Electrophysiological and antiarrhythmic actions of tocainide in isolated heart preparations of the guinea pig

Comparison of the action of tocainide in guinea pig atrial and ventricular myocardium has led to the following results: Tocainide effects a similar increase in threshold of alternating current induced arrhythmias in spontaneously beating right atria as well as stimulated left atria and papillary muscles. APD30 and APD90 (action potential duration at 30 and 90% repolarization) are decreased by tocainide in papillary muscles, especially at a low stimulation rate, but increased in left atria. On the other hand, maximum upstroke velocity of the action potential (Vmax) is decreased at a high stimulation rate (use-dependence) in both tissues. These effects are completely reversed by washing with drug-free solution within 15 min in papillary muscles and 60 min in left atria, respectively. Resting state block of Na-channels by tocainide occurs in left atria to a small degree (10-20%), but is negligible in ventricular myocardium. Recovery of Vmax following stimulus-induced inactivation is delayed by tocainide in papillary muscles and left atria. Functional refractory period is increased in left atria and in papillary muscles by tocainide. In the concentration range above 75 mumol/l the concentration response curve reaches a plateau in papillary muscles but shows a further steep increase in left atria. Quantitative analysis of the dynamic Na-channel blockade by tocainide in atrial myocardium using the modulated receptor hypothesis suggests that the drug shows a high affinity to activated and a low affinity to inactivated Na-channels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Electrophysiologic effects of TYB-3823, a new antiarrhythmic agent, on isolated guinea pig ventricular muscles

The effects of a newly synthesized antiarrhythmic agent, TYB-3823 on the transmembrane action potential were examined in isolated papillary muscles of guinea pig. TYB-3823 (3 x 10(-6)-3 x 10(-5)M) caused a dose-dependent decrease in the maximum upstroke velocity (Vmax) and a shortening of action potential duration (APD). In the presence of TYB-3823, trains of stimuli at rates greater than or equal to 0.2 Hz led to an exponential decline in Vmax. This use-dependent block was enhanced at higher stimulation frequency. The time constant for the recovery of Vmax from the use-dependent block was 12.6-13.4 s. The curves relating membrane potential and Vmax were shifted by TYB-3823 (3 x 10(-5)M) to the direction of more negative potentials (5.7 mV). In preparations treated with TYB-3823 (10(-5)-3 x 10(-5) M), the Vmax of test action potentials preceded by conditioning clamp pulses to 0 mV was progressively decreased by increasing the duration of a single clamp pulse or by increasing the number of multiple brief clamp pulses. These findings suggest that TYB-3823 has use- and voltage-dependent inhibitory action on the fast sodium channel by binding to the channel during its activated and inactivated states, and that the unbinding rate of the drug from the channel is very slow. Such characteristics of sodium channel block in combination with APD shortening effect would provide unique antiarrhythmic activities of this substance.     

Electrophysiological effects of ivabradine in dog and human cardiac preparations: potential antiarrhythmic actions

Ivabradine is a novel antianginal agent which inhibits the pacemaker current. The effects of ivabradine on maximum rate of depolarization (V_max), repolarization and spontaneous depolarization have not yet been reported in human isolated cardiac preparations. The same applies to large animals close to human in heart size and spontaneous frequency. Using microelectrode technique action potential characteristics and by applying patch-clamp technique ionic currents were studied. Ivabradine exerted concentration-dependent (0.1–10 μM) decrease in the amplitude of spontaneous diastolic depolarization and reduction in spontaneous rate of firing of action potentials and produced a concentration- and frequency-dependent V_max block in dog Purkinje fibers while action potential duration measured at 50% of repolarization was shortened. In the presence of ivabradine, at 400 ms cycle length, V_max block developed with an onset kinetic rate constant of 13.9 ± 3.2 beat⁻¹ in dog ventricular muscle. In addition to a fast recovery of V_max from inactivation (τ = 41–46 ms) observed in control, a second slow component for recovery of V_max was expressed (offset kinetics of V_max block) having a time constant of 8.76 ± 1.34 s. In dog after attenuation of the repolarization reserve ivabradine moderately but significantly lengthened the repolarization. In human, significant prolongation of repolarization was only observed at 10 μM ivabradine. Ivabradine in addition to the Class V antiarrhythmic effect also has Class I/C and Class III antiarrhythmic properties, which can be advantageous in the treatment of patients with ischemic heart disease liable to disturbances of cardiac rhythm.     

Cardiac effects of amrinone on rabbit papillary muscle and guinea pig Langendorff heart preparations

Amrinone (50-1,000 microgram/ml) produces a dose-dependent inotropic action on rabbit papillary muscle. The hypodynamic state following prolonged stimulation is prevented or abolished by amrinone, and contractile force remains significantly elevated over drug-free controls throughout the ensuing 3-h duration of exposure. In a concentration of 1 mg/ml, dysrhythmic phenomena occasionally appeared, e.g., bigeminy, automaticity, and elevated threshold to electrical stimulation. Bigeminy could be abolished either by increasing the external K+ concentration in the bathing media, or by raising the stimulating voltage. However, amrinone failed to alter the refractory period following 60 min of exposure. In isolated perfused guinea pig Langendorff heart preparations, amrinone (50 microgram/ml) significantly increased coronary flow, myocardial oxygen consumption (MVO2), cardiac work, and, during the period of peak activity, dP/dt. However, it had no significant effect on cardiac efficiency. And, as in the papillary muscle preparation, the effect of amrinone was easily reversed by perfusing the preparation with fresh (no-drug) media. Preliminary evidence shows that amrinone fails to reverse the negative inotropic action of verapamil as well as calcium-free media, although the effects on heart rate, coronary flow, and MVO2 were reversed. However, the higher the external calcium concentration, the greater was the level of contractile response achieved by amrinone. Thus, the mechanism of amrinone-induced augmentation appears to be dependent upon the availability of calcium.     

Electrophysiologic effects of nicainoprol, a putative class I antiarrhythmic agent, on the guinea pig ventricular papillary muscle

We examined the effects of nicainoprol (1-50 microM), a new antiarrhythmic agent, on the transmembrane action potentials in isolated papillary muscles of the guinea pig. Nicainoprol (greater than or equal to 5 microM) produced dose-dependent decreases in the maximal upstroke velocity (Vmax) of the action potential. Only the highest concentration (50 microM) decreased the amplitude and the overshoot of the action potential and shortened its duration at 50 or 90% repolarization levels (APD50, APD90). The potential at rest was not affected by any concentration tested (1-50 microM). In the presence of nicainoprol, trains of stimuli at the rate of 0.2, 0.5, 1.0, and 2.0 Hz, introduced after a sufficient period of rest, led to an exponential decay of the Vmax to the steady state levels (use-dependent block, UDB). The UDB was augmented with an increase in the stimulation frequency or with a decrease in the potentials at rest. The time constant for the recovery from the UDB was 51.6 +/- 9.4 s at 50 microM. The Vmax and the amplitude of the slow response elicited in the presence of 27 mM [K+]o and 0.2 mM Ba2+ was significantly decreased by application of nicainoprol (10-100 microM), with a significant shortening of APD50 (100 microM). These findings suggest that nicainoprol has electrophysiologic properties in common with those of other class I antiarrhythmic drugs with slow kinetics (Ic) and has a minor but significant inhibitory effect on slow inward current (class IV effect).     

Electrophysiologic and antiarrhythmic actions of sulphinpyrazone and its sulfide metabolite G25671

In anesthetized dogs, the cumulative intravenous administration of 1.0-40.0 mg/kg sulphinpyrazone failed to alter the ventricular excitation threshold, ventricular refractory period and ventricular fibrillation threshold determined during nonobstructed coronary blood flow. Sulphinpyrazone, however, did attenuate the reduction in the ventricular fibrillation threshold occurring during transient myocardial ischemia. G25671, the sulfide metabolite of sulphinpyrazone, failed to alter ventricular refractoriness and 'nonischemic' ventricular fibrillation thresholds, and was minimally effective in reducing the decrease in 'ischemic' fibrillation thresholds when administered in cumulative intravenous doses of 5.0-20.0 mg/kg. In conscious dogs in the subacute phase of anterior myocardial infarction, the administration of a cumulative 10.0-40.0 mg/kg sulphinpyrazone failed to alter the mode of induction, rate or morphology of ventricular tachyarrhythmias initiated by programmed ventricular stimulation. These data suggest that neither sulphinpyrazone nor its sulfide metabolite possess primary electrophysiologic properties which might contribute directly to significant antiarrhythmic or antifibrillatory activity.     

IHC-66对豚鼠心肌细胞电生理特性的影响

目的：为进一步研究ＩＨＣ－６６抗心律失常作用的电生理机制。方法：采用细胞内微电极技术，研究了ＩＨＣ－６６对豚鼠心肌细胞电活动的影响。结果：ＩＨＣ－６６可缩短心室肌细胞动作电位复极５０％时程（ＡＤＰ５０），大剂量时降低动作电位零相最大上升速率。但可延长心房肌细胞动作电位时程。对Ｃｄ２＋影响下的心室肌细胞电活动的作用较对Ｍｎ２＋影响下的电活动更为显著。但对乌头碱（ａｃｏｎｉｔｉｎｅ，ＡＣ）诱发的异常电活动无明显对抗作用。结论：ＩＨＣ－６６对豚鼠心肌细胞电生理的作用与其影响了Ｃａ２＋、Ｎａ＋、Ｋ＋的跨膜转运有关。     

依那普利对离体豚鼠乳头状肌的电生理作用

目的：研究依那普利（Ｅｎａ）对豚鼠乳头状肌电生理特性，哇巴因诱发的延迟后除极（ＤＡＤ）和触发电活动（ＴＡ）的直接作用方法与结果，采用标准玻璃微电极技术记录豚鼠乳头状肌动作电位，Ｅｎａ呈浓度依赖性增加静息膜电位（ＲＰ）和动作电位幅度（ＡＰＡ），而对０期最大除极，超射，和动作电位时程无明显影响Ｅｎａ１０μｍｏｌ．Ｌ＾－１则可明显抑制哇巴因０．５μｍｏｌ．Ｌ＾－１则可明显抑制哇巴因０．５μｍｏｌ．Ｌ＾－     

Electrophysiologic actions of aprindine in rabbit atrioventricular node

Summary Aprindine hydrochloride is a potent antiarrhythmic agent against various atrial and ventricular tachyarrhythmias. To elucidate its pharmacological actions in the atrioventricular node, electrophysiologic experiments were conducted by applying microelectrode and voltage clamp methods to small preparations of the rabbit atrioventricular node.At a concentration 1 mol/l, aprindine decreased the spontaneous firing frequency, maximal rate of depolarization, action potential amplitude, and take-off potential (P < 0.05, n = 7). The spontaneous and rate-controlled action potential durations at 50 and 100% repolarization were prolonged by aprindine. Voltage-clamp experiments using the double microelectrode method revealed that aprindine blocked the slow inward current (I_si) in a voltage-dependent manner with a dissociation constant of 10 mol/l and Hill coefficient of 0.8. The steady-state inactivation curve for I_si was shifted toward more negative potentials by 2.5 ± 0.9 mV (P < 0.05, n = 5) without a significant change in the slope factor. This finding suggests that aprindine has a higher affinity for inactivated slow inward (or Ca²⁺) channels than for resting channels. Aprindine caused use-dependent block of I_si, a result consistent with the drug's slow dissociation from inactivated Ca²⁺ channels. The delayed rectifying K⁺ current (I_K) tail obtained on repolarization from +10 mV to –60 mV was significantly decreased from 15.4 ± 2.4 to 6.8 ± 1.4 nA (P < 0.01, n = 6) and the deactivation time constant significantly increased by 20.7% (P < 0.01, n = 6). The steady-state activation curve for I_K was shifted in the hyperpolarized direction by 6.9 ± 2.9 mV, suggesting a potent voltage-dependent block of this current by aprindine. The hyperpolarization-activated inward current (1_h) was decreased from 14.4 ± 5.4 to 12.0 ± 5.5 nA (P < 0.05, n = 5). The transient outward and inward currents induced by 1 mol/l acetylstrophanthidin were almost completely suppressed after the addition of 1 mol/l aprindine.These results suggest that aprindine exerts a negative chronotropic action both by slowing deactivation of I_K and by reducing Is; and Ih, and delays atrioventricular nodal conduction by reducing Is; and IK. These blocking actions of aprindine together with its inhibition of the transient outward and inward currents may explain its antiarrhythmic effects on the atrioventricular node. Send offprint requests to Yoshio Watanabe at the above address     

Possible mechanisms for inotropic actions of vanadate in isolated guinea pig and rat heart preparations

Summary The mechanism of inotropic actions of vanadate was studied in isolated, electrically stimulated atrial and ventricular muscle preparations of rat or guinea-pig heart. Vanadate produced a negative inotropic effect in guinea-pig left atrial preparations associated with a marked shortening of the action potential plateau. In guinea-pig papillary muscle, or rat atrial or ventricular muscle preparations, vanadate produced a positive inotropic effect, which was not affected by either propranolol, phentolamine or metiamide. The positive inotropic effect was observed when action potential duration was either increased or decreased. Inotropic concentrations of vanadate failed to significantly alter the ouabain-sensitive ⁸⁶Rb⁺-uptake, an estimate of sodium pump activity, or tissue concentration of cyclic AMP in electrically stimulated preparations. In partially depolarized rat atrial preparations in which fast sodium channels were inactivated in the presence of a high concentration of K⁺ (22 mmol/l), vanadate restored electrical activity (calcium-dependent action potentials) and the contraction, similar to isoproterenol. This action of vanadate was abolished by Mn²⁺, a slow channel inhibitor, but not by tetrodotoxin. The characteristic of vanadate- and isoproterenol-restored preparations, however, were substantially different. Moreover, vanadate failed to restore the contraction or action potential in partially depolarized guinea pig atrial preparations unlike isoproterenol. These results indicate that vanadate may either enhance or inhibit slow channels in cardiac muscle.     

Electrophysiologic effects of sophocarpine on papillary muscle in guinea pig

Sophocarpine prolonged the action potential duration of guinea pig papillary muscle in a dose-dependent manner. After the preparations were exposed to sophocarpine 50 mumol/L for 30 min, APD50 and APD90 were prolonged from 189 +/- 21 and 216 +/- 24 ms to 205 +/- 27 and 241 +/- 25 ms (P less than 0.01). Simultaneously, ERP was prolonged from 202 +/- 14 to 211 +/- 16 ms, although the ERP/APD90 ratio was not changed. Sophocarpine had no significant effects on other AP parameters. Propranolol did not block sophocarpine effects.     

Electrophysiological properties of a new antiarrhythmic agent,bisaramil on guinea-pig,rabbit and canine cardiac preparations

Electrophysiological effects of bisaramil, a novel antiarrhythmic agent, were examined using the conventional microelectrode technique applied to cardiac multicellular preparations from guinea-pigs, rabbits and dogs and the whole-cell patch-clamp technique applied to guinea-pig ventricular myocytes. Bisaramil at 10(-6) M or higher concentrations produced a dose-dependent decrease in the maximum rate of rise (Vmax) of action potentials of guinea-pig papillary muscles without changes in resting membrane potentials. In the presence of bisaramil, trains of stimuli at rates greater than 0.1 Hz led to the use-dependent block of Vmax, which was enhanced at higher frequencies. At a concentration of 3 x 10(-6) M, the degree of use-dependent block was about 35% at 3.3 Hz, of which degree was comparable to those of 10(-4) M disopyramide and lidocaine. The development of Vmax block by bisaramil was expressed by a single exponential function in the same manner as flecainide, whereas the time courses of the block development by disopyramide and lidocaine were described by two exponentials. Recovery time constants from Vmax block were 44.1 +/- 3.4 s and 20.3 +/- 2.3 s for bisaramil and flecainide, respectively. Bisaramil at 10(-6) and 3 x 10(6) M did not change the action potential duration of guinea-pig papillary muscles and rabbit atrial muscles with a significant reduction of Vmax. No change in action potential duration can be explained by depression of both the Ca2+ and the delayed outward K+ currents by bisaramil. On the other hand, 10(-6) M bisaramil shortened action potential duration of canine Purkinje fibers at 50% and 90% of repolarization.(ABSTRACT TRUNCATED AT 250 WORDS)     

Electrophysiologic characterization of dronedarone in guinea pig ventricular cells

The electrophysiological properties of dronedarone (SR33589), a noniodinated amiodarone-like agent, were studied on action potential (AP) and contraction of papillary muscle and on membrane ionic currents, Ca2+ transient, and shortening of ventricular cells of the guinea pig heart. In multicellular preparations, dronedarone (3, 10, and 30 microM) decreased maximum rate of rise of AP (dV/dt max) with a concentration- and frequency-dependent relationship; resting potential was not modified and AP amplitude was decreased only at 30 microM. The effects of dronedarone on AP durations (APDs) at different percentages of repolarization were not significantly changed, except for a slight decrease in APD30 and APD50 at the highest concentration. In isolated ventricular myocytes, dronedarone inhibited rapidly activating delayed-rectifier K+ current (I(Kr)) (median inhibitory concentration [IC50] /= 30 microM). Dronedarone blocked L-type Ca2+ current (I(Ca(L))) (IC50 = 0.18 +/- 0.018 microM at a stimulation frequency of 0.033 Hz) in a use- and frequency-dependent manner. Simultaneously to these electrophysiological effects, dronedarone reduced contraction amplitudes of papillary muscle and decreased Ca2+ transient and shortening of ventricular myocytes. The results show that dronedarone is a multichannel blocker because it decreases dV/dt max (I(Na)), I(Ca(L)), I(Kr), I(Ks), and I(K1). These effects are accompanied by a reduction in free intracellular calcium and contraction amplitudes. Dronedarone does not significantly change APD whatever the stimulation frequency. Our data demonstrate that the acute electrophysiological characteristics of dronedarone, despite absence of iodine in its molecular structure, are very similar to those of amiodarone in cardiac ventricle.     

Electrophysiologic effect of dipfluzine on guinea pig papillary muscles in vitro

用细胞内微电极技术记录正常和部分除极豚鼠乳头肌动作电位,研究双苯氟嗪（３－３０μｍｏｌ·Ｌ－１）对豚鼠乳头肌细胞电生理的影响．结果表明,双苯氟嗪轻度缩短正常乳头肌动作电位的平台期（ＰＰＤ）,５０％和９０％复极化时程（ＡＰＤ５０和ＡＰＤ９０）,但对静息电位（ＲＰ）,动作电位幅度（ＡＰＡ）,超射（ＯＳ）和０相最大上升速率（Ｖｍａｘ）均无显著影响．在高Ｋ＋部分去极化的豚鼠乳头肌标本,双苯氟嗪可轻度降低慢反应动作电位的ＯＳ,ＡＰＡ和Ｖｍａｘ,并缩短ＰＰＤ,ＡＰＤ５０和ＡＰＤ９０,对ＲＰ同样无显著影响．在相同浓度下,双苯氟嗪对离体豚鼠乳头肌动作电位的影响与氟桂利嗪无显著差别．提示双苯氟嗪在较高浓度时,可轻度缩短豚鼠乳头肌的复极过程及降低部分除极乳头肌的ＯＳ,ＡＰＡ和Ｖｍａｘ．     

Electrophysiologic effect of enalapril on guinea pig papillary muscles in vitro

目的：研究依那普利（Ｅｎａ）对豚鼠乳头状肌电生理特性，哇巴因诱发的延迟后除极（ＤＡＤ）和触发电活动（ＴＡ）的直接作用．方法与结果：采用标准玻璃微电极技术记录豚鼠乳头状肌动作电位．Ｅｎａ呈浓度依赖性增加静息膜电位（ＲＰ）和动作电位幅度（ＡＰＡ），而对０期最大除极，超射，和动作电位时程无明显影响．Ｅｎａ１０μｍｏｌ·Ｌ－１则可明显抑制哇巴因０５μｍｏｌ·Ｌ－１诱发的ＤＡＤ和ＴＡ，ＤＡＤ幅度分别由５３±２３，５９±２８，７４±２１和８９±１３降至２６±０７，３１±１０，３７±１５和５３±１１（ｍＶ）（Ｐ均＜００１），刺激周长为２００ｍｓ时ＴＡ数目由３６±０７降至０８±０２（Ｐ＜００５）．结论：Ｅｎａ通过增加心肌细胞ＲＰ和ＡＰＡ抑制哇巴因诱发豚鼠乳头状肌ＤＡＤ和ＴＡ．     

双苯氟嗪在体外对离体豚鼠乳头肌电生理的影响

用细胞内微电极技术记录正常和部分除极豚鼠乳头肌动作电位, 研究双苯氟嗪(3-30 μmol· L^-1)对豚鼠乳头肌细胞电生理的影响. 结果表明,双苯氟嗪轻度缩短正常乳头肌动作电位的平台期(PPD), 50%和90%复极化时程(APD₅₀和APD₉₀),但对静息电位(RP),动作电位幅度(APA),超射(OS) 和 0 相最大上升速率(V_max)均无显著影响.在高K+部分去极化的豚鼠乳头肌标本, 双苯氟嗪可轻度降低慢反应动作电位的OS,APA和V_max,并缩短PPD, APD₅₀和APD₉₀, 对RP同样无显著影响. 在相同浓度下, 双苯氟嗪对离体豚鼠乳头肌动作电位的影响与氟桂利嗪无显著差别.提示双苯氟嗪在较高浓度时,可轻度缩短豚鼠乳头肌的复极过程及降低部分除极乳头肌的OS, APA和V_max.     

Electrophysiological actions of a new antiarrhythmic drug, bisaramil, on isolated heart preparations.

Electrophysiological effects of bisaramil--a new antiarrhythmic drug under clinical trial--were investigated on isolated heart preparations, at a concentration range of 2.3-23 x 10(-6) M. Bisaramil dose dependently decreased the maximum rate of depolarization (Vmax), action potential amplitude (APA) and overshoot (OS) both in auricle and in papillary muscle of guinea-pig heart. There was no significant and obvious effect on the duration of the action potential and the resting membrane potential was also unchanged. Bisaramil slowed the spontaneous frequency of pacemaker cells in rabbit sinus node preparation due to its inhibitory effect on slow diastolic depolarization (SDD). Bisaramil was able to inhibit slow Ca(2+)-action potentials induced by isoprenaline on K(+)-depolarized papillary muscle. Results obtained with transmembrane current measurements revealed that bisaramil inhibited both fast Na(+)-current and slow Ca(2+)-current in frog sinoauricular fibres at the same concentration. Bisaramil with a mixed mode of the action seems to be a very promising drug.     

Electrophysiologic effects of a novel Ca antagonist, SA2572, in isolated rabbit and guinea pig hearts

Cardiac effects of SA2572, a newly synthesized Ca antagonist, were evaluated in guinea pig and rabbit hearts with electrophysiologic technique. SA2572(10(-6)-10(-5) M) decreased the upstroke velocity (Vmax) and the duration of the action potential (APD30) in guinea pig papillary muscles in a concentration- and frequency-dependent manner without affecting the resting potential. The slow responses (high K+ + isoproterenol) were suppressed by SA2572 at 10(-6) M. In rabbit sinus node, SA2572(10(-7)-5 x 10(-6) M) caused a concentration-dependent decrease in the amplitude and Vmax of the action potential and tended to prolong the spontaneous cycle length. In Langendorff-perfused rabbit hearts electrically driven at 2 Hz, SA2572(5 x 10(-8)-10(-6) M) produced concentration-dependent prolongations of the atrio-His bundle conduction time (A-H interval) and the His bundle-ventricular conduction time (H-V interval) concomitantly with a reduction of the developed tension of the ventricular muscle. These effects of SA2572 on the A-H and H-V intervals were more pronounced at higher stimulation frequency. Enantiospecificity was observed in these actions of SA2572, (-)-isomer of SA2572 having more potent inhibitory effects on slow channel-dependent than on fast channel-dependent phenomena. These results indicate that SA2572 has characteristics of both slow and fast channel blockers, and that these inhibitory effects are frequency dependent.