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S Nattel

Publications and source records attributed to S Nattel.

At least 163 records · Page 9Linked to original sources
PubMed1991

Kinetics of use-dependent ventricular conduction slowing by antiarrhythmic drugs in humans.

BACKGROUND: Rate-dependent conduction slowing by class I antiarrhythmic agents has clinically important consequences. Class I drugs are known to produce use-dependent sodium channel blockade. If rate-dependent conduction slowing by class I agents is due to sodium channel blocking actions, the kinetics of conduction slowing should be similar to those of depression of sodium current indexes in vitro. The purpose of the present investigation was to study the onset time course of ventricular conduction slowing caused by a variety of class I agents in humans. METHODS AND RESULTS: Twenty-seven patients undergoing electrophysiological evaluation for antiarrhythmic therapy were studied. Changes in QRS duration at initiation of ventricular pacing at cycle lengths of 400 and 500 msec were used to evaluate the kinetics of drug action. Mean time constants for each drug were similar to values for Vmax depression reported in vitro studies: flecainide, 24.9 +/- 11.6 beats in eight patients (versus 34.5 beats reported for Vmax block); propafenone, 17.8 +/- 6.9 beats in five patients (versus 8.4-20.8 beats); quinidine, 7.0 +/- 2.4 beats in six patients (versus 5.6-6.2 beats); and amiodarone, 3.6 +/- 2.0 beats for eight patients (versus 3.0 beats). Time constants were significantly different among the various drugs tested (p = 0.0002 at a cycle length of 400 msec; p = 0.002 at 500 msec), and there was a strong correlation (r = 0.89, p less than 0.0001) between values obtained at a cycle length of 400 msec and those at a cycle length of 500 msec. No rate-dependent changes in QRS duration were seen at onset of ventricular pacing among eight age- and disease-matched control patients not taking class I antiarrhythmic drugs, including three patients subsequently showing such changes during type I antiarrhythmic drug therapy. CONCLUSIONS: We conclude that class I agents produce use-dependent QRS prolongation in humans with characteristic kinetics for each agent that are similar to the kinetics of Vmax depression in vitro. These results suggest that rate-dependent ventricular conduction slowing by antiarrhythmic drugs in humans is due to use-dependent sodium channel blockade.

Anti-Arrhythmia Agents↗
PubMed1991

A unified model of atrioventricular nodal conduction predicts dynamic changes in Wenckebach periodicity.

The atrioventricular (AV) node responds in a complex fashion to changes in activation rate. A variety of approaches have been used to explain these dynamic AV nodal responses, but none has been able to account fully for AV nodal behavior. Three specific rate-dependent properties of the AV node have been described: 1) time-dependent recovery after excitation, 2) an effect of short cycles to advance recovery ("facilitation"), and 3) a gradual slowing of conduction in response to sustained, high-frequency activation ("fatigue"). We hypothesized that a model incorporating quantitative descriptors of all three processes might be able to account for a wide variety of AV nodal behaviors. Quantitative descriptors of AV nodal recovery, facilitation, and fatigue were developed based on AV nodal conduction changes during selective pacing protocols in seven autonomically blocked dogs. These descriptors were incorporated into a set of mathematical equations that define AV nodal conduction of any beat based on activation history. The equations were then applied to predict pacing-induced Wenckebach periodicity in each dog. Experimental data were obtained after nine to 19 step decreases in atrial cycle length into the Wenckebach zone in each animal. Observed behaviors included complex patterns of block, a progressive increase in the level of block over 5 minutes of rapid pacing, and periods of alternating patterns of block. The model accurately predicted the onset of AV block at each cycle length, the relation between conduction ratio and cycle length as a function of time, and the changing patterns of Wenckebach periodicity during sustained atrial pacing. All three terms of the model equation (describing recovery, facilitation, and fatigue) were essential to account fully for the observed behaviors. Elimination of AV nodal fatigue from the model resulted in failure to account for time-dependent changes in Wenckebach patterns, whereas exclusion of facilitation led to consistent overestimation of the degree of AV block at each cycle length. We conclude that a mathematical model incorporating terms to describe recovery, facilitation, and fatigue accurately predicts a wide range of Wenckebach-type behavior and that complex conduction patterns of the AV node can be fully accounted for by simple functional AV nodal properties.

Animals↗
PubMed1991

Antiarrhythmic drug classifications. A critical appraisal of their history, present status, and clinical relevance.

Classifications of antiarrhythmic drugs have developed because of a need to organize the large number of agents available according to pharmacological properties of clinical relevance. The current classification is a hybrid of classification systems developed in the early 1970s. It subdivides drugs according to 4 major pharmacological actions: (a) depression of phase 0 sodium current; (b) antagonism of adrenergic effects on the heart; (c) prolongation of of action potential duration; and (d) calcium channel blockade. Further subdivision of sodium channel blockers is based on the kinetics of sodium channel blockade and drug effects on action potential duration. A critical analysis of selected aspects of the clinical actions of antiarrhythmic drugs indicates the value of the current classification, as well as some limitations in its ability to separate drugs into distinct groups with characteristic clinical properties. The strengths of the current classification are due to the clinical importance of the pharmacological properties on which it is based. These results in electrophysiological actions, indications, and adverse effects that are typical for each group of drugs. The limitations of the current system relate to the propensity of individual drugs to have actions of more than one class simultaneously, the way that the various actions of a given drug are dependent on concentration, rate, and tissue type, and to problems in subclass definition. Some of these shortcomings could be alleviated by returning to the concept, originally put forward by Singh and Vaughan Williams, of classes of drug action rather than classes of drug per se. This approach would be pharmacologically more realistic than trying to assign each antiarrhythmic agent to a single unique class, would be better able to incorporate the complexities of drug action, and would potentially be more flexible. The wide use of antiarrhythmic drug classifications attests to their value, and suggests that they are likely to continue to be important in the future.

Anti-Arrhythmia Agents↗
PubMed1991

Actions of intravenous magnesium on ventricular arrhythmias caused by acute myocardial infarction.

Although the antiarrhythmic properties of magnesium are well recognized, its mechanisms of antiarrhythmic action are poorly understood. This study was designed to characterize the effects of magnesium on ventricular tachyarrhythmias related to acute myocardial infarction (MI) in dogs. When the circumflex coronary artery was occluded repeatedly for 10 min at 30-min intervals, ventricular fibrillation (VF) occurred in 30, 35 and 33% of dogs during occlusions 1, 2 and 3, respectively. Magnesium pretreatment reduced the incidence of VF to 14% during occlusion 3 (P less than .05 compared to occlusions without magnesium pretreatment). Neither the prevalence of ventricular ectopic complexes 24 h after MI nor arrhythmia inducibility 4 days after infarction were significantly altered by i.v. magnesium. Magnesium significantly attenuated the ST segment elevation (an index of ischemic injury) and ventricular conduction slowing caused by MI. Because magnesium has been reported to reverse the effects of hyperkalemia, we evaluated the role of this action by infusing potassium directly into a coronary artery (to mimic ischemia-induced hyperkalemia) and administered i.v. magnesium. Potassium infusion markedly slowed intraventricular conduction, an effect fully reversed by discontinuing potassium administration but unaffected by i.v. magnesium. We conclude that magnesium has antiarrhythmic actions only during the early phases of an experimental MI, and that these actions are associated with attenuation of indices of ischemic injury and conduction slowing. These properties of magnesium are similar to those of calcium antagonists, and suggest that magnesium's calcium antagonist properties may be important in its antiarrhythmic actions.

Animals↗
PubMed1990

Determinants and significance of diltiazem plasma concentrations after acute myocardial infarction. The Multicenter Diltiazem Postinfarction Trial Research Group.

A total of 1,975 plasma diltiazem concentrations were obtained from 1,067 patients enrolled in a multicenter secondary intervention study of diltiazem after acute myocardial infarction. To evaluate the determinants and significance of diltiazem concentrations in this patient population, we related drug concentrations to a variety of clinical variables recorded on the case history forms. Multiple linear regression analysis showed that (1) time from the last drug dose, (2) drug dose taken, (3) patient height (an index of lean body weight), and (4) patient age were important determinants of plasma concentration. For an equivalent dose, plasma diltiazem concentrations in a 75-year-old patient were about double those of a 25-year-old patient. Total weight and drug dose prescribed did not significantly affect plasma concentrations. Whereas drug concentrations were higher (p = 0.01) among patients with left-sided heart failure, they were not altered by renal dysfunction, hepatic disease or beta blockers. Diltiazem concentrations were a significant determinant of diastolic arterial pressure (p less than 10(-9), but neither systolic pressure nor heart rate were significantly related to diltiazem concentration. The overall incidence of adverse experiences was not related to drug concentrations, but the occurrence of second- and third-degree atrioventricular block in the coronary care unit and the need for a temporary pacemaker were substantially higher among patients with a drug concentration greater than 150 ng/ml (7.4 and 1.9%, respectively) than among patients with lower concentrations (2.6% for atrioventricular block, 0.3% for pacemaker; p = 0.02 for each). The risk of atrioventricular block was particularly increased by high diltiazem concentrations in the face of acute inferior infarction. These results suggest that diltiazem's pharmacologic and clinical effects in a large population are concentration-related, and that the consideration of patient size, age, and left ventricular function in selecting a diltiazem dose may allow for effective drug therapy with a reduced likelihood of adverse effects.

Adult↗
PubMed1990

Pharmacologic response of cesium-induced ventricular tachyarrhythmias in anesthetized dogs.

Cesium chloride administration causes ventricular tachyarrhythmias in dogs, with many of the features of the clinical long QT syndrome. We developed a model of cesium-induced arrhythmias, using loading and maintenance doses of cesium to produce continuous cesium effects. The purpose of the present experiments was to study the response of arrhythmias in this model to a variety of pharmacologic interventions. Cesium chloride caused ventricular tachyarrhythmias that either degenerated to ventricular fibrillation (VF) or remained stable for greater than 30 min. Cesium-induced arrhythmias were suppressed by the calcium antagonist diltiazem, magnesium chloride, beta blockade (with atenolol), or vagal nerve stimulation--all interventions that can suppress calcium entry. beta-Adrenergic stimulation with isoproterenol initiated ventricular arrhythmias in the presence of subarrhythmic doses of cesium. Sodium channel blockers (lidocaine and high concentrations of quinidine) also suppressed cesium-induced arrhythmias. Intravenous (i.v.) bolus doses of isotonic saline solution at times corresponding to the other interventions studied did not alter the severity of cesium-induced arrhythmia. We conclude that cesium-induced ventricular arrhythmias in this model are suppressed by agents that reduce transmembrane calcium currents as well as by high doses of sodium channel blockers. These findings may have relevance to the mechanisms of, and the therapeutic approach to, the clinical long QT syndrome.

Animals↗
PubMed1990

Cycle length alternation during supraventricular tachycardia: occurrence and mechanism in a canine model of AV reentrant tachycardia.

Cycle length alternation (CLA) is commonly observed during supraventricular tachycardia (SVT) onset and termination. The present study was designed to gain insights into the mechanism and potential clinical relevance of CLA by comparing computer simulations of tachycardia to directly observed behavior in a canine model of AV reentrant tachycardia (AVRT). The computer model was based on the hypothesis that CLA is secondary to feedback between AV nodal output during SVT and subsequent AV nodal input, and used the measured anterograde AV nodal recovery curve (AV vs A1A2) to predict sequential AV and RR intervals during SVT. Orthodromic AVRT was created experimentally in 11 open-chested, autonomically-blocked (atropine plus nadolol) dogs using a sensing and pacing circuit that mimicked a retrograde-conducting accessory pathway. Steady-state cycle length and AV interval during experimental AVRT closely paralleled predictions made by the computer model. CLA appeared consistently at the onset of experimental AVRT at programmed VA intervals less than or equal to 100 msec (corresponding to VA less than or equal to 150 msec as measured clinically) in all dogs. The amplitude and duration of CLA increased as the VA interval decreased, and closely paralleled predictions based on the computer model. Abrupt accelerations in atrial pacing to the same rate as AVRT did not result in alternation of cycle length. In conclusion, alternation of cycle length results from feedback between AV nodal output and subsequent AV nodal input at the onset of reentrant supraventricular tachycardia, and does not require changes in autonomic tone or dual AV nodal pathways. CLA occurrence, amplitude, and duration are predictable based on AV node recovery properties, and depend on retrograde conduction properties of the reentrant circuit. The presence of CLA suggests that the AV node is an integral component of the SVT reentry circuit, and may be useful clinically to identify the mechanism of supraventricular tachycardias.

Animals↗
PubMed1990

Electrophysiological effects of alpha-adrenergic stimulation.

Autonomic blockade for in vivo electrophysiological studies generally involves atropine and beta blockers, ignoring the potential role of alpha-adrenergic activity. To evaluate the importance, if any, of alpha-adrenergic tone, the electrophysiological effects of incremental doses of phenylephrine were examined in eight chloralose-anesthetized dogs. In order to study direct effects, all dogs were both beta blocked (with nadolol) and vagally blocked (with the combination of vagotomy and atropine). Results were also obtained after normalization of blood pressure with nitroprusside or the alpha-blocker, prazosin. Phenylephrine caused dose-dependent increases in systolic and diastolic blood pressure. This was accompanied by consistent but modest decreases in sinus cycle length (control RR interval 492 +/- 34 msec vs 459 +/- 29 msec after dose 1 of phenylephrine, P less than 0.05, 516 +/- 41 vs 484 +/- 34 msec control versus dose 2, P less than 0.05). These increases in automaticity were not prevented after normalization of arterial pressure by nitroprusside, but were reversed when concomitant alpha-receptor blockade was achieved with prazosin, suggesting that sinus node acceleration resulted directly from alpha-receptor stimulation. No effects on atrial, AV nodal or His-Purkinje conduction were noted. In addition, phenylephrine did not affect atrial, AV nodal, or ventricular refractoriness. In conclusion, conduction and refractoriness of normal cardiac tissue (other than the sinus node) are unaffected by direct alpha-receptor stimulation. This justifies the use of combined beta and muscarinic blockers to achieve autonomic blockade under most circumstances.

Adrenergic alpha-Agonists↗
PubMed1990

Direct electrophysiological actions of pentobarbital at concentrations achieved during general anesthesia.

Pentobarbital and alpha-chloralose are widely used for experimental anesthesia, but their direct electrophysiological actions at anesthetic concentrations are unknown. Trough and peak concentrations measured by high-performance liquid chromatography averaged 27 +/- 3 and 45 +/- 13 mg/l (means +/- SD) for pentobarbital and 41 +/- 15 and 103 +/- 13 mg/l for alpha-chloralose in dogs receiving them for general anesthesia. The direct effects of each agent on papillary muscle action potentials obtained from guinea pigs killed by decapitation were studied in vitro. Pentobarbital increased action potential duration to 95% by 24 +/- 6 and 33 +/- 4% at 25 and 50 mg/l (P less than 0.001 for each), respectively, and caused corresponding increases in effective refractory period. Furthermore, pentobarbital reduced maximum rate of voltage change (Vmax) of phase 0 in a voltage-, rate-, and concentration-dependent fashion, suggesting use-dependent sodium channel blocking actions. The voltage dependence of Vmax was shifted by 3.7 +/- 1.7 (P less than 0.01) and 6.5 +/- 1.8 mV (P less than 0.001) by 25 and 50 mg/l pentobarbital, respectively. In canine ventricular muscle, pentobarbital caused rate- and concentration-dependent decreases in Vmax and increases in action potential duration and refractory period over a concentration range of 5-100 mg/l. alpha-Chloralose was devoid of direct electrophysiological effects in both species. We conclude that pentobarbital has potentially important electrophysiological actions on ventricular tissues at concentrations required for general anesthesia and may confound the results of in vivo studies.

Anesthesia, General↗
PubMed1990

Antiarrhythmic actions of diltiazem during experimental atrioventricular reentrant tachycardias. Importance of use-dependent calcium channel-blocking properties.

The purpose of this study was to determine if the known frequency-dependent effects of diltiazem on inward calcium current result in selective actions during supraventricular tachycardia. These effects were evaluated by use of an experimental model of orthodromic atrioventricular reentrant tachycardia (AVRT). AVRT was induced in 15 dogs over a wide range of retrograde conduction times before and after two doses of diltiazem. Diltiazem produced a tachycardia-related suppression of atrioventricular nodal conduction resulting in greater efficacy for faster than for slower AVRTs. The degree of slowing for tachycardias that remained inducible after diltiazem administration was greater for AVRTs with a rapid initial rate (dose 1, 29%; dose 2, 40%) than for slower AVRTs (dose 1, 11%, p less than 0.01; dose 2, 18%, p less than 0.001). Rate-dependent AVRT slowing occurred because of a time-dependent phase of AH interval prolongation after the onset of tachycardia, which was observed only after diltiazem administration. to further clarify the mechanism of diltiazem's selective actions against faster tachycardias, its effects on the minimum pathway for reentry, or wavelength, were examined in four dogs. The ratio of refractory period to revolution time (RP/RT), an index of wavelength, was measured for each AVRT before and after diltiazem administration. Diltiazem increased the positive slope of the relation between RP/RT and the AVRT rate threefold compared with control (p less than 0.05). This rate-dependent effect prevented AVRT when RP/RT became greater than unity. In conclusion, rate-dependent atrioventricular node depression by diltiazem results in greater tachycardia slowing and higher rates of termination during atrioventricular reentrant tachycardias with faster initial rates and shorter retrograde conduction intervals.

Animals↗
PubMed1990

Effects of flecainide and quinidine on human atrial action potentials. Role of rate-dependence and comparison with guinea pig, rabbit, and dog tissues.

Flecainide and other class IC antiarrhythmic drugs are effective in the prevention and termination of atrial fibrillation, but the mechanism of this action is unknown. To gain insights into potential cellular mechanisms, we evaluated the response of human atrial action potentials to equimolar therapeutic concentrations of flecainide and quinidine and compared this response to that of guinea pig, rabbit, and dog atria. Both compounds reduced Vmax more as activation rate increased, but flecainide was more potent than quinidine and had slower kinetics. The rate-dependence of Vmax reduction was similar for all species, but human tissue was more sensitive to the drugs tested. In contrast to changes in Vmax, drug-induced alterations in action potential duration showed opposite rate-dependence for the two drugs. Quinidine increased action potential duration to 95% repolarization (APD95) in human atria by 33 +/- 7% (mean +/- SD) at a cycle length of 1,000 msec, but this effect was reduced as cycle length decreased, to 12 +/- 4% (p less than 0.001) at a cycle length of 300 msec. Flecainide increased APD95 (by 6 +/- 3%) much less than quinidine at a cycle length of 1,000 msec, but its effect was increased by faster pacing, to 27 +/- 12% at a cycle length of 300 msec and 35 +/- 8% (p less than 0.001) at the shortest 1:1 cycle length. The rate-dependent response of APD to drugs was qualitatively similar but quantitatively different among species. Human tissue showed the greatest frequency-dependent drug effects on repolarization, followed by tissue from dogs and rabbits. Guinea pig atria showed the least (and statistically nonsignificant) rate-dependence of drug effect on APD. Drug-induced changes in refractoriness paralleled those in APD. We conclude that: 1) flecainide and quinidine both increase APD in human atrial tissue but with opposite rate-dependence, 2) the effects of flecainide to increase atrial APD and refractoriness are enhanced by the rapid rates typical of atrial fibrillation, and 3) animal tissues may differ importantly from human in both their sensitivity and rate-dependent response to antiarrhythmic drugs. The salutary response of atrial fibrillation to flecainide may be due to enhancement of drug action by the rapid atrial activation rates characteristic of this arrhythmia.

Action Potentials↗
PubMed1990

Vagal modulation of the rate-dependent properties of the atrioventricular node.

Vagal effects on atrioventricular (AV) nodal conduction are accentuated by increases in heart rate. To establish the mechanism of these rate-dependent negative dromotropic actions, we studied the properties governing AV nodal adaptation to changes in heart rate in chloralose-anesthetized dogs in the absence and presence of bilateral cervical vagal nerve stimulation (20 Hz, 0.2 msec). Stimulation protocols were applied to evaluate the contributions of changes in AV nodal recovery, facilitation, and fatigue independently of each other. Vagal stimulation slowed AV nodal recovery in a voltage-dependent way, increasing the time constant of recovery (tau r) from 80 +/- 7 to 194 +/- 16 msec (mean +/- SEM, p less than 0.01) at the highest voltage studied. The facilitating effect of a premature (A2) beat was manifested by a leftward shift of the recovery curve (A3H3 versus H2A3) of a subsequent A3 beat. The magnitude of shift depended on the A1A2 coupling interval and was reduced by vagal stimulation at all A1A2 intervals (maximum shift: control, 63 +/- 12 msec; vagus, 24 +/- 11 msec; p less than 0.01). When recovery and facilitation were kept constant, abrupt increases in AV nodal activation rate caused a slow (tau = 75 beats) increase in AH interval (fatigue). Vagal stimulation increased the magnitude of this process (maximum: control, 11 +/- 2 msec; vagus, 27 +/- 3 msec; p less than 0.001), without altering its time course. At activation rates comparable to sinus rhythm in humans, vagal stimulation at an intermediate voltage increased the AH interval by 25 msec. As heart rate increased, vagally induced changes in dynamic processes amplified AH prolongation up to fivefold at maximum rate. The role of vagal changes in individual functional properties depended on heart rate, but slowing of recovery was the single most important factor, constituting over 50% of overall vagal action at rapid rates. We conclude that vagal stimulation alters the ways in which the AV node responds to changes in activation rate and that at rapid rates most of the negative dromotropic action of the vagus is due to changes in the AV nodal response to tachycardia. Alterations in rate-dependent AV nodal properties are a novel and potentially important mechanism through which interventions may affect AV nodal conduction.

Animals↗
PubMed1990

Autonomic modulation of the frequency-dependent actions of diltiazem on the atrioventricular node in anesthetized dogs.

Calcium antagonists have rate-dependent effects on atrioventricular node refractoriness in autonomically blocked dogs. Autonomic reflexes can attenuate diltiazem's actions and could alter their frequency-dependence. We evaluated the effects of four steady-state drug concentrations in each of seven dogs with intact autonomic tone, six with muscarinic blockade (atropine) and eight with combined muscarinic and beta adrenergic blockade. Diltiazem depressed atrioventricular nodal function less in autonomically intact dogs than in the other two groups. The concentration-response relationship for increases in Wenckebach cycle length (compared to intact dogs) was twice as steep among dogs with muscarinic blockade (P less than .001) and three times as steep with combined blockade (P less than .001). For an equal dose of diltiazem, the slope of drug-induced refractory period prolongation vs. pacing cycle length was similar (-0.20 +/- 0.11%/msec, mean +/- S.D.) in intact dogs compared to atropinized dogs (-0.21 +/- 0.10%/msec) and dogs with combined blockade (-0.24 +/- 0.14%/msec). Amplification of diltiazem's actions by the rapid atrial rate during atrial fibrillation was associated with increases in mean RR interval which were 8.3 times as large as changes in refractory period produced by the drug at slow heart rates. We conclude: 1) autonomic reflexes reduce diltiazem's effect for any given plasma concentration; 2) changes in vagal tone can play an important role in the autonomic response to diltiazem; and 3) despite altering the magnitude of diltiazem's effects, autonomic mechanisms do not prevent frequency-dependent drug action.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1989

Concentration dependence of class III and beta-adrenergic blocking effects of sotalol in anesthetized dogs.

Sotalol is unique among beta-adrenergic blocking drugs in possessing significant class III antiarrhythmic actions. The present study was designed to assess the relative concentration dependence of beta-blocking and class III actions of sotalol and to relate the findings to concentrations achieved during oral sotalol therapy in humans. Measurements were made in anesthetized dogs under control conditions, and then in the presence of a series of stable sotalol plasma concentrations produced by sequential loading and maintenance infusions. Beta-blocking effects of sotalol, determined by attenuation of the chronotropic actions of isoproterenol, were seen at the lowest dose used. Increases in atrial and ventricular refractory periods (observed in dogs with autonomic blockade to exclude beta-receptor-mediated or reflex autonomic effects) required much larger doses of sotalol. Half-maximal beta-blocking effects occurred at an average sotalol concentration of 0.8 +/- 0.3 mg/liter, an order of magnitude lower than the concentrations required for half-maximal effects on atrial (6.9 +/- 1.2 mg/liter, p less than 0.01) and ventricular (6.8 +/- 2.8 mg/liter, p less than 0.05) refractoriness. These results show that substantially higher concentrations are needed for the class III effects of sotalol than for its beta-blocking action. These pharmacodynamic differences need to be considered in evaluating the antiarrhythmic efficacy and mechanisms of this unusual drug.

Adrenergic beta-Antagonists↗
PubMed1989

Cardiovascular and metabolic effects of caesium chloride injection in dogs--limitations as a model for the long QT syndrome.

Caesium chloride administration has been used in an animal model to reproduce the acquired long QT syndrome observed in man, but the transient nature of the arrhythmogenic action of caesium has made systematic study difficult. We developed a loading and maintenance infusion regimen to produce stable caesium effects for over 30 min. The results of sustained caesium administration were compared to those of bolus dose caesium and found to be similar in terms of changes in metabolic, electrophysiological, and haemodynamic variables, and the nature of resulting ventricular arrhythmias. Caesium administration by either method consistently induced ventricular tachyarrhythmias that were either monoform or polymorphic, rarely had the morphological features of Torsades de Pointes, and frequently degenerated to ventricular fibrillation. Both forms of caesium administration produced substantial increases in arterial pressure [from 131(SEM12)/63(SEM8) to 246(30)/138(20) mm Hg with sustained infusion; from 120(8)/55(2) to 263(19)/178(16) mm Hg with bolus caesium; p less than 0.01 for each] and serum potassium concentration [from 3.6(0.2) to 8.6(0.8) mmol.litre-1, and from 3.2(0.1) to 7.8(0.7) mmol.litre-1 respectively; p less than 0.01 for each]. Ventricular overdrive pacing transiently accelerated the spontaneous arrhythmia in 48/60 (80%) trials, with overdrive suppression occurring in only five trials. The morphological features of these caesium induced ventricular tachyarrhythmias, their response to overdrive pacing, and their occurrence despite substantial hyperkalaemia are quite different from the properties of the clinical long QT syndrome, which is overdrive suppressible, favoured by hypokalaemia, and rarely degenerates to ventricular fibrillation. We conclude that stable ventricular tachyarrhythmias can be produced by loading and maintenance infusions of caesium in dogs and that the effects of sustained caesium infusion are similar to those of bolus dose caesium, but that caution is necessary in using caesium administration as a model for the clinical long QT syndrome.

Animals↗
PubMed1989

Attenuation of class 3 and sinus node effects of amiodarone by experimental hypothyroidism.

Amiodarone's class III effects may be due to inhibition of the cardiac effects of thyroid hormone. If so, amiodarone would not be expected to cause QT prolongation in hypothyroid subjects. The electrocardiographic (ECG) changes induced after treatment with amiodarone were compared in euthyroid and hypothyroid guinea pigs. Hypothyroidism was induced with intraperitoneal (i.p.) administration of 1 mCi I131 (eight animals). Three of these animals also received oral methimazole to block any residual thyroid hormone production. Significant increases in body weight (28 +/- 9%), RR (14 +/- 8%), QT (14 +/- 5%), and QTc (7 +/- 2%) intervals occurred after induced hypothyroidism. Pilot studies with amiodarone treatment for 4 weeks in euthyroid guinea pigs demonstrated that maximal effects on ECG intervals were achieved after 1 week of drug therapy. Therefore, both euthyroid and hypothyroid groups were treated with daily i.p. amiodarone (80 mg/kg) for 7 days. Euthyroid guinea pigs treated with amiodarone had significant increases in RR (33 +/- 10%), QT (31 +/- 15%), and corrected QT (13 +/- 11%) intervals. In contrast, when hypothyroid animals were treated with amiodarone, no statistically significant changes occurred in ECG intervals. Plasma concentrations of amiodarone did not differ between the two groups (0.7 +/- 0.6 vs. 0.7 +/- 0.4 mg/L in hypothyroid and euthyroid groups, respectively). We conclude that intact thyroid function is a prerequisite for class III and sinus node effects of amiodarone in the guinea pig. This implies that at least some of amiodarone's effects are mediated through antagonism of thyroid action.

Amiodarone↗