its effects on the incidence of arrhythmias, the left anterior descending coronary artery was occluded for 6-min periods separated by 30 min of reperfusion, under control conditions and after injection of lidocaine, at a dose of either 2.5, 5.0, or 10.0 mg/kg i.v., in 29 open-chest anesthetized pigs. Sixty-three unipolar electrograms and a surface lead electrocardiogram were continuously recorded during atrial pacing and spontaneous ventricular arrhythmias. Ventricular fibrillation (VF) occurred only in four of a total of 45 control occlusions. VF occurred in two of five pigs following injection of lidocaine 2.5 mg/kg, in 15 or 17 pigs following injection of a 5 mg/kg dose, and in all three preparations following injection of a 10 mg/kg dose. Just prior to VF during occlusions preceded by injections of lidocaine 5 mg/kg, activation time of ischemic myocardium in atrial-paced beats was delayed by only 30 +/- 17 ms beyond preocclusion values, compared with 18 +/- 11 ms at a similar time during control occlusions and 33 +/- 18 ms at the end of control occlusions (mean +/- SD; n = 8). As ventricular tachycardia (VT) developed in the presence of lidocaine, conduction was further slowed or blocked in ischemic areas, and slowed in nonischemic regions; at the transition from VT to VF, excitation patterns displayed circus movement involving nonischemic regions.     

Influence of lidocaine on ouabain-induced inotropic response in rat atria

In this paper we demonstrated that lidocaine broadens the therapeutic range of ouabain action having a protective effect on ouabain-induced toxicity on rat atria. The lidocaine effect on therapeutic ouabain action was associated with the increase in the sensitivity of Na(+)-K(+)-ATPase related to a decreased in the equilibrium dissociation constant (K(d)) of high affinity binding sites. Lidocaine suppressed the ouabain-induced tonotropic effect and arrhythmias, decreasing the number of low affinity binding sites (B(max)) without changes in K(d). Blockade of Na(+)-Ca(2+) exchange with KB-R7943 or dual Na(+)-Ca(2+) channel with flunarizine, mimicked lidocaine effect increasing ouabain therapeutic action, extending its concentration range tolerated, delaying the onset of contracture. Lidocaine itself triggered negative inotropic response at high concentration. This effect was increased in the presence of flunarizine and verapamil but not by the inhibition of calcium/calmodulin with W-7. The mechanism underlying the lidocaine-induced negative inotropic response, appears to be different that underlying the positive inotropic effect on ouabain action. This study provides evidence that lidocaine can interact with the same or similar binding sites for ouabain in rat atrial tissue, providing a protective effect on ouabain-induced changes in contractility. The contribution of Na(+)-Ca(2+) exchange and/or Ca(2+) overload on lidocaine effect is discussed.     

Hypertension and concurrent arrhythmias

Hypertension and cardiac arrhythmias commonly coexist in many patients. In this review, we will initially discuss arrhythmogenesis in hypertension, with particular emphasis on atrial and ventricular tachyarrhythmias and sudden cardiac death, whilst in the final part, we will focus our attention on the effects of anti-hypertensive therapies on supra-ventricular and ventricular arrhythmias and on sudden cardiac death prevention. Many patients with atrial fibrillation or frequent premature ventricular contractions have hypertension, and both need to be managed appropriately. Furthermore, hypertensive left ventricular hypertrophy could cause a wide variety of ventricular arrhythmias, which could end in sudden cardiac arrest. Most anti-hypertensive therapies, such as the beta blockers or ACE inhibitors, by slowing or interrupting the progression towards atrial and ventricular remodelling might exert some anti-arrhythmic effect, thus reducing the risk of sudden cardiac death in these patients.     

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

AZD7009 (tert-Butyl-2-(7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethylcarbamate) is an antiarrhythmic agent that increases atrial refractoriness, shows high antiarrhythmic efficacy and has low proarrhythmic potential. This study was primarily undertaken to determine the effects of AZD7009 on the late sodium current and to examine the impact of late sodium current inhibition on action potential duration in various myocardial cells. AZD7009 inhibited the late sodium current in Chinese Hamster Ovary K1 (CHO K1) cells expressing hNa(v)1.5 with an IC(50) of 11+/-2 microM. The late sodium current in isolated rabbit atrial and ventricular myocytes was also concentration dependently inhibited by AZD7009. Action potentials were recorded during exposure to 5 microM E-4031 (1-[2-(6-methyl-2pyridyl)ethyl]-4-(4-methylsulfonyl aminobenzoyl)piperidine), a compound that selectively inhibits the rapid delayed rectifier potassium current (I(Kr)), and to E-4031 in combination with AZD7009 or lidocaine in rabbit atrial and ventricular tissue and Purkinje fibres. In Purkinje fibres, but not in ventricular tissue, AZD7009 and lidocaine attenuated the E-4031-induced action potential duration prolongation. In atrial cells, AZD7009, but not lidocaine, further prolonged the E-4031-induced action potential duration. E-4031 induced early afterdepolarisations (EADs) in Purkinje fibres, EADs that were totally suppressed by AZD7009 or lidocaine. In conclusion, excessive action potential duration prolongation induced by E-4031 was attenuated by AZD7009 and lidocaine in rabbit Purkinje fibre, but not in atrial or ventricular tissue, most likely by inhibiting the late sodium current. Furthermore, the opposite effect by AZD7009 on action potential duration in atrial tissue suggests that AZD7009, in addition to inhibiting I(Kr), also inhibits other repolarising currents in the atria.     

Phenytoin in treatment of amiodarone-induced Torsades de pointes

Phenytoin, a class IB anti-arrhythmic agent, is considered the drug of choice for ventricular arrhythmias due to digoxin toxicity. We report successful reversion of polymorphic ventricular tachycardia secondary to amiodarone toxicity by phenytoin administration that was resistant to the conventional drugs (magnesium sulphate, lidocaine and atropine).     

Mode of stimulatory actions of cadmium ion on the mouse diaphragm.

Effects of Cd2+ on the phrenic nerve-diaphragm preparation of the mouse varied markedly in media containing various Ca2+ concentrations. In normal 2.5 mM Ca2+ medium, Cd2+ inhibited acetylcholine release from nerve endings without appreciable effect on the muscle membrane. However, Cd2+ elicited stimulatory effects on the muscle membrane in low Ca2+ medium (10(-3)-1 mM). These stimulatory effects included the induction of spontaneous contractions, augmentation of twitch responses to direct electrical stimulation and potentiation of the muscle contracture induced by acetylcholine, carbachol and high K+. By contrast, caffeine contracture was not affected by Cd2+. Tetrodotoxin, procaine, cysteine and glycerol pretreatment abolished these stimulatory effects of Cd2+. Moreover, changing the ionic composition of the bathing medium to one containing low Na+, high K+, high Mg2+ or high Ca2+ also antagonized these effects of Cd2+. In contrast, low Mg2+ markedly potentiated the frequency of spontaneous contractions induced by Cd2+. (+)-Tubocurarine and beta-bungarotoxin had no effect on Cd2+-induced spontaneous contractions indicating that they may be myogenic rather than neurogenic in origin. By use of conventional microelectrodes, it was found that Cd2+ not only depolarized the muscle membrane but also induced spontaneous action potentials at a high frequency (173 +/- 17 Hz). It is concluded that increased Na+ permeability of the muscle membrane is the essential step bringing about spontaneous contractions. The binding of Cd2+ to -SH groups of the membrane is closely related to the induction of these effects.     

The effects of crude venoms of Conus magus and Conus striatus on the contractile response and electrical activity of guinea-pig cardiac musculature.

R. Endean, P. Gyr and J. Surridge. The effects of crude venoms of Conus magus and Conus striatus on the contractile response and electrical activity of guinea-pig cardiac musculature. Toxicon17, 381–395, 1979.—Positive inotropic activity of long duration elicited in atrial or ventricular musculature by the venom of Conus striatus or that of C. magus can be antagonized by manganese, lanthanum, verapamil or tetrodotoxin. The block of ventricular contractility by each of these four blocking agents can be overcome by either venom as can the block of atrial contractility by tetrodotoxin or lanthanum. Positive inotropic activity similar to that in non-reserpinized guinea-pigs was produced in ventricular musculature from reserpinized guinea-pigs by standard doses of either venom but atrial musculature from reserpinized guinea-pigs required increased amounts of the venoms before such activity was exhibited. Although the crude venoms did not affect resting potentials they caused marked increases in overshoot and overall duration of action potentials in both atrial and ventricular musculature. The abolishing, by manganese and lanthanum, of the plateau of the action potentials in atrial musculature was reversed by C. striatus venom but not C. magus. The venom of C. magus, but not C. striatus, antagonizes the depressant effect of tetrodotoxin on the rate of rise and overshoot of the action potential of atrial or ventricular musculature.     

A possible mechanism of the antiarrhythmic action of glucagon

The effects of glucagon on ouabain-induced ventricular arrhythmias were studied in dogs with normal cardiac conduction systems and in dogs with surgically induced complete heart block. Glucagon, 20 μg/kg, effected conversion to a sinus rhythm in eight of nine animals with normal conduction systems, and in each instance the conversion occurred with a sinus tachycardia whose rate exceeded the rate of pre-existing ventricular arrhythmia. The one animal which failed to convert to a sinus rythm did not develop a sinus nodal rate faster than the rate of the ventricular arrhythmia. In 10 animals with ouabain-induced ventricular arrhythmias atrial pacing was employed to overdrive the arrhythmia, and in 6 cases this was successful. In all 6 experiments subsequent administration of glucagon after pacing resulted in conversion to a sinus rhythm at a rate greater than the minimum atrial pacing rate required to effect capture of the ventricules. In 4 of the 10 animals neither atrial overdrive nor glucagon were successful in effecting sinus conversion, but ventricular rate was slowed by lidocaine. In addition, in 5 animals with complete heart block and ouabain-induced ventricular tachycardia which were given glucagon, 20 μg/kg, there was no change in the tachycardia and no change in the ECG pattern associated with the arrhythmia. It was concluded that the antiarrhytmic action of glucagon in this arrhythmia is mediated through a supraventricular action to elevate sinus rate above that of the dominant ventricular focus and thus allow a return to dominance of the sinus node.     

Cardiac arrhythmias after phenylpropanolamine ingestion

Physicians and pharmacists should be alerted to the potential adverse effects of phenylpropanolamine-containing products, which may include exaggerated hypertensive effects, arrhythmias (premature ventricular and atrial contractions together with paroxysmal ventricular or atrial tachycardia), psychotic reactions, and neurologic effects (grand mal seizures and intracerebral hemorrhage). A case of paroxysmal atrial tachycardia in a woman, after the ingestion of diet pills containing phenylpropanolamine and caffeine is reported.     

The effects of theophylline and cyclic AMP on intestinal smooth muscle contractions

The effects of 10^?4-10^?3 M theopphylline, cyclic 3'5'-adenosine monophosphate (cyclic AMP), dibutyryl cyclic AMP (DBC) and theophylline plus DBC were observed on the spontaneous and potassium (K)-induced contractions of the guinea-pig taenia coli. All of the compounds inhibited spontaneous contractions as well as the phasic and tonic components of the K-contracture. The effects of cyclic AMP, a compound which will not readily penetrate the cell membrane, were similar to those of the other compounds in inhibiting the spontaneous and phasic contractions, but it was a less effective inhibitor of the tonic contracture. Inhibition of spontaneous and phasic activity may occur at the cell membrane while the inhibitory actions on the tonic contracture may depend on cellular penetration by the inhibitor. There was no evidence that theophylline and DBC have different sites of action.     

Investigation of electrophysiologic mechanisms for the antiarrhythmic actions of R 56865 in cardiac glycoside toxicity.

R 56865 is an experimental compound that has been shown to ameliorate the effects of cardiac glycoside toxicity and myocardial ischemia. We evaluated the direct electrophysiological effects of R 56865 and its effects on the electrophysiological sequelae of ouabain toxicity in vivo and in vitro. In normal anesthetized dogs, R 56865 alone at doses of 0.04 to 0.16 mg/kg i.v. had no effect on atrial, AV nodal, or ventricular conduction times and refractoriness, but at doses of 0.64 to 2.5 mg/kg it tended to increase these parameters. In ouabain-pretreated dogs, R 56865 (0.08 to 0.32 mg/kg i.v.) dose-relatedly reduced ouabain-induced ventricular arrhythmias. In normal isolated canine Purkinje fibers, R 56865 (1-10 microM) reduced Vmax at short pacing cycle lengths and decreased the action potential duration at concentrations of 0.1 to 10 microM. R 56865 at concentrations through 10 microM had no significant effect on normal action potentials of canine ventricular muscle and slow response action potentials in guinea pig papillary muscles. In Purkinje fibers exposed to toxic concentrations of ouabain, R 56865 (1 microM) reduced the delayed after depolarization (DAD) amplitude and inhibited triggered activity. R 56865 had no effect on normal automaticity in canine Purkinje fibers at 1 microM, but 10 microM significantly slowed it. R 56865 at 10 microM did not affect isoproterenol-enhanced automaticity and only slightly reduced barium-induced abnormal automaticity that occurred at reduced membrane potentials. These results demonstrate that R 56865 reverses cardiac glycoside-induced arrhythmias in anesthetized dogs at doses that do not significantly affect conduction or refractoriness. Suppression of ouabain-induced DAD and triggered activity in isolated Purkinje fibers, at concentrations not affecting normal or abnormal automaticity, may be the mechanism of R 56865's antiarrhythmic actions in vivo. Suppression of DAD does not appear to be associated with blockade of voltage-dependent calcium channels, but R 56865 may prevent intracellular sodium overload by limiting excessive sodium entry during ouabain intoxication.     

Effects of artilide on spontaneous and induced ventricular arrhythmias in 24-hour canine myocardial infarction

The electrophysiologic and antiarrhythmic effects of artilide were evaluated in dogs 24 h after myocardial infarction. Artilide (0.1 to 3.0 mg/kg or 0.2 to 7.0 μuM/kg iv) prevented programmed stimulation induced ventricular arrhythmias in 9 out of 9 dogs that had demonstrated inducibe ventricular arrhythmias prior to treatment. This antiarrhythmic action was associated with significant increases in ventricular refractoriness and monophasic action potential duration. Lower doses of artilide tended to reduce the incidence of spontaneous ventricular arrhythmias but these effects were not significant. These results are consistent with the concept that spontaneous and pacing induced ventricular arrhythmias result from different mechanisms, and that class III anti-arrhythmic agents are more effective in suppressing induced ventricular tachycardia due to reentry than spontaneous arrhythmias which result from nonreentrant mechanisms. © 1993 wiley-Liss, Inc.     

The actions of nifedipine and nisoldipine on the contractile activity of human coronary arteries and human cardiac tissue in vitro

We have studied the action of nifedipine and nisoldipine on the contractile activity of human isolated coronary arteries and human isolated auricular and ventricular muscles. Nisoldipine depressed dose dependently the spontaneous rhythmic contractions displayed by the coronary artery preparations and at 1 nM abolished these contractions. Nisoldipine was twenty times more potent than nifedipine as an inhibitor of increase in tone induced by depolarization (100 mM K+). The rhythmic activity induced by serotonin (10 microM) was about five times more sensitive to nisoldipine than to nifedipine. In both auricular and ventricular preparations, isoprenaline evoked an increase in the rate of force development and in the rate of relaxation. Nifedipine was five times (ventricular muscles) and ten times (auricular muscles) more potent than nisoldipine as a negative inotropic agent. The present observations in human isolated preparations indicate that nisoldipine shows a higher vascular selectivity than nifedipine.     

The effects of a toxin (ATX II) from the sea anemone Anemonia sulcata on the electrical and mechanical activity of the denervated hemidiaphragm of the rat

Isolated strips of rat diaphragm denervated 9 – 21 days prior to experimentation were used to study the effects of the sea anemone toxin ATX II on electrical and mechanical activity in mammalian skeletal muscle. ATX II increased twitch tension transiently and induced a concentration-dependent rise in muscle tone. The resting membrane potential was increased to more negative values by low concentrations of ATX II (? 10^?7M) and was decreased only with high concentrations (? 2 × 10^?7M). ATX II at 10^?7M) prolonged the action potential duration, however, individual fibres exhibited a large variation in response. Lidocaine (5 × 10^?5M) reversed the toxin-induced contracture, but did not inhibit the ATX II-induced prolongation of action potential duration. ATX II increased the incidence of spontaneous action potentials which occur in denervated skeletal muscle. This effect was partially reversed by tetrodotoxin (10^?5M), which also partially abolished the ATX II-induced contracture. Reduction in toxin-induced spontaneous activity was also observed in the presence of lidocaine (5 × 10^?5M) or acetylcholine (10^?5M). Both agents diminished ATX II-induced contracture. It is concluded that the increased muscle tone observed with ATX II may reflect a summation of increased fibrillatory activity.     

Propafenone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in the treatment of arrhythmias

Propafenone is a Class I antiarrhythmic agent with weak beta-adrenoceptor antagonist activity which can be given both intravenously and orally. Dosage must be individualised because of dose-dependent pharmacokinetics, a wide range of clinically effective plasma concentrations (64 to 3271 micrograms/L) after comparable doses, the presence of an active metabolite (5-hydroxy-propafenone) and genetically determined metabolic oxidation. In non-comparative studies propafenone 450 and 900 mg/day orally significantly suppressed premature ventricular complexes and couplets in 96% and 75% of patients, respectively, and abolished ventricular tachycardia in 75% of patients. Efficacy was confirmed in placebo-controlled studies in which propafenone 300 to 900mg daily suppressed premature ventricular complexes (greater than 80%) in 77% of patients; 87% of patients had significant reductions in couplets and abolition of ventricular tachycardia. In patients with ventricular arrhythmias refractory to other antiarrhythmic agents, propafenone 450 to 1200 mg/day suppressed arrhythmias in 63% of patients (in long term therapy 66%). Electrically induced arrhythmias were prevented by intravenously administered propafenone in 12 to 23% of patients. However, long term oral therapy was effective in 77% of patients selected using programmed electrical stimulation. Propafenone was also effective in suppressing atrial and AV nodal/junctional re-entrant tachycardias and Wolff-Parkinson-White tachycardias involving accessory pathways. A limited number of comparisons with other antiarrhythmic drugs indicate that the antiarrhythmic efficacy of propafenone is superior or similar to that of quinidine, disopyramide and tocainide, and comparable to that of lignocaine (lidocaine), flecainide and metoprolol against ventricular arrhythmias and a smaller number of atrial arrhythmias. Cardiovascular side effects indicate a proarrhythmic effect similar to that with other Class I drugs, occasional precipitation of congestive heart failure and conduction abnormalities; the latter two occur more often in patients with underlying ventricular dysfunction. Non-cardiovascular side effects (neurological, gastrointestinal) are well tolerated and generally resolve with continued therapy or dosage reduction. Thus, propafenone is an effective antiarrhythmic agent, and is a useful addition to currently available drugs, although further studies will be required to determine clearly its place in therapy compared with more established antiarrhythmic drugs.     

Effects of ibutilide on spontaneous and induced ventricular arrhythmias in 24-hour canine myocardial infarction: a comparative study with sotalol and encainide.

The electrophysiologic and antiarrhythmic effects of ibutilide, sotalol, and encainide were compared in dogs 24 h after myocardial infarction. Ibutilide (0.03 to 0.3 mg/kg i.v.) prevented the induction of ventricular arrhythmias in 100% of the dogs that had demonstrated inducible ventricular arrhythmias prior to treatment. This antiarrhythmic action was associated with significant increases in ventricular refractoriness and monophasic action potential duration. Sotalol (1.0 to 10.0 mg/kg i.v.) increased the ventricular refractory period and monophasic action potential duration and prevented the induction of ventricular arrhythmias in 75% of the dogs that demonstrated inducible ventricular tachyarrhythmias at baseline. Although 10 mg/kg of sotalol was required to prevent the initiation of ventricular tachycardia, this dose produced marked cardiovascular depression and hypotension in 50% of the dogs tested. Neither ibutilide nor sotalol significantly decreased the incidence of spontaneous ventricular arrhythmias. The class IC agent encainide (0.3 to 3.0 mg/kg i.v.) was successful in preventing the induction of ventricular arrhythmias in only 20% of the dogs tested. However, in contrast to ibutilide and sotalol, encainide significantly reduced spontaneous arrhythmias. Atrial and ventricular refractoriness were significantly increased only after the highest dose of encainide tested (3.0 mg/kg). Over the dose ranges studied, the relative efficacy for prevention of pacing-induced ventricular arrhythmias was ibutilide greater than sotalol much greater than encainide. For suppression of spontaneous ventricular arrhythmias, the relative efficacy was encainide much greater than ibutilide = sotalol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Electrocardiographic effects of intravenous cocaine: an experimental study in a canine model

Cocaine abuse causes cardiac dysfunction. Acute intravenous administration of cocaine may lead to development of severe arrhythmias, conduction abnormalities, ST-T changes, and sudden death. Understanding arrhythmogenesis due to cocaine may provide a therapeutic approach to reduce morbidity and mortality. We studied the arrhythmogenic activity and other electrocardiographic abnormalities resulting from an intravenous bolus of cocaine. Baseline and postanesthetic electrocardiographic findings were compared with those after administration of intravenous bolus of various doses of cocaine hydrochloride in 20 dogs. The study was done in three phases (phase I: low dose of cocaine [1 mg/kg, 15 experiments]; phase II: medium dose [2 mg/kg, 30 experiments]; and phase III: high dose [5-7 mg/kg, 10 experiments]). Plasma levels of cocaine were estimated. The low dose induced sinus bradycardia, sinus arrhythmia, atrial ectopic, wandering pacemaker, unifocal ventricular premature contractions, and ventricular couplets. The medium dose generated moderately severe arrhythmias that were of supraventricular origin. Atrial flutter and atrial fibrillation were observed in two experiments each. Ventricular arrhythmias were manifested as unifocal, multifocal, interpolated ventricular premature contractions as well as bigeminy, trigeminy, couplets, and salvos. The high dose of 5-7 mg/kg increased electrocardiographic intervals and caused ST-segment elevation as well as serious life-threatening arrhythmias. Three of the dogs developed sustained ventricular tachycardia followed by ventricular flutter-fibrillation and death.