Monique M. Adamantidis

Cisapride‐induced prolongation of cardiac action potential and early afterdepolarizations in rabbit Purkinje fibres

Cisapride, a gastrointestinal prokinetic agent, has been associated with cases of Torsades de Pointes but its effects on the cardiac action potential have not been described. We investigated its electrophysiological effects on rabbit isolated Purkinje fibres. The results demonstrated that cisapride (0.01 ×10 μm) lengthened concentration‐dependently the action potential duration without modifying other parameters and induced early after depolarizations and subsequent triggered activity. This typical class III antiarrhythmic effect, that showed ‘reverse’ rate‐dependence and was reduced by increasing external K concentration, can account for clinical arrhythmogenesis.

Sparfloxacin but not levofloxacin or ofloxacin prolongs cardiac repolarization in rabbit Purkinje fibers

Summary— Sparfloxacin, a fluoroquinolone antibacterial, has been reported to prolong cardiac repolarization in some patients. In this study, we have investigated the in vitro cardiac electrophysiological effects of two other fluoroquinolones, levofloxacin and ofloxacin, and compared them with those exerted by Sparfloxacin. Cardiac action potentials have been recorded from rabbit Purkinje fibers using conventional glass microelectrodes. The influence of a sudden decrease in stimulation rate on repolarization is examined. It is found that ofloxacin and levofloxacin (1–100 μM) do not alter the action potential parameters even at a concentration as high as 100 μM. The stimulation rate is without effect on repolarization. On the contrary, Sparfloxacin (1–100 μM) lengthens concentration‐dependently the duration of action potential, this effect being significant from the concentration of 10 μM. A non significant decrease in maximal rate of rise of phase 0 depolarization was observed at the concentration of 100 μTM. Under low stimulation rate, the sparfloxacin‐induced prolonging effect was magnified and early afterdepolarizations occurred in one of seven fibers from the concentration of 30 μM and in four other fibers at the concentration of 100 μM. These results suggest that levofloxacin and ofloxacin had no effect on cardiac cellular electrophysiology whereas Sparfloxacin exerts pure class III electrophysiological effects, which can explain the prolongation of QT interval observed clinically in some patients and might become arrhythmogenic in the presence of other predisposing factors.

The association between the neuroleptic malignant syndrome and malignant hyperthermia

The neuroleptic malignant syndrome (NMS) is an uncommon but dangerous complication of treatment with neuroleptic drugs. A primary defect in skeletal muscle has been suggested in view of similarities in the clinical presentations of NMS and anaesthetic‐induced malignant hyperthermia (MH). The in vitro halothanecaffeine contracture tests are the most reliable method of identifying individuals susceptible to MH. The aim of this study was to define if a relationship exists between NMS and MH susceptibility. Hence, the in vitro halothane and caffeine contracture tests were performed on muscle tissue obtained from eight NMS, ten MH‐susceptible and ten control patients. The results, which are expressed in accordance with the criteria of the European MH Group, defined the eight NMS subjects as MH non‐susceptible. The response to halothane and caffeine exposure of skeletal muscle from NMS and control subjects was the same and significantly different from that of muscle from patients susceptible to MH. Furthermore, muscle from subjects in NMS and control group responded similarly to increasing concentrations of chlorpromazine. These results do not point towards an association between NMS and MH.

electrophysiological and arrhythmogenic effects of the histamine type 1-receptor antagonist astemizole on rabbit Purkinje fibers : clinical relevance

Astemizole is a potent histamine HI-antagonist that has been associated with cases of life-threatening cardiac arrhythmias, including torsade de pointes and atrioventricular (AV) block. However, its effects on cardiac action potential (AP) has not been described. We examined the electrophysiological effects of astemizole on rabbit Purkinje fibers using conventional glass microelectrodes in parallel with the effects of the widely used histamine H2-antagonist cimetidine, selected because it has no known cardiac arrhythmic toxicity. Astemizole (0.01–3 μM) exerted a concentration-dependent prolonging effect on final repolarization that did not reach steady state after 3 h of exposure. This effect was more pronounced at low stimulation frequency and was less marked at high stimulation frequency. In addition, early afterdepolarizations (EADs) occurred in one third of the fibers. Increasing extracellular concentration of KC1 (2.7–5.4 mM) or MgCl2 (1–5 mM) suppressed EADs and reversed the prolonging effect that was conversely exaggerated by decreasing KC1 (4–2.7 mM) or MgCl2 (1–0.5 mM) concentration. At higher concentrations (3–30 μM), astemizole induced an increasing depressant effect on the maximal rate of depolarization (Vmax) that became more pronounced with high stimulation frequency. All parameters were strongly depressed at 10 μM astemizole, leading to cellular inexcitability in 5 of 12 fibers when exposed to 30μM astemizole. In comparison, cimetidine induced minor changes on AP characteristics, i.e., a prolongation in plateau duration at high (30–100 μM) concentrations. These results provide evidence that astemizole exerts quinidine-like effects on cardiac APs that are compatible with the occurrence of the clinically observed arrhythmias.

Repolarization abnormalities and their arrhythmogenic consequences in porcine tachycardia-induced cardiomyopathy

OBJECTIVES Action potential prolongation related to the alteration of several membrane currents is constantly reported in heart failure (HF) but reports about its role in arrhythmogenesis are sparse. Our aim was to determine, by analogy with long QT syndromes, whether prolonged repolarization is associated with increased dispersion or linked to bradycardia-dependent ventricular arrhythmias in pacing-induced cardiomyopathy. METHODS QT intervals, action potentials and transmural activation-to-recovery intervals (ARIs) along with whole-cell delayed rectifier (I(K)) and transient outward (I(to1)) K+ currents were recorded in left ventricle from pigs with HF and controls. HF was obtained after 14 days of rapid pacing at 250 ms. RESULTS Repolarization was delayed as indexed by corrected QT intervals (13.7% increase, P<0.01) or ARIs (252+/-4 to 340+/-7 ms, P<0.01). ARIs were uniformly prolonged with disappearance of the transmural gradient, spatial dispersion of repolarization decreased by 50% (P<0.05). I(to1) density was reduced in HF from 1.35+/-0.1 to 0.57+/-0.04 pA/pF subepicardially, from 1.05+/-0.19 to 0.55+/-0.08 pA/pF midmyocardially and from 1.04+/-0.1 to 0.48+/-0.04 pA/pF subendocardially. I(K) density was significantly decreased in HF pigs vs. controls: subepicardially from 0.46+/-0.04 to 0.22+/-0.02 pA/pF; midmyocardially from 0.46+/-0.05 to 0.25+/-0.03 pA/pF; and subendocardially from 0.49+/-0.04 to 0.20+/-0.04 pA/pF following depolarization at +50 mV. Electrocardiogram (ECG) monitoring at the time of death did not disclose any polymorphic ventricular tachyarrhythmia. CONCLUSION Despite a profound alteration in K+ currents, repolarization is uniformly prolonged in this model with no proclivity to develop bradycardia-dependent arrhythmias.

Risperidone prolongs cardiac action potential through reduction of K+ currents in rabbit myocytes

Prolongation of QT interval by antipsychotic drugs is an unwanted side effect that may lead to ventricular arrhythmias. The antipsychotic agent risperidone has been shown to cause QT prolongation, especially in case of overdosage. We investigated risperidone effects on action potentials recorded from rabbit Purkinje fibers and ventricular myocardium and on potassium currents recorded from atrial and ventricular rabbit isolated myocytes. The results showed that (1) risperidone (0.1-3 microM) exerted potent lengthening effects on action potential duration in both tissues with higher potency in Purkinje fibers and caused the development of early afterdepolarizations at low stimulation rate; (2) risperidone (0.03-0.3 microM) reduced significantly the current density of the delayed rectifier current and at 30 microM decreased the transient outward and the inward rectifier currents. This study might explain QT prolongation observed in some patients treated with risperidone and gives enlightenment on the risk of cardiac adverse events.

Repercussions of pharmacologic reduction in ionic currents on action potential configuration in rabbit Purkinje fibers: Are they indicative of proarrhythmic potential?

The evaluation of the cardiac safety of newly developed drugs by electrophysiological studies are today mandatory in several countries. A number of experimental models performed either on multicellular preparations or on native or cloned ionic channels have been used but the predictivity of the results remains a matter of debate, particularly if a drug exerts mixed ionic channel‐blocking effects. The present study was designed to scrutinize the repercussions of selectively decreasing the main ionic currents which play a role in the repolarization process. Using conventional microelectrodes, action potentials were recorded from rabbit Purkinje fibers stimulated at 1 Hz and 0.2 Hz and exposed to a broad range of cumulative and increasing concentrations. The compounds used were 1) potassium channel blockers (4‐aminopyridine, dofetilide, terikalant, and indapamide), 2) chloride current blocker (4,4′‐diisothiocyanatostilbene‐2,2′‐disulfonic acid), and 3) calcium channel antagonists (nifedipine, verapamil, and cadmium). It appears from our results that the modifications observed in the repolarization phase and in the spike‐and‐dome aspect showed that the antagonists evaluated were not as specific as one would expected and that they affected action potential profiles as a result of additional nonspecific effects which may influence the incidence of proarrhythmic events. In conclusion, we propose the use of rabbit Purkinje fibers as an in vitro model adequate for the evaluation of the cardiac safety of newly developed drugs. Drug Dev. Res. 47:63–76, 1999.

Fiber-type caffeine sensitivities in skinned muscle fibers from humans susceptible to malignant hyperthermia.

BackgroundThe response to contracture tests may depend upon the relative proportion of muscle fiber types within the muscle specimen. To determine whether a difference in fiber-type caffeine sensitivities exists between malignant hyperthermia susceptible (MHS) and malignant hyperthermia-non-susceptible (MHN) skeletal muscle, we compared the fiber-type caffeine sensitivities in chemically skinned muscle fibers dissected from vastus lateralis muscle from 15 MHS and 16 MHN patients. MethodsMuscle fiber type was determined in each fiber by the difference in strontium-induced tension measurements and in 36 fibers, after contracture testing, by ATPase enzyme his-tochemistry. Caffeine sensitivity was defined as the threshold concentration inducing more than 10% of the maximal tension obtained with a calcium 1.6 × 10 2 HIM solution. ResultsSignificant difference in the mean (±SD) caffeine sensitivity was found between type I MHS fibers (2.63 ± 0.85 HIM) versus type II MHS fibers (3.47 ± 1.2 HIM) and between type I MHN fibers (5.89 ± 1.8 HIM) versus type II MHN fibers (10.46 ± 2.6 miu). The mean (±SD) caffeine sensitivities for a given muscle fiber type (I or II) were different between groups of MHS and MHN patients. Both type I and II MHS fibers had significantly lower caffeine sensitivities, and this increase in caffeine sensitivity was significantly smaller in type I than in type II fiber. ConclusionsThe current study indicates that a truly MHS patient cannot have a false-negative result solely related to abnormal type II fibers contained In a given muscle strip. Although the occurrence of a very high proportion of type I fibers in MHN human muscle could result in a false-positive contracture outcome, such an occurrence is expected to be rare.

Effects of Calcium-free Solution, Calcium Antagonists, and the Calcium Agonist BAY K 8644 on Mechanical Responses of Skeletal Muscle from Patients Susceptible to Malignant Hyperthermia

The purpose of this investigation was to determine if alteration in the function of the dihydropyridine receptor may in turn modify halothane-induced contractures in muscle bundles from patients susceptible to malignant hyperthermia (MH). The effects of Ca(2+)-free Krebs Ringer (KR) solution, 5 microM verapamil, 5 microM nifedipine, and 10 microM of the Ca2+ agonist BAY K 8644 on halothane-induced contracture were therefore investigated. The halothane-induced contracture was prevented in the absence of extracellular Ca2+ and significantly reduced in the presence of verapamil or nifedipine. BAY K 8644 significantly enhanced the 0.5-, 1.0-, and 1.5-vol % halothane-induced contracture in MH-susceptible muscle bundles. When BAY K 8644 was dissolved in Ca(2+)-free KR solution, no contracture was observed in MH-susceptible muscle bundles. These results on cut MH-susceptible human muscle bundles support the hypothesis that halothane-induced contracture in MH can be modified by the binding of Ca2+ agonists or antagonists to the dihydropyridine receptor. The role of Ca2+ entry phenomena remains unclear, but the results suggest that extracellular Ca2+ is required to reprime or to bind to some sites of the dihydropyridine receptors.

Factors affecting epicardial dispersion of repolarization: a mapping study in the isolated porcine heart

OBJECTIVE Non-uniform drug-induced prolongation of repolarization predominating in the midmyocardial (M) cell layers has been shown to be responsible for perpetuation of reentry, giving rise to torsade de pointes. However, the absence of M cells in immature animals, especially the pig, suggests other possible underlying mechanisms. We sought to examine, in this species, the effects of predisposing factors to torsade de pointes on the dispersion of epicardial repolarization and their contribution to arrhythmogenesis. METHODS Computerized mapping of repolarization and activation was conducted on the epicardial surface in 29 Langendorff-perfused hearts of eight-week-old pigs. Activation-recovery intervals were measured simultaneously from 128 unipolar electrograms. RESULTS Baseline iso-interval maps were dipolar (41%) or multipolar (59%). Dispersion of repolarization was reverse frequency-dependent but was unaffected by lowering [K+]o. DL-Sotalol (0.1 mmol/l) reinforced local gradients and thus increased epicardial dispersion, whereas intramural recordings did not demonstrate any predominant effect in midmyocardial layers. Phenylephrine (1 mumol/l) notably augmented DL-sotalol effects. After [Mg++]o lowering, although dispersion was not significantly increased, DL-sotalol was associated with the spontaneous occurrence of polymorphic ventricular tachycardia in seven out of nine experiments. When maps of repolarization of escape beats were compared with activation maps of first arrhythmic beats, an arc of functional dissociation was observed in the vicinity of a steep gradient of repolarization in two out of nine tachycardias. CONCLUSION Epicardial dispersion of repolarization is increased by slow rates, DL-sotalol and phenylephrine but is not the only requirement for initiation of polymorphic ventricular tachycardia. In combination with other factors, it helps continuation of the arrhythmia in this model.