Electrical and mechanical effects of new aminosteroids on guinea-pig isolated ventricular muscle.

1. LND 623 and LND 796 are two aminosteroid derivatives which exert similar positive inotropic effects to digitalis. Their electrophysiological, toxic and inotropic effects were investigated in both normal and partially K+-depolarized ventricular muscle. 2. In guinea-pig myocardial fibres, LND 623 and LND 796 required tenfold higher concentrations than digoxin to induce the same signs of toxicity; e.g. triggered activities generated from delayed afterdepolarizations, leading to the marked depression of action potential characteristics and inexcitability. These abnormal rhythms and delayed afterdepolarizations were abolished by 1 mM caffeine. The toxic effects were reversed by washout, particularly in the case of LND 796. 3. In normal-K+ solution, LND 623 and LND 796 exhibited concentration-dependent positive inotropic effects on guinea-pig papillary muscle and increased concomitantly resting membrane potential and action potential amplitude. The range of active concentrations (0.1 to 1 microM) of LND 623 was larger than that of digoxin (0.3 to 1 microM). Like digoxin, LND 796 exerted negative inotropic effects at the lowest concentrations (0.01 to 0.03 microM) and positive inotropic effects at high concentrations (1 and 3 microM). 4. In partially K+-depolarized papillary muscle, in the presence of 2 microM histamine, LND 623 (3 and 10 microM) and LND 796 (10 and 30 microM) enhanced the two components P1 and P2 of the contraction and increased slow action potential amplitude, resting potential and maximal rate of depolarization. Low concentrations (0.03 to 0.3 microM) of LND 796 induced negative inotropic effects. beta-Adrenoceptor blockade with atenolol (1 microM) did not modify the activity of LND 623 but significantly enhanced the negative inotropic effect on P2 induced by 1 and 3 microM LND 796 and reduced the positive inotropic effect on P1 and P2 of the highest concentration (30 microM) studied. 5. In the presence of either caffeine (1 mM) or Ca2+-free, Sr2+-rich (3.6 mM) solution, LND 623 and LND 796 produced a positive inotropic effect which was stronger with LND 623. 6. It is suggested that two mechanisms are involved in the inotropic effects of these aminosteroids: (i) an enhanced Ca2 + entry via the slow calcium channels partially brought about by a local release of endogenous catecholamines in the case of LND 796, (ii) an inhibitory effect on Na+-K+ ATPase which, at the highest concentrations, lead to similar signs of cellular toxicity to those described for digitalis drugs. Because of their enlarged positive inotropic range, both aminosteroids may be of interest in the treatment of congestive heart failure.

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 microM) 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.

"Use-dependent" effects of cisapride on postrest action potentials in rabbit ventricular myocardium.

Repercussions of cisapride-induced blocking effects on repolarisation of K(+) channels in open and inactivated states investigated in rabbit ventricular myocardium during rest and under stimulation were compared with effects of K(+)-blocking drugs (4-aminopyridine, dofetilide, terikalant). Major lengthening in the first postrest action potential indicates affinity for closed channels. Gradual lengthening during stimulation implies affinity for open channels. Four (control, add-in, steady-state, washout) 20-min rest periods were alternated with regular stimulation (0.5 Hz). Each drug was added during add-in and steady-state periods. Similarly to dofetilide (10 nM) and terikalant (0.3 microM), cisapride (1 microM) increasingly lengthened action potentials during stimulation, whereas 4-aminopyridine (1 mM) prolonged mostly the first postrest action potential. Our results indicate that cisapride induced use-dependent lengthening of repolarisation, compatible with an affinity for open K(+) channels. We also found that in isolated rabbit ventricular myocytes, cisapride (1-10 microM) decreased the inward rectifier K(+) current, an effect contributing to the proarrhythmic potential.

In vitro electrophysiological detection of iatrogenic arrhythmogenicity.

Cardiac arrhythmias and sudden death have been associated with both therapeutic and toxic doses of a number of cardiotropic and non-cardiac drugs. Generally the drug-induced electrocardiographic (ECG) alterations have been well described, whereas corresponding cellular electrophysiological effects are poorly documented or lacking. Taking into account the recent advances in the understanding of the mechanisms underlying arrhythmias and antiarrhythmic effects, suitable relationships can be established between ECG alterations and drug effects on cardiac action potential. Thus, a decrease in maximal upstroke velocity (Vmax) and membrane depolarisation leading to cellular inexcitability may slow conduction, prolong QRS interval duration and result in incessant wide QRS ventricular tachycardia. On the other hand, lengthening of the repolarisation phase and early afterdepolarisations (EADs) have been proposed as a mechanism for prolonged QT interval and subsequent Torsades de Pointes. A representative study aimed at detecting the arrthymogenic potentiality of a drug is given, by examining carefully the concentration- and frequency-dependent effects of four neuroleptics (sultopride, droperidol, thioridazine and clozapine) on Purkinje fibers and comparing them with the reported iatrogenic arrhythmias. The results showed that 10 to 100 microM sultopride and 0.01 to 1 microM droperidol exerted "pure" class III effects. In addition, higher concentrations (3 to 30 microM) of droperidol reversed the prolonging effect on repolarisation concomitantly with a dose- and frequency-dependent decrease in Vmax, action potential amplitude and resting membrane potential (class I effects) resulting in cellular inexcitability at 30 microM. Similar class I effects were induced by thioridazine and clozapine concomitantly with a slight prolonging effect on final repolarisation (class Ia effects). In the presence of sultopride (30 and 100 microM) and droperidol (0.3 to 3 microM), EADs developed at plateau level. Their incidence, amplitude and number were influenced by extracellular K or Mg concentration, stimulation frequency, modification of Ca entry (by nifedipine or isoproterenol). These experimental results fit well with clinical data although they need further development to precise underlying ionic mechanisms. Therefore, in vitro studies should be considered before clinical prospects for future drug development.

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

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 microM) do not alter the action potential parameters even at a concentration as high as 100 microM. The stimulation rate is without effect on repolarization. On the contrary, sparfloxacin (1-100 microM) lengthens concentration-dependently the duration of action potential, this effect being significant from the concentration of 10 microM. A non significant decrease in maximal rate of rise of phase 0 depolarization was observed at the concentration of 100 microM. 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 microM and in four other fibers at the concentration of 100 microM. 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.

Sodium lactate reversal of electrophysiological effects of imipramine in guinea-pig ventricular myocardium.

Overdose cardiac effects of imipramine are due to fast Na channel blockade and are clinically reversed by administration of sodium lactate which induces alkalosis (about pH 7.50) and hypernatremia (about 8 mM). The mechanisms of this beneficial effect of Na lactate were explored in vitro on guinea-pig ventricular myocardium using the microelectrode technique. The time-course effects of the clinically relevant concentration of 10 microM imipramine on action potential characteristics were examined at pH 7.20 and pH 7.50. To test whether alkalinisation per se is important or whether an increase in Na concentration plays a major role in the reversal effect, preparations were exposed to increasing concentrations (1, 3, 10, 30, 100 mM) of either Na lactate, bicarbonate or chloride in the absence or in the presence of 10 microM imipramine at pH 7.50. The influence of elevating osmolality was evaluated with equivalent concentrations of sucrose. Imipramine alone significantly depressed Vmax and shortened action potential duration at all phases of repolarisation. All three high sodium solutions reversed imipramine effects. However the reversal effect was already obvious with 10 mM Na lactate and 10 mM NaHCO3 but not 10 mM NaCl. Osmolality did not reverse the imipramine-induced Vmax depression. The results suggest that at the clinically relevant 10 mM concentration, sodium lactate and bicarbonate may displace imipramine from its receptor site on the Na channel by causing alkalosis at the membrane level without profoundly affecting the driving force of the Na current, whereas at the upper concentrations, the increase in Na ion concentrations is predominantly involved in the reversal of imipramine effects.

Comparative in vivo and in vitro study of the cardiac effects of midalcipran and imipramine.

Midalcipran is a new antidepressant drug inhibiting both noradrenaline and serotonin uptake without any postsynaptic and anticholinergic activities. Its cardiac effects were compared with those of imipramine, a tricyclic antidepressant drug. In anaesthetised guinea-pigs intravenous perfusion of imipramine and midalcipran (1 ml/min from a solution at 0.66 mg/ml) brought about ventricular arrhythmias, respectively at 16.5 and 26.4 mg/kg and cardiac arrest at 58 and 97 mg/kg. The safety index (ratio of i.v. lethal dose and ED50 evaluated by the yohimbine test) is 22 times wider for midalcipran than imipramine. In in vitro studies on guinea-pig ventricular myocardium, imipramine exerted a greater class 1 antiarrhythmic effect than midalcipran. The reduction of Vmax was significant at 3 X 10(-6) M for imipramine and 1 X 10(-5) M for midalcipran in normal (4 mM K+) and hyperpolarizing (2.7 mM K+) conditions. At the concentration of 1 X 10(-5) M midalcipran significantly lengthened, whereas imipramine non significantly shortened the action potential durations (APD50, APD90). The results provide confirmation of a lesser depression in sodium conductance with midalcipran as compared to imipramine. Therefore it is proposed that less adverse cardiac effects may be observed at therapeutic doses.

[Mechanisms of action of class III anti-arrhythmia agents]. / Mécanisme d'action des antiarythmiques de classe III.

Vaughan-Williams class III antiarrhythmic agents act mainly by prolonging the duration of the cardiac action potential and, thus, the refractory period. This effect may be obtained: 1) by increasing the inward sodium or calcium currents, which may lead to an intracellular calcium overload and induce a very proarrhythmic situation, or 2) by decreasing the outward potassium currents, the objective of the new class III antiarrhythmic drugs under development. They selectively block one or several potassium channels regulated by the membrane potential (transient outward current Ito, delayed rectifying current IK and rectifying inward current IK1). Under physiological conditions the blockade of potassium channels regulated by a ligand (for example, ATP-dependent) does not lead to a class III effect. Prolongation of ventricular repolarisation is accompanied by a slowing of the heart rate and a positive inotropic effect. It is attenuated by rapid rhythms and amplified by slow rhythms: this is the reverse frequency-dependent phenomenon. However, normal frequency dependence (or "use-dependence") has been reported with the ionic channel, this paradox apparently being related to the complexity of the relations between the relative contributions of the ionic currents of repolarisation and their modulation by the heart rate. The class III effect confers a proarrhythmic potential and may lead to torsades de pointes, favorised by bradycardia, hypokalaemia and hypomagnesaemia. Experimentally, it favorises early after depolarisations which are presumed to be the cellular trigger event. The comprehension of factors influencing the antiarrhythmic and proarrhythmic class III effects has led to the establishment of a pharmacological profile of the "ideal" drug conferring the least proarrhythmic risk and the best efficacy.

High extracellular sodium and digoxin-induced arrhythmias in guinea-pig ventricular myocardium.

Oscillatory fluctuations in diastolic potential [4, 10] and triggered rhythmical activity [4] are well known manifestations of digitalis intoxication and are attributed to intracellular Ca2+ overload consecutive to an elevated intracellular Na+ [7]. In the present paper we report the electrophysiological effects of elevated extracellular Na+ on the spontaneous rhythmical activity and oscillatory fluctuations in digoxin-intoxicated ventricular cells. Our results show that by increasing extracellular Na+ from 135 mM to 175 mM, we were able to abolish spontaneous rhythmical activity but were not able to suppress the damped sinusoidal oscillations in the resting membrane potential. We suggest that Na+-Ca2+ exchange would be stimulated by a greater Na+ gradient, resulting in an enhanced Ca2+ extrusion.

Triggered activity induced by combined mild hypoxia and acidosis in guinea-pig Purkinje fibers.

The effects of prolonged exposure to combined mild hypoxia (Po2 230 +/- 20 mmHg) and acidosis (pH: 6.8 +/- 0.05) were studied in guinea-pig left ventricular myocardium superfused in vitro. Only Purkinje fibers were impaled by microelectrodes. Triggered activity developed in depolarized Purkinje fibers after 48 +/- 9 min of exposure to hypoxic and acid conditions and was initiated either by short periods of rapid electrical driving or by the background slow Purkinje automaticity. Triggered activity occurred when a delayed afterdepolarization attained its threshold potential and terminated after a subthreshold afterdepolarization. Interaction between triggered activity and slow background automaticity was observed until 90 to 180 min of exposure to hypoxic and acid conditions. These effects were reversed by replacement in standard conditions (Po2 510 +/- 20 mmHg; pH 7.35 +/- 0.05). Norepinephrine (1 X 10(-6)M) significantly accelerated the rate of discharge of triggered foci and led to a stable sustained triggered activity. Increasing extracellular Ca2+ concentration aggravated the effects of combined mild hypoxia and acidosis and led to the occurrence of early afterdepolarizations initiating triggered activity. In addition abnormal automaticity developed in quiescent fibers without any triggering action potential. Lidocaine and verapamil suppressed the triggered activity following a subthreshold afterdepolarization. Their effects were reversed on wash-out. It is concluded that prolonged exposure to combined mild hypoxia and acidosis induces triggered activity by a basic mechanism common to other situations leading to a calcium overload and showing such behaviour.

Calcium channels and excitation-contraction coupling in cardiac cells. I. Two components of contraction in guinea-pig papillary muscle.

Biphasic contractions have been obtained in guinea-pig papillary muscle by inducing partial depolarization in K+-rich solution (17 mM) containing 0.3 microM isoproterenol; whereas in guinea-pig atria, the same conditions led to monophasic contractions corresponding to the first component of contraction in papillary muscle. The relationships between the amplitude of the two components of the biphasic contraction and the resting membrane potential were sigmoidal curves. The first component of contraction was inactivated for membrane potentials less positive than those for the second component. In Na+-low solution (25 mM), biphasic contraction became monophasic subsequent to the loss of the second component, but tetraethylammonium unmasked the second component of contraction. The relationship between the amplitude of the first component of contraction and the logarithm of extracellular Ca2+ concentration was complex, whereas for the second component it was linear. When Ca2+ ions were replaced by Sr2+ ions, only the second component of contraction was observed. It is suggested that the first component of contraction may be triggered by a Ca2+ release from sarcoplasmic reticulum, induced by the fast inward Ca2+ current and (or) by the depolarization. The second component of contraction may be due to a direct activation of contractile proteins by Ca2+ entering the cell along with the slow inward Ca2+ current and diffusing through the sarcoplasm. These results do not exclude the existence of a third "tonic" component, which could possibly be mixed with the second component of contraction.

Calcium channels and excitation-contraction coupling in cardiac cells. II. A pharmacological study of the biphasic contraction in guinea-pig papillary muscle.

Biphasic contractions were obtained in guinea-pig papillary muscle by inducing partial depolarization in K+-rich solution (17 mM) in the presence of 0.3 microM isoproterenol. Mn2+ ions inhibited the two components of contraction in a similar way. Nifedipine and particularly Cd2+ ions specifically inhibited the second component of contraction. Isoproterenol and BAY K 8644 markedly increased the amplitude of the second component (P2) of contraction. Nevertheless, a moderate positive inotropic effect of isoproterenol was found on the first component (P1) of contraction when excitability was restored by 0.2 mM Ba instead of isoproterenol. Acetylcholine and hypoxia decreased the amplitude of the second component of contraction to a greater extent. In the presence of digoxin or Na+-free solution, P1 was strongly increased. When sarcoplasmic reticular function was hindered by 1mM caffeine or in the presence of Ca2+-free Sr2+ solution, digoxin always induced a negative inotropic effect on P2. Inversely in these conditions the transient positive inotropic effect of Na+-free solution was strongly reduced. These results are consistent with the hypothesis that the late component of contraction is triggered by the slow inward Ca2+ current and that the early component is due to Ca2+ release from the sarcoplasmic reticulum.

[Electrophysiological study of the arrhythmogenic effects of digoxin in ventricular myocardial fragments of guinea pigs stimulated at low frequency. Inhibitory action of caffeine]. / Etude électrophysiologique des effets arythmogènes de la digoxine sur des fragments de myocarde ventriculaire de cobaye stimulés à basse fréquence. Action inhibitrice de la caféine.

Arrhythmogenic effects of digoxin were studied in guinea pig ventricular myocardium driven at a low frequency, using microelectrode technique. Prolonged exposure to digoxin made two distinct phases of arrhythmias to appear: the first phase early occurred without apparent alteration in membrane diastolic potential of the impaled ventricular cells, the second phase was later initiated from oscillatory afterpotentials in diastolic potential. It is proposed that phase 1 of arrhythmias is initiated from oscillatory afterpotentials generated in Purkinje fibers more sensitive to digoxin-induced arrhythmogenic effects than myocardial cells. Phase 2 of arrhythmias would be originated in ventricular muscle fibers. Caffeine abolished oscillatory afterpotentials and suppressed sustained rhythmical activities of phases 1 and 2. The results indirectly confirm the important role of calcium movements between the myoplasm and sarcoplasmic reticulum in the origin of digoxin-induced arrhythmias triggered by oscillatory afterpotentials.

Digoxin-induced toxicity and experimental atrioventricular block in dogs. Relation between ventricular arrhythmias and oscillatory afterpotentials.

In anesthetized dogs, digoxin intoxication was performed after and before production of a definitive complete atrioventricular (A-V) block induced by formaldehyde injection in A-V node area, compared to intoxication in dogs in sinus or junctional rhythm. The results showed that digoxin toxicity was decreased in dogs with previous A-V block. This A-V block protective effect was abolished by resetting initial sinus-like frequency with ventricular pacing before digoxin administration. Ventricular arrhythmias were suppressed by production of complete A-V block. The A-V block protective effect can be explained by a lesser myocardial uptake of digoxin because of the low idioventricular frequency. However, ventricular arrhythmias in dogs with A-V block presented similarities both in occurrence and spreading with the development of oscillatory afterpotentials (OAPs) and rhythmical triggered activity demonstrated in isolated digitalis-poisoned Purkinje fibers and ventricular myocardium: the repetitive discharge of toxic foci masked normal idioventricular pacemakers and was interrupted by variable pauses followed by the resumption of either a very slow idioventricular rhythm or a toxic focus. It is suggested that because of the low idioventricular frequency, competition and/or superimposition of slow enhanced diastolic depolarization and OAPs can be electrocardiographically displayed. The terminal event was asystole in dogs with unpaced A-V block, and ventricular fibrillation in dogs with sinus, junctional and paced A-V block rhythms. The asystole (at least 30 seconds of electrical quiescence) may be explained partly as an intense depression of normal idioventricular pacemaker being overdriven by the discharge of toxic pacemakers, and partly as a consequence of the suppression of local autonomic influences in the A-V node area induced by the formaldehyde injection.

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

Astemizole is a potent histamine H1-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 microM) 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 KCl (2.7-5.4 mM) or MgCl2 (1-5 mM) suppressed EADs and reversed the prolonging effect that was conversely exaggerated by decreasing KCl (4-2.7 mM) or MgCl2 (1-0.5 mM) concentration. At higher concentrations (3-30 microM), 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 microM astemizole, leading to cellular inexcitability in 5 of 12 fibers when exposed to 30 microM astemizole. In comparison, cimetidine induced minor changes on AP characteristics, i.e., a prolongation in plateau duration at high (30-100 microM) 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.

Droperidol exerts dual effects on repolarization and induces early afterdepolarizations and triggered activity in rabbit Purkinje fibers.

This study was designed to clarify discrepancies concerning the effects of droperidol on cardiac repolarization. Myocardial electrical activity was recorded by using microelectrode technique in rabbit Purkinje fibers and guinea pig ventricular muscle. In Purkinje fibers stimulated at 60 pulses/min, low concentrations (0.01-0.3 microM) of droperidol increased in a dose-dependent fashion action potential duration (APD) without altering the other parameters. At 1 and 3 microM, droperidol led to the reversal of the prolonging effect. The highest concentrations used (10 and 30 microM), produced shortening in APD at 50% repolarization concomitantly with a significant decrease in Vmax, action potential amplitude and resting membrane potential. Inexcitability occurred in 4 of 15 preparations exposed to 30 microM. In 8 of 15 Purkinje fibers, the prolonging effect induced by low concentrations was so important that APD exceeded the 1000-msec period of basal stimulation and early afterdepolarizations (EADs) and triggered activity developed. In guinea pig ventricular muscle, these effects were notably less pronounced. Prolongation of action potential showed a reverse use-dependence (i.e., much greater at the lowest stimulation frequencies), whereas Vmax depression was use-dependent. Decreasing extracellular K concentration from 4.0 to 2.7 mM enhanced the incidence of EADs in Purkinje fibers, whereas elevating the K concentration from 2.7 to 5.4 mM abolished them completely and shortened drastically APD. EADs were also eliminated by increasing magnesium concentration from 1 to 5 mM. Addition of isoproterenol favored EADs, whereas these were suppressed at plateau level by exposure to 0.3 microM nifedipine. The results indicate that in rabbit Purkinje fibers, droperidol exerts a dual effect on repolarization, prolongation with low concentrations with development of EADs and subsequent triggered activity. These abnormalities were suppressed at high concentrations concomitantly with a marked depression of other characteristics. These observations suggest multiple ionic channel activities and further studies are required to precise the underlying mechanisms at channel level.

[The effects of propranolol and sotalol on the electrophysiologic and enzymatic impact of myocardial ischemia induced in vitro in the guinea pig heart]. / Effets du propranolol et du sotalol sur les répercussions électrophysiologiques et enzymatiques de l'ischemie myocardique réalisée in vitro chez le cobaye.

Antiarrhythmic and cardioprotective effects of propranolol and sotalol were examined by studying their action on cellular electrical activity (recorded using standard microelectrode techniques) and creatine-kinase leakage (measured in the effluent from the experimental bath chamber) in the in vitro guinea-pig left ventricular myocardium exposed to conditions mimicking severe or moderate ischemia. Returning the tissue to the normal conditions was considered as equivalent to ischemic-heart reperfusion. Propranolol (2 X 4 mg/kg) was intraperitoneally administered to guinea-pigs, daily for 21 days. It was perfused in vitro (1.10(-6) M) during the whole experiments. Propranolol decreased action potential duration in control conditions (p less than 0,05), precipitated the occurrence of inexcitability during severe ischemia (p less than 0,01) and improved the recovery of cellular excitability during reperfusion. Propranolol did not significantly affect the creatine-kinase leakage during ischemia and reperfusion.

Is resting membrane potential a possible indicator of viability of muscle bundles used in the in vitro caffeine contracture test?

In 22 patients susceptible to and 34 patients not susceptible to malignant hyperthermia, we examined which muscle conditions may influence the degree of sensitivity of skeletal muscle to the in vitro caffeine contracture test: predrug resting membrane potential, predrug twitch tension, and maximum contracture induced by 32 mM caffeine in two caffeine tests performed respectively at 30 and 75 min after biopsy. No differences in the measured variables were observed between the first and the second caffeine tests in the 34 patients susceptible to malignant hyperthermia. The first caffeine test was found to be positive in all of the 22 patients susceptible to malignant hyperthermia. However, in eight patients, the second caffeine test was negative and the muscle fibers were found to be significantly depolarized. Resting membrane potential was -73.4 +/- 7.9 mV before the first caffeine test and -65.8 +/- 8.8 mV before the second test. We suggest that when time-induced partial depolarization of malignant hyperthermia-susceptible fibers occurs, fibers may become less sensitive to caffeine.

[Electrophysiological effects of subtherapeutic levels of procainamide on hypoxic myocardial cells (author's transl)]. / Effets électrophysiologiques de concentrations subthérapeutiques de procainamide sur des cellules myocardiques soumises à l'hypoxie.

1. The electrophysiological effects of hypoxia alone or combined with subtherapeutic concentrations of procainamide superfusion were investigated in guinea-pig ventricular muscle fibres in order to elucidate the procainamide activity on suffering myocardial cells. 2. A first 30 minute-long hypoxia depressed action potential characteristics but never induced cellular inexcitability. These alterations were entirely reversible. A second consecutive hypoxia period similarly affected cellular activity. 3. After a control hypoxia period, procainamide 0.15 microM and 1.5 microM further depressed or abolished the hypoxia-altered transmembrane potentials. 4. In procainamide 0.15 microM and 1.5 microM pretreated cells, hypoxia more extensively depressed or abolished the myocardial cell activity than in unpretreated cells. 5. It has been demonstrated that antiarrhythmic drugs only slowly and incompletely reached the ischaemic myocardium. The present results suggest that in clinical situations, such weak concentrations may be efficient for inducing pronounced modifications in ischaemic areas and rapid antiarrhythmic effects.

Clinical concentrations of verapamil affect the in vitro diagnosis of susceptibility to malignant hyperpyrexia.

We examined the effects of verapamil on the in vitro caffeine and halothane tests for malignant hyperpyrexia (MH) susceptibility. Ten consecutive MH-susceptible patients were investigated according to the protocol of the European MH group. Additional tests were carried out in the presence of verapamil 10(-6) mol litre-1. In four of the 10 patients, the halothane contracture response following pretreatment with verapamil was classified as positive to halothane. In contrast, in nine of the 10 patients, contracture tests of muscle in the presence of verapamil were classified as negative to caffeine. It is advised that verapamil should be discontinued before performing a contracture test.