Comparison of the sodium currents in normal Purkinje fibres and Purkinje fibres surviving infarction--a pharmacological study.

1. Purkinje fibres surviving infarction showed a lower maximum upstroke velocity (Vmax) and a longer action potential duration when compared to normal Purkinje fibers. A reduction in the fast sodium current and an increase in the sodium 'window' current may be responsible for the observed alterations in Vmax and action potential duration respectively. 2. Since voltage clamp studies were not feasible, a pharmacological approach was used. The responses to tetrodotoxin (TTX) and lignocaine in normal Purkinje fibres and Purkinje fibres surviving infarction were used to examine the sodium currents in these fibres. 3. Vmax, an indirect measure of the fast sodium current, was more sensitive to lignocaine in Purkinje fibres surviving infarction than in normal Purkinje fibres. The reduction in Vmax by lignocaine was more prominent at the shorter stimulation cycle length. Significant reduction of Vmax was observed with the higher concentration of TTX and no differential effect on Vmax between normal Purkinje fibres and Purkinje fibres surviving infarction was detected. 4. Reduction of action potential duration in the presence of TTX or lignocaine was used as a measure of the sodium 'window' current. A greater reduction of action potential duration by TTX and lignocaine was observed in normal Purkinje fibres than in Purkinje fibres surviving infarction. 5. The results suggested that the fast sodium current in Purkinje fibres surviving infarction is more sensitive to pharmacological agents with local anaesthetic properties and the prolonged action potential duration in these Purkinje fibres cannot be due to an increase in the sodium 'window' current. The results are compatible with an enhanced effect of antiarrhythmic drugs on Vmax and conduction in the ischaemic heart.     

Electrophysiologic effects of McN-4130, a new antiarrhythmic compound, on isolated cardiac tissue

McN-4130 has antiarrhythmic efficacy in a number of animal models of ventricular arrhythmia and fibrillation. We used standard microelectrode techniques to characterize the electrophysiological effects of McN-4130 on isolated cardiac tissue. In canine Purkinje fibers, McN-4130 reduced the maximum rate of depolarization (Vmax) and shortened action potential duration at 50% repolarization (APD50) in a concentration-dependent manner (2-10 microM). These effects occurred without significant changes in membrane potential. APD100 tended to prolong with continued superfusion with McN-4130. The depression of Vmax was rate dependent and accompanied by increases in conduction time. The reductions in Vmax and APD50 induced by McN-4130 did not reach a steady-state until 90-150 min of superfusion. At 10 microM, fibers became inexcitable within 60-90 min. In addition, the effects on the action potential were not readily reversible. McN-4130 depressed membrane responsiveness in Purkinje fibers. It shortened the effective refractory period slightly but had a much greater effect on APD50. McN-4130 also reduced Vmax in ventricular muscle preparations. In contrast to its effects on the Purkinje fiber action potential, McN-4130 prolonged the duration of the ventricular muscle transmembrane potential and effective refractory period. Slow-response action potentials induced by high [K+]o and isoproterenol were not affected by McN-4130 at concentrations up to 10 microM. McN-4130 (2 and 4 microM) had no significant effect on normal Purkinje fiber automaticity. However, continued exposure to McN-4130 at 4 microM induced early afterdepolarizations and triggered activity in five of eight spontaneously discharging fibers. In guinea pig papillary muscle, McN-4130 caused marked rate-dependent depression of Vmax at concentrations that caused minimal tonic depression of Vmax. These results indicate that McN-4130 has effects at the cellular level that are similar to those of other potent local anesthetic antiarrhythmic agents. These effects may contribute to the antiarrhythmic and antifibrillatory activity of McN-4130.     

Depression of maximum rate of depolarization of guinea-pig ventricular action potentials by metabolites of encainide.

1. Standard microelectrode methods have been used to record action potentials from guinea-pig ventricular myocardium and dog Purkinje fibres, and to study the effects of the two major metabolites of encainide, O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (MODE). 2. In concentrations similar to those found in patients during chronic encainide therapy, neither ODE nor MODE produced significant depression of maximum rate of depolarization (Vmax) of action potentials in unstimulated tissue. Repetitive stimulation, however, was associated with depression of Vmax which increased with increasing driving rates (rate-dependent block, RDB). At the fastest rate studied (interstimulus interval = 300 ms) ODE 1 microM depressed Vmax by 47.5 +/- 5.7% and MODE 1 microM, reduced Vmax by 52.2 +/- 12%. 3. The onset and offset kinetics of this rate-dependent block were very slow. Full development of RDB during a train required over 100 action potentials and the time constants of recovery of Vmax from RDB were 86.4 +/- 37 s for ODE and 100.4 +/- 18 s for MODE. The amount of RDB and its rate of onset increased with drug concentration. The recovery time constants were independent of inter-stimulus interval or drug concentration. Both metabolites also produced rate-dependent depression of conduction velocity in canine Purkinje fibres, but no evidence of selective depression of conduction of interpolated premature potentials was seen. 4. Early afterdepolarizations occurred spontaneously in three preparations in the presence of MODE, 1 microM and one preparation in ODE, 1 microM. 5. It is concluded that these metabolites of encainide may play a role in producing both its antiarrhythmic and its proarrhythmic effects.     

Cardiac electrophysiologic effects of McN-5691, a new calcium-channel blocking antihypertensive agent.

The purpose of this study was to evaluate the cardiac electrophysiological effects of McN-5691, a new calcium-channel blocking antihypertensive drug. In anesthetized dogs, the primary electrophysiological effect of McN-5691 was dose-related prolongation of AV-nodal conduction time and refractoriness (0.1-1.0 mg/kg i.v.), which correlated with McN-5691 plasma levels. There were no significant effects on atrial or ventricular conduction times, QTc, or ventricular monophasic action potential duration. This profile was similar to that of verapamil. McN-5691 caused concentration-related, rate-dependent reductions in Vmax and amplitude of slow-response action potentials in guinea pig papillary muscle: ED-20% for depression of Vmax was 0.72 +/- 0.32 microM. Verapamil was more potent in depressing these action potentials: ED-20% for depression of Vmax was 0.03 +/- 0.01 microM. McN-5691 also caused rate-dependent reduction in Vmax and amplitude of canine Purkinje fiber action potentials, but only at relatively high concentrations: ED-20% for depression of Vmax was 55 +/- 12 microM. McN-5691 also reduced the action potential duration (0.3-30 microM) without affecting the slope of phase 4 depolarization and the maximum diastolic potential. Verapamil also reduced Vmax in Purkinje fibers (ED-20% for depression of Vmax was 32 +/- 3 microM) and shortened the action potential duration. The results show that McN-5691 has cardiac electrophysiological effects consistent with blockade of the slow inward calcium current, and that this activity occurs at concentrations well below those having local anesthetic activity. In addition, its lower potency in comparison to verapamil in depressing slow responses suggests a lesser propensity for negative inotropic effects.     

Electrophysiological mechanism for the antiarrhythmic action of propafenone: a comparison with mexiletine.

1. The antiarrhythmic potency of propafenone was evaluated in the guinea-pig isolated heart; arrhythmias were induced with (a) digitalis intoxication and (b) hypoxia followed by reoxygenation. 2. Propafenone, 0.5 microM, was found to be the minimal but effective antiarrhythmic concentration. The antiarrhythmic activity of propafenone developed slower than that of 10 microM mexiletine, which was the lowest effective concentration under the same experimental conditions. 3. The electrophysiological effects of propafenone were then studied on sheep cardiac Purkinje fibres (manifesting oscillatory afterpotentials and triggered automaticity induced by barium or strophanthidin) and compared with those of 10 microM mexiletine. 4. Both 0.5 microM propafenone and 10 microM mexiletine consistently blocked triggered activity in sheep Purkinje fibres. The onset of the effect of propafenone was slower than that of mexiletine. 5. Unlike mexiletine, propafenone did not reduce the amplitude of oscillatory afterpotentials. 6. In contrast, propafenone significantly reduced Vmax in barium- and strophanthidin-treated preparations. 7. It is concluded that the antiarrhythmic action of propafenone on digitalis- and reoxygenation-induced arrhythmias is probably due to an electrophysiological mechanism different from that of mexiletine. Mexiletine, by reducing the amplitude of oscillatory afterpotentials, prevents the attainment of the threshold; propafenone, by reducing the excitability of the cell, increases the threshold and consequently an oscillatory afterpotential of the same amplitude will not generate arrhythmias.     

The actions of pentobarbitone, procaine and tetrodotoxin on synaptic transmission in the olfactory cortex of the guinea-pig.

1 It has been suggested that the depression of excitatory synaptic potentials produced by general anaesthetics can be attributed to a partial blockade of impulse conduction in the terminal branches of axons. This hypothesis has been tested by comparing the actions of pentobarbitone, procaine and tetrodotoxin (TTX) on synaptic transmission in the guinea-pig olfactory cortex. 2 Pentobarbitone (0.1-0.3mM) depressed the evoked synaptic potentials without any significant depression of impulse conduction in the afferent fibres of the lateral olfactory tract (1.o.t). It had no effect on the electrical excitability of either the l.o.t axons or the postsynaptic neurones. 3 Tetrodotoxin (TTX; 1-5x10(-8 M) slowed conduction of impulses in the l.o.t. and decreased the amplitude of the l.o.t compound action potential in proportion to the concentration applied. All concentrations of TTX elevated the electrical threshold of the l.o.t. axons and there was evidence to suggest that the threshold of the postsynaptic neurones was also elevated. The synaptic potentials were depressed in direct proportion to the depression of the l.o.t. compound action potential. 4 Procaine (0.1-0.5 mM) exhibited a pattern of activity intermediate between pentobarbitone and TTX. The most marked effect, seen at all concentrations tested, was a slowing of impulse conduction and a decrease in the electrical excitability of the l.o.t. axons. 5 It is concluded that general anaesthetics (exemplified by pentobarbitone) depress synaptic transmission by interfering with the processes involved in chemical transmission and not by blocking impulse conduction in the terminal branches of afferent nerves.     

Electrophysiological studies of indecainide hydrochloride, a new antiarrhythmic agent, in canine cardiac tissues

The intracellular electrophysiological properties of a new, orally effective antiarrhythmic agent, indecainide hydrochloride, were studied in isolated canine myocardial preparations stimulated at 1 Hz and superfused with Tyrode's solution. In Purkinje fibers, indecainide (10(-6) and 3 X 10(-6) M) decreased the maximal rate of rise of phase 0 (Vmax), conduction velocity, action potential duration APD, and effective refractory period, and shifted the membrane response curve by 5 mV in a hyperpolarizing direction. In papillary muscle, APD was unchanged, but Vmax was decreased. The effect of the drug on Vmax was rate dependent, but over physiologically relevant cycle lengths (370 to 1,000 ms), Vmax remained relatively constant. In the presence of indecainide (3 X 10(-6) M) and at a basic cycle length of 333 ms, the rate constant for block onset was 0.06 and 0.1 action potentials-1 in Purkinje fiber and papillary muscle, respectively. The recovery of Vmax from maximum steady-state block was half completed in Purkinje fibers and muscle in 52 and 49 s, respectively. No resting block was apparent in either tissue at normal resting membrane potential. Indecainide had only minimal effects on automaticity arising from normal or depolarized (barium) membrane potentials. Thus, indecainide is a potent class I local anesthetic antiarrhythmic agent that depresses Vmax and conduction in cardiac tissues. The depressant effects of indecainide are completely dependent on prior activation of the tissue, but because of its slow kinetics for recovery from sodium channel block, little additional change in Vmax occurs within physiologically relevant heart rates and prematurity intervals.     

Effects of aprindine on conduction velocity and Vmax in guinea-pig papillary muscles

One of the effects of antiarrhythmic drugs is the reduction of conduction velocity. Cable theory predicts that there is a nonlinear relationship between conduction velocity and upstroke velocity (Vmax) of action potential. By using conventional microelectrode techniques, aprindine-induced reduction of Vmax of action potential and conduction velocity in guinea-pig papillary muscles were measured. Aprindine-produced, use-dependent, and concentration-dependent changes in conduction velocity and the decline of square of conduction velocity was well fit by a single exponential. Time constants for square of conduction velocity were comparable to simultaneously measured time constants for effects of Vmax. At a concentration of 1 to 10 microM aprindine, onset changes between Vmax and conduction velocity had a log-linear relationship in a predicted fashion. Whereas, in the recovery process from aprindine-induced depression, slow recovery time course of conduction velocity was observed. In conclusion, in the presence of aprindine, only onset block of conduction velocity can be analyzed quantitatively in the relationship to observation on Vmax in vitro. These results suggested that in the presence of aprindine, the recovery of internal conductance may be slower than that of Vmax.     

Electrophysiological effects of labetalol on canine atrial, cardiac Purkinje fibres and ventricular muscle.

1. Using conventional microelectrode techniques for the intracellular recordings of the membrane potential, the effects of labetalol were studied on cardiac Purkinje, atrial and ventricular muscle fibres of the dog. 2. Labetalol (1-10 microM) reduced, in a concentration-dependent manner, the action potential amplitude (APA) and the maximum rate of rise of the action potential (Vmax) in Purkinje fibres. 3. The action potential duration (APD) was decreased in Purkinje fibres but significantly increased in ventricular fibres after small concentrations of labetalol (1-3 microM). The atrial fibres were not very sensitive to labetalol. 4. Depolarization of the cardiac Purkinje fibres by increasing the external potassium concentration (8-12 mM), potentiated the labetalol effects on APA and Vmax but blocked its effects on the APD. 5. The effects of labetalol on Vmax of Purkinje fibres were dependent on the frequency of stimulation. 6. The ratio of the effective refractory period to the APD was increased both in normally polarized and depolarized Purkinje fibres after treatment with labetalol (10 microM). 7. Labetalol (10 microM) shifted the membrane responsiveness curve of Purkinje fibres by about 10 mV in the hyperpolarizing direction. 8. The slow response obtained in K-depolarized, Ba-treated Purkinje fibres was not significantly affected by labetalol (10-100 microM). 9. It is suggested that labetalol can exert Class I and Class III antiarrhythmic actions in cardiac muscle of the dog in vitro.     

Electrophysiological mechanisms for the antiarrhythmic action of mexiletine on digitalis-, reperfusion- and reoxygenation-induced arrhythmias.

The antiarrhythmic potency of mexiletine was evaluated on three groups of guinea-pig isolated hearts. Arrhythmias were induced (a) with digitalis intoxication, (b) with hypoxia followed by reoxygenation and (c) with ischaemia followed by reperfusion. Mexiletine 10 microM was found to be very effective against all three types of arrhythmias in all three groups. The electrophysiological effects of mexiletine were then studied on sheep cardiac Purkinje fibres manifesting oscillatory afterpotentials and triggered automaticity induced by barium or strophanthidin. Mexiletine 10 microM consistently decreased the amplitude of oscillatory afterpotentials and blocked subsequent triggered activity in sheep Purkinje fibres. In contrast, mexiletine 10 microM had no significant effect on Vmax in normal, barium- and strophanthidin-treated preparations. The results are discussed in relation to the mechanisms of antiarrhythmic action of mexiletine.     

Sotalol and mexiletine: combination of rate-dependent electrophysiological effects.

The rate-dependent electrophysiological effects of sotalol (30 microM), mexiletine (10 and 18 microM), and their coadministration were examined in isolated dog cardiac Purkinje fibers following abrupt changes in pacing cycle length. Combination of 30 microM sotalol with 10 microM mexiletine significantly lengthened premature action potential durations at diastolic intervals of less than 50 ms while the basic action potential duration evoked at a stimulus frequency of 2 Hz was not affected. This effect on the premature action potential duration was attenuated when the higher mexiletine concentration (18 microM) was coadministered with sotalol. The fast time constant for restitution of the action potential duration was significantly slowed by either combination. Coadministration of sotalol and mexiletine, like mexiletine alone, produced a rate-dependent depression of Vmax that displayed a second slow time component during recovery. This slow component for recovery of Vmax was not distinguished in the absence of drug or in the presence of sotalol alone. Sotalol-induced lengthening of the action potential duration observed at slow pacing frequencies was also attenuated by addition of mexiletine; and, under these conditions, Purkinje fiber early afterdepolarizations were prevented. In addition, the range of premature action potential durations was significantly decreased by mexiletine and by the combination, while sotalol alone increased this range slightly. These results indicate that coadministration of sotalol and mexiletine may provide beneficial electrophysiological effects expected to provide enhanced antiarrhythmic efficacy and fewer proarrhythmic complications in patients.     

Electrophysiologic and antiarrhythmic actions of pirmenol on rabbit and guinea pig cardiac preparations.

The electrophysiological and antiarrhythmic effects of pirmenol HCl were examined using the microelectrode technique applied to multicellular preparations and the suction-pipette whole-cell clamp method applied to ventricular myocytes from rabbit and guinea pig hearts. Pirmenol at 5 microM and higher doses suppressed the sinus node automaticity by depressing the slow diastolic depolarization without changing the maximum diastolic potential. Pirmenol at 1 microM and higher doses depressed the maximum upstroke velocity (Vmax) of action potentials and prolonged the action potential duration at 90% repolarization in atrial muscles and Purkinje fibers without affecting resting membrane potentials. Pirmenol at 5 microM depressed the early part of the plateau and lengthened the final repolarization of the action potentials in ventricular myocytes, of which effects were attributed to the depression of the calcium current and the delayed outward K+ current. Triggered tachyarrhythmias arising from delayed afterdepolarizations in papillary muscles and ventricular myocytes were markedly inhibited by 1-5 microM pirmenol. The drug changed the amplitude and appearance of the transient inward current in ventricular myocytes. These results suggest that pirmenol has electrophysiologic properties that could provide an antiarrhythmic action on various types of arrhythmias.     

Electrophysiologic effects of RS-2135, a new antiarrhythmic compound, on canine Purkinje fibers.

RS-2135 is the (+) isomer of a novel, fused carbazol derivative. The agent, when administered orally, shows long-lasting antiarrhythmic effects in several models of arrhythmia. We used standard microelectrode techniques to characterize the electrophysiological effects of the agent on canine Purkinje fibers. RS-2135 reduced the maximum upstroke velocity of the action potential (Vmax) and shortened the action potential duration (APD) in a concentration-related manner (0.3-3 microM). RS-2135 decreased Vmax at lower concentrations than disopyramide, flecainide, and mexiletine. RS-2135 shortened the effective refractory period (ERP), but significantly increased the ratio of ERP to APD90. Additionally, the effects of the (-) optical isomer of RS-2135 were compared with those of RS-2135, the (+) enantiomer. The (-) isomer was much less potent than RS-2135 in decreasing Vmax. These data suggest that RS-2135 belongs to the class I or "local anesthetic" type of antiarrhythmic agent and that the stereochemistry of the drug molecule is an important determinant of Na channel blocking activity.     

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

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

Inotropic and electrophysiological effects of AB--2, a new antiarrhythmic agent, on isolated cardiac preparations

Effects of AB--2, a compound structurally related to quinidine, on the force of contraction and intracellular potentials were studied in isolated cardiac preparations obtained from guinea pigs, rabbits, cats and dogs. AB--2 in concentrations of 3 and 6 microM increased the force of contraction of both ventricular and atrial muscle. This effect was absent in reserpinized preparations. In concentrations of 24-96 microM, AB--2 induced a concentration-dependent depression of contraction (ED50 approximately equal to 55 microM). Electrophysiological effects consisted of: 1) concentration-dependent reduction of maximum rate of depolarization (Km for guinea pig ventricular and atrial muscles was 72 and 111 microM, resp.) with no change in the resting membrane potential; 2) shortening of action potential duration in ventricular and Purkinje fibers while prolongation in atrial muscle; 3) reduction of pacemaker activity in Purkinje fibers. It is concluded that electrophysiological effects of AB--2 are similar to those of Class I antiarrhythmic agents.     

Inhibition of tetrodotoxin-sensitive plateau sodium current by amiodarone in guinea pig cardiac muscles

1. The acute effects of amiodarone (AM), a potent antiarrhythmic drug, on tetrodotoxin (TTX)-sensitive component of action potentials of Purkinje fibers from guinea pig were studied by use of conventional microelectrode techniques, and compared the findings with the results obtained in the papillary muscle. 2. The present study showed that the action potentials of Purkinje fibers (PF) were more sensitive to AM, compared to those of papillary muscle. 3. Acute exposure (30 min) to 4.4 x 10(-5) M AM led to a depression of plateau potential of PF action potential, but the drug did not affect the total action potential duration. 4. TTX (2-4 x 10(-6) M) shortened the PF action potential duration at all levels of repolarization. 5. The depression of PF plateau potential in the presence of AM was, at least in part, involved in a decrease in TTX-sensitive plateau sodium current, because no further depression of the plateau potential was observed by addition of TTX in the presence of AM.     

Inhibitory effects of forskolin and papaverine on nerve conduction partially blocked by tetrodotoxin in the frog sciatic nerve.

The effects of forskolin, sodium fluoride and papaverine on compound action potentials were investigated in de-sheathed sciatic nerve preparations of the frog. Forskolin decreased in a concentration-dependent manner the amplitude of compound action potentials when nerve conduction was partially blocked by tetrodotoxin (TTX). In the presence of TTX a 50% decrease in the action potential amplitude recorded was obtained with about 2.5 microM forskolin. Sodium fluoride did not modify the amplitude of compound action potentials partially blocked by TTX. Papaverine also decreased the amplitude of compound action potentials partially inhibited by TTX. A 50% decrease in the action potential amplitude recorded in the presence of TTX was obtained with about 10 microM papaverine. The possibility that cyclic AMP modulates axonal excitability by interfering with the entry of sodium through the TTX-sensitive sodium channel is discussed.     

Electrophysiologic properties of UK-66,914, a novel class III antiarrhythmic agent.

A class III antiarrhythmic agent that preferentially increases the effective refractory period without altering conduction velocity holds considerable promise for the treatment of life-threatening cardiac arrhythmias dependent on a reentrant mechanism. In the present study, the cellular electrophysiologic effects of a novel class III antiarrhythmic agent, UK-66,914, were evaluated. UK-66,914 prolonged action potential duration and extended the effective refractory period in isolated canine ventricular muscle and Purkinje fibers in a concentration-dependent manner, beginning at a threshold concentration of 0.1 microM. Analogous effects were found in isolated rabbit atrium beginning at a threshold concentration of 2 microM. At concentrations of UK-66,914 up to 20 microM there was no effect on the maximum rate of phase 0 depolarization (Vmax) or the amplitude of the action potential. In guinea pig papillary muscles. UK-66,914 at concentrations from 0.1 to 20 microM increased the effective refractory period at stimulation frequencies of 1 or 5 Hz, but did not slow conduction velocity. Therefore, UK-66,914 exhibits high selectivity for a class III antiarrhythmic effect in normal tissue. To elucidate the mechanisms responsible for the increase in effective refractory period, voltage clamp procedures were used in guinea pig ventricular myocytes. UK-66,914 reduced the amplitude of outward tail currents following depolarizing clamp steps with little effect either on the background K+ current or calcium currents, indicating that UK-66,914 selectively blocked the time-dependent potassium current. In anesthetized dogs, UK-66,914 (10 micrograms/kg to 1 mg/kg i.v.) prolonged both atrial and ventricular effective refractory periods, but in contrast to the studies performed in vitro, the minimum effective doses required to increase the effective refractory period in atria and ventricle were the same. Therefore, UK-66,914 is a potent selective class III antiarrhythmic agent, which owes its electrophysiologic profile to blockade of the time-dependent potassium current.     

Use-dependent effects of pirmenol on Vmax and conduction in guinea-pig ventricular myocardium.

1. The use-dependent effects of pirmenol, a new antiarrhythmic drug, on the maximal rate of rise (Vmax) of the action potential, conduction velocity, and their corresponding recovery kinetics were studied in isolated papillary muscles of guinea-pig. Standard microelectrode techniques were used to monitor the conduction and action potential characteristics of the muscles. 2. Pirmenol decreased Vmax and the overshoot of action potentials in a dose-dependent fashion. Also, doses of pirmenol greater than 1 mM abolished the generation of action potentials. Low concentrations of pirmenol (3 and 10 microM) prolonged the action potential duration, while concentrations greater than 0.1 mM shortened it markedly. 3. The resting block of Vmax in the presence of 10 and 30 microM pirmenol was 9.48 +/- 3.12 and 20.36 +/- 3.61%, and that of conduction velocity 2.87 +/- 1.52 and 6.58 +/- 2.09%, respectively. 4. The degree of use-dependent block induced by 10 and 30 microM pirmenol during 0.2, 1, 2 and 3 Hz stimulations was dose- and rate-dependent. 5. In the presence of 30 microM pirmenol, mean values of time constants for the onset of the use-dependent inhibition of Vmax and conduction velocity during a 2 Hz stimulation were 1.32 +/- 0.15 and 1.28 +/- 0.09 s, respectively. The recovery time constants averaged 15.83 +/- 2.14 (for Vmax) and 27.80 +/- 8.74 (for conduction velocity) s in the presence of 30 microM pirmenol. 6. These results showed that the characteristics of the use-dependent inhibition of Vmax and conduction velocity induced by pirmenol are similar to those of slow kinetic drugs such as disopyramide rather than of fast ones.     

Cellular electrophysiology of the new antiarrhythmic agent recainam (Wy-42,362) in canine cardiac Purkinje fibers

Recainam, [N-2,6-dimethylphenyl-N'-3-(1-methylethyl-amino)propylurea] hydrochloride (Wy-42,362), is a new class I antiarrhythmic agent that has been shown to be very effective in suppressing premature ventricular contractions in humans. To clarify the mechanism of antiarrhythmic action, the electrophysiologic effects of recainam were examined in canine cardiac Purkinje fibers using standard microelectrode techniques. Recainam at 3-100 microM (1-30 micrograms/ml) produced concentration-dependent decreases in action potential duration (APD), membrane responsiveness, and maximal upstroke velocity (Vmax). The reduction in Vmax was strongly modulated by the frequency of stimulation--i.e., Vmax block was use dependent. The rate of development of use-dependent block produced by recainam was much slower than typically seen with lidocaine, but comparable with that of the class Ia agents disopyramide and procainamide. However, unlike agents of the Ia subclass, recainam did not prolong APD at any concentration or cycle length tested. In summary, recainam appears to possess a novel cardiac cellular electrophysiologic profile, in that it shares characteristics with all three current class I antiarrhythmic subclasses.