Tetrodotoxin potentiation of the antiarrhythmic action of lidocaine in the late stage of experimental myocardial infarct

Lidocaine (4--12 mg/kg) and the specific fast sodium current blocker tetrodotoxin (TTX) (1--6 mg/kg, i. v.) reduced ventricular arrhythmias that occurred 24 h after coronary artery ligation in dogs. Infusion of a mixture of subthreshold doses of lidocaine and TTX decreased ventricular arrhythmias to the same degree as infusion of threshold doses of either agent alone. This finding suggests that the antiarrhythmic action of lidocaine in the late stage of myocardial infarction is due to inhibition of the fast inward, sodium current. The possible mechanisms of rhythm disturbances in the late stage of myocardial infarction are discussed.     

Effect of fluorine on heart arrhythmias in rats

The antiarrhythmic activity of fluoride was studied in a model of CaCL2-induced heart arrhythmias in male albino rats. The prolonged intake of sodium fluoride with drinking water (2 mg/l for 1 month) significantly reduced the severity of arrhythmias that was evident as an increase in the latency and a decrease in the frequency and duration of arrhythmias. A less pronounced effect was noted when the concentration of sodium fluoride was increased to 5 mg/l. At larger concentrations (11 mg/l) the fluoride exerted a toxic effect and potentiated the arrhythmogenic action of CACL2. The antiarrhythmic action of fluoride in low concentrations may be associated with the blockade of an inward Ca current.     

Effect of nonachlazine on transmembrane ionic currents in the frog atrial trabeculae

The effect of the antianginal drug nonachlazine displaying antiarrhythmic properties on transmembrane ionic currents in the frog atrial fibers was studied in experiments on isolated trabeculae of the frog atria. The transmembrane ionic currents were measured by a voltage clamp technique based on a double sucrose gap arrangement. Nonachlazine (1.03 X 10(-5) mol/l) decreased the amplitude of the fast inward current whatever the magnitude of membrane potential. The drug inhibited the slow inward current and prevented the adrenaline-increased permeability of the slow sodium-calcium channel if external sodium ions were replaced by choline chloride. Nonachlazine (1.03 X 10(-5) mol/l) diminished the amplitude of the inward ionic current in a calcium-free medium as well. The stimulatory effect of prostacycline (2 X 10(-7) mol/l) on the fast inward ionic current was inhibited by nonachlazine. The data obtained suggest that the antiarrhythmic effect of nonachlazine might be linked with the inhibition of the fast sodium inward current and the slow calcium inward current.     

Effect of diethylamine analog of ethmozine on parameters of fast sodium current in normal and depolarized myocardial fibers

The effect of a diethylamine analog of ethmozine (DAAE) on fast sodium current of normal and depolarized frog atrial trabeculae was studied by means of the double sucrose gap technique. The depolarization of the fibers was produced both by increasing extracellular potassium concentration up to 8 +/- 9 mM and by current passing. The resting potential of normal fibers was within the range of 75-80 mV, and the depolarized one was within 65 +/- 60 mV. DAAE (8 X 10(-7) g/ml) reduced sodium conductivity, slowed inactivation and reactivation of fast sodium current and shifted the steady-state activation curve (h infinity) to a more negative potential, but the steady-state activation curve (m infinity) to a more positive potential. All these effects were expressed more considerably in the depolarized fibers. The depressing ability of DAAE is assumed to be due to high concentration of the drug in the membrane owing to its high solubility in lipids. The slowing of sodium reactivation and inactivation shows the existence of a receptor for DAAE linked with a h-gate. Prolonged antiarrhythmic action is accounted for by a very slow recovery of sodium current after the drug superfusion. A stronger effect of DAAE on sodium current in the depolarized fibers is likely to point to its selective action on ischemic tissue.     

Influence of light on membrane potential of Neurospora crassa cells

In experiments with left atrial and right ventricular tissues fast sodium current (INa) was decreased by substituting sucrose for sodium in Tyrode's solution and with antiarrhythmic drugs--INa blockers (lidocaine, diphenylhydantoine and ethmozine). It was shown that INa decrease results in the growth of refractoriness (R) of the cardiac tissues. The hypothesis is advanced that the R growth caused by INa decrease is one of the mechanisms of selective sensitiveness of ischemic heart tissues to antiarrhythmic drugs--INa blockers.     

Different sensitivities of two mechanisms of excitation waves in heart tissue to anti-arrhythmia agents--blockers of fast sodium currents

In experiments with rabbit ventricular tissue sensitivity of two kinds of spiral wave sources of excitation to fast sodium current inhibition was compared. These spiral wave sources were circulation in a ring around an obstacle and circulation in tissue without an obstacle (reverberator). It was observed that after application of antiarrhythmic drugs lidocaine or mexiletine there was a prominent growth of cycle length of reverberator during first few seconds of circulation and a little change of cycle length for the circus movement around obstacle. It is proposed that different sensitivity of both kinds of spiral wave sources to antiarrhythmic drugs can be used for their distinguishing in clinical practice.     

Inhibition of Sodium Current by Taurine Magnesium Coordination Compound Prevents Cesium Chloride-Induced Arrhythmias

The mechanism(s) by which taurine magnesium coordination compound (TMCC) inhibits experimental arrhythmias remains poorly understood. The purpose of this study was to observe the effects of TMCC against cesium chloride-induced arrhythmia in the rabbit heart and find whether the antiarrhythmic activity is related to inhibition of sodium current. Early afterdepolarization was induced by 1.5 mM cesium chloride (1 ml kg⁻¹) through intravenous injection. The monophasic action potentials (MAP) and electrocardiograms were simultaneously recorded. The effect of TMCC on functional refractory periods (FRPs) in the left atrium was also observed in vitro. Arrhythmias onset was significantly retarded by TMCC. The number of ventricular premature contractions and incidence of monophasic ventricular tachycardia and polyphasic ventricular tachycardia in 10 min were decreased by TMCC. These effects can be abolished by veratridine (10 μg kg⁻¹). MAP duration at 90% repolarization was significantly prolonged by TMCC, which can be prolonged even longer by veratridine (10 μg kg⁻¹). In vitro experiments showed that FRPs was prolonged by TMCC which can be cancelled by veratridine (10 μg kg⁻¹). TMCC prevents cesium chloride-induced arrhythmias, and inhibition of sodium current, in part, contributes to the antiarrhythmic effect of TMCC.     

Anti-arrhythmic activity of the beta2-adrenoblockader alpheprol]

Experiments were conducted on dogs, cats and rats in which various disturbances of the cardiac rhythm were induced. Beta2-adrenoblocker alpheprol proved to produce a marked antiarrhythmic action. The preparation arrested the auricular arrhythmias caused by electric stimulation of the auricles or by aconitine application, eliminated the auricular arrhythmias resulting from occlusion of a branch of the coronary artery or oubaine intoxication, prevented lethal auricular fibrillation in rats after the calcium chloride intoxication. It is supposed that along with the beta-adrenoreceptor block the antiarrhythmic effect of alpheprol was also caused by quinidine-like action of the preparation.     

Effects of allapinin on sodium currents in isolated neurons of the trigeminal ganglia and cardiomyocytes of rats

Block of sodium currents by allapinin (diterpene alkaloid with strong antiarrhythmic properties) was investigated in isolated, voltage clamped rat trigeminal neurons and cultured neonatal rat single ventricular myocytes. Allapinin produces a decrease in sodium current amplitude without any changes in voltage dependent properties. Possible differences between the mechanisms of antiarrhythmic effect of diterpene alkaloids and classic antiarrhythmic agents have been analysed.     

The antiarrhythmic effect of prostaglandin E2 on catecholamine-induced arrhythmias

The antiarrhythmic effect of PGE2 as compared with the adrenergic beta-receptor blocking substance propranolol and the unspecific antiarrhythmic agent ajmaline was examanined on catecholamine-induced arrhythmias of the guinea-pig after preliminary sensibilisation by means of chloroform. Prophylactic administration of the tested substances resulted in a decrease in severity of arrhythmia by 91% after propranolol, by 37% after PGE2 and by 34% after ajmaline. Onset and duration of the arrhythmia were affected only to a negligible degree. The possible mode of action is still under discussion.     

Effects of arachidonic,linoleic, linolenic and oleic acid on experimental arrhythmias in cats,rabbits and guinea-pigs

Antiarrhythmic effects of the Prostaglandin (PG) precursors arachidonic and Linoleic acid were demonstrated on three models of experimental arrhythmias, whereas the fatty acids linolenic and oleic acid proved to be ineffective in these models. In ouabain-induced arrhythmias infusions of arachidonic acid (1,0 mg/kg/min) caused a strong antiarrhythmic effect in 80 percent of the animals. On the same model linoleic acid showed a maximum effect in 40 percent of the animals. BaCl₂-induced arrhythmias were abolished by arachidonic and linoleic acid in 60 percent and 66 percent of the rabbits, respectively. Pretreatment by indomethacin reduced the antiarrhythmic effect of linoleic acid from 40 percent to 9 percent on ouabain-induced arrhythmias in cats. The results suggest a participation of PG synthesis in the antiarrhythmic effect of PG precursors.     

Anti-arrhythmic effect of ryanodine in the guinea pig with glycoside poisoning

The effect of ryanodine on membrane potential oscillations in vitro (in isolated guinea-pig papillary muscle) and on ventricular arrhythmias in vivo (in glycoside intoxication) were studied. 3-5 minutes after ryanodine (0.5 microM) addition the membrane potential oscillations induced by ouabain (1 microM) were abolished. 4-5 minutes after intravenous ryanodine infusion (15 micrograms/kg) ventricular arrhythmias induced by ouabain intoxication (75-115 micrograms/kg) disappeared and 8-10 minutes later sinus rhythm was restored. It is suggested that antiarrhythmic effect of ryanodine is a result of the inhibition of diastolic membrane potential oscillations.     

The vagal involvement in the antiarrhythmic and arrhythmogenic effects of prostaglandin F2 alpha on ouabain-induced cardiac arrhythmias in cats

The effects of prostaglandin F2 alpha (PGF2 alpha) on ouabain-induced cardiac arrhythmias were investigated in chloralose-anaesthetized cats. Bilateral vagotomy and atropine intervention were employed to elucidate the involvement of vagal neural influences. PGF2 alpha (2-16 micrograms/kg i.v. bolus) predominantly suppressed the ouabain-induced ventricular and supraventricular arrhythmias and less commonly aggravated them in vagi-intact cats. The antiarrhythmic effect of PGF2 alpha was considerably, but not statistically significantly, decreased while its arrhythmogenic effect was significantly (p less than 0.05) increased in atropine-pretreated group. In vagotomised group PGF2 alpha failed to abolish the arrhythmias but it aggravated them to a degree comparable to that observed in vagi-intact group. It is concluded that the PGF2 alpha exhibits both antiarrhythmic and arrhythmogenic properties and these are largely due to elicitation of two opposing neural reflexes - one being protective and another being deleterious to ouabain-induced arrhythmias.     

Role of delta opioid receptors and their ligands in the development of adaptive heart protection against arrhythmogenesis

It has been found that stimulation of delta-1 opioid receptors by intravenous administration of DPDPE (0.5 mg/kg) decreases the incidence of ischemic and reperfusion-induced arrhythmias and also increases myocardial tolerance to the arrhythmogenic action of epinephrine in rats. Pretreatment with a selective delta-2 agonist, DSLET, had no antiarrhythmic effect. The inhibition of the enzymatic breakdown of endogenous enkephalins by intravenous administration of acetorphan decreased the incidence of epinephrine-induced arrhythmias. Pretreatment with a selective delta opioid receptor antagonist, ICI-174.868, completely abolished this antiarrhythmic effect. Adaptation of rats to repeated immobilization stress during 12 days increased myocardial tolerance to the arrhythmogenic action of coronary artery occlusion (10 min) and reperfusion (10 min). Pretreatment with a selective delta opioid receptor antagonist, TIPP(Psy), did not abolish the antiarrhythmic effect of adaptation to immobilization stress. It seems that endogenous agonists of delta opioid receptors are not involved in the antiarrhythmic effect resulting from adaptation to stress.     

The actions of prostaglandins I2 and E2 on arrhythmias produced by coronary occlusion in the rat and dog.

Prostaglandins E2 and I2 were compared with known antiarrhythmics for their actions against arrhythmias produced by occlusion of the left anterior descending coronary artery in the anaesthetised rat while PGI2 was also examined in the dog. PGI2 in the dog suppressed early arrhythmias produced during occlusion but did not influence those produced by occlusion-release or those occurring 24 hours after a permanent occlusion; none of the A,B,C or D series prostaglandins tested markedly reduced 24 hour arrhythmias. In the rat PGE2 was antiarrhythmic against early occlusion arrhythmias (30 minutes occlusion) in a dose related manner (infusions of 1-4 microgram/kg/min) whereas PGI2 infusions potentiated the arrhythmogenic effect of occlusion. PGE2 was as effective an antiarrhythmic as 10mg/kg Org. 6001 which was more effective in this test situtation than dl-propranolol. No obvious mechanisms for the actions of PGE2 or PGI2 were apparent although both agents lowered blood pressure and reduced the size of the occluded zone produced by ligation.     

The antiarrhythmic action of prostacyclin (PGI2) on aconitine induced arrhythmias in rats.

Prostacyclin (PGI2) produces an antiarrhythmic effect on aconitine induced arrhythmias in rats. The ED50 of PGI2 was 0.7 microgram/kg and the maximum antiarrhythmic effect 54 per cent. The equi-effective doses of PGE2 and PGF2alpha were higher (ED50 of PGF2alpha = 1.2 microgram/kg, ED50 of PGE2 = 2.7 microgram/kg). However, PGF2alpha and PGE2 had a maximum antiarrhythmic effect of 80 per cent in this model.     

Comparative evaluation of anticonvulsant and anti-arrhythmic effects of phenazepam, a benzodiazepine receptor agonist

It was established on white mice that benzodiazepine receptor agonist phenazepam possessed a high anticonvulsant activity to antagonize bicuculline, corrasol, picrotoxin and thiosemicarbazide. It was also shown that phenazepam had a potent antiarrhythmic effect on ischemic and reperfusion cardiac arrhythmias in Wistar rats in situ. The effect was of a central nature since it was irreproducible in isolated heart. It seems to be due to the potentiating effect of phenazepam on the realization of GABA inhibitory control of centers of the heart regulation. The facts obtained evidence a possibility of using phenazepam not only as an anticonvulsant but also as an antiarrhythmic means.     

Frequency-dependent and independent effects of tetrodotoxin on Vmax in cardiac fibers

Superfusion with 3 microM tetrodotoxin (TTX) induced both a use-dependent and a frequency-independent depression of the rate rise of the action potential (Vmax) in dog Purkinje and guinea pig ventricular muscle fibers. The recovery from block was fast and exponential with a time constant of 225.4 +/- 7.1 ms in dog Purkinje fibers (n = 6). The onset kinetics of the frequency-dependent Vmax block was rapid, i.e. reached steady state after 3.0 +/- 0.3 beats in guinea pig ventricular muscle (n = 6). The rapid use-dependent interactions with sodium channel make TTX similar to antiarrhythmic drugs with fast kinetics i.e. lidocaine, mexiletine, and tocainide, but unlike antiarrhythmic drugs, TTX-induces a large frequency-independent Vmax block at the same concentrations.     

Ca2+-antagonistic properties of phospholipase A2 inhibitors, mepacrine and chloroquine

The effects of putative phospholipase A2 inhibitors mepacrine and chloroquine on membrane ionic currents were studied in intact frog atrial trabeculae. Both agents decreased slow calcium channel current Isi and fast sodium channel current If. Isi was affected twice at least in comparison to If. Half-block of Isi was observed at approximately 10(-6) mol/l mepacrine and at approximately 10(-5) mol/l chloroquine. These effects on transmembrane ionic transport should be considered when using the above agents as phospholipase inhibitors or antiarrhythmic drugs.     

Effects of Taurine–Magnesium Coordination Compound on Ionic Channels in Rat Ventricular Myocytes of Arrhythmia Induced by Ouabain

Taurine-magnesium coordination compound (TMCC) has anti-arrhythmic effects. The aim of the present study was to explore the targets of the anti-arrhythmic effect of TMCC and the electrophysiological effects of TMCC on ouabain-induced arrhythmias in rat ventricular myocytes. Sodium current (I(Na)), L-type calcium current (I(ca, L)), and transient outward potassium current (I(to)) were measured and analyzed using whole-cell patch-clamp recording technique in normal rat cardiac myocytes and rat ventricular myocytes of arrhythmia induced by ouabain. In isolated ventricular myocytes, I(Na) and I(to) were blocked by TMCC (100, 200, 400 μM) in a concentration-dependent manner, and the effects of TMCC (400 μM) were equal to that of amiodarone. However, I (ca, L) was moderately increased by TMCC (400 μM) while significantly decreased by amiodarone. Ouabain (5 μM) significantly decreased sodium, L-type calcium, and transient outward potassium currents. TMCC (100 μM) relieved abnormal sodium currents induced by ouabain through facilitation of steady-state inactivation. TMCC (200 and 400 μM) relieved abnormal L-type calcium currents induced by ouabain through facilitation of steady-state activation and retardation of steady-state inactivation. TMCC failed to further inhibit abnormal transient outward potassium currents induced by ouabain. However, amiodarone inhibited the decreasing sodium, L-type calcium, and transient outward potassium currents further. These data suggest that I(Na), I(ca, L), and I(to) may be the targets of the antiarrhythmic effect of TMCC, which can antagonize ouabain-induced changes of ionic currents in rat ventricular myocytes.