Frequency- and voltage-dependent effects of disopyramide in canine Purkinje fibers

The voltage- and frequency-dependent blocking actions of disopyramide were assessed in canine Purkinje fibers within the framework of concentrations, membrane potentials, and heart rates which have relevance to the therapeutic actions of this drug. Vmax was used to assess the magnitude of sodium channel block. Disopyramide produced a concentration- and rate-dependent increase in the magnitude and kinetics of Vmax depression. Effects on activation time (used as an estimate of drug effect on conduction) were exactly analogous to effects on Vmax. A concentration-dependent increase in tonic block was also observed. Despite significant increases in tonic block at more depolarized potentials, rate-dependent block increased only marginally with membrane potential over the range of potentials in which propagated action potentials occur. Increases in extracellular potassium concentration accentuated drug effect on Vmax but attenuated drug effect on action potential duration. Recovery from rate-dependent block followed two exponential processes with time constants of 689 +/- 535 ms and 15.7 +/- 2.7 s. The latter component represents dissociation of drug from its binding site and the former probably represents recovery from slow inactivation. A concentration-dependent increase in the amplitude of the first component suggested that disopyramide may promote slow inactivation. There was less than 5% recovery from block during intervals equivalent to clinical diastole. Thus, depression of beats of all degrees of prematurity was similar to that of basic drive beats. Prolongation of action potential duration by therapeutic concentrations of drug following a long quiescent interval was minimal. However, profound lengthening of action potential duration occurred following washout of drug effect at a time when Vmax depression had reverted to normal, suggesting that binding of disopyramide to potassium channels may not be readily reversed. Variable effects on action potential duration may thus be attributed to a block of the window current flowing during the action potential being partially or over balanced by block of potassium channels. Purkinje fiber refractoriness was prolonged in a frequency-dependent manner. Disopyramide did not significantly alter the effective refractory period of basic beats but did increase the effective refractory period of sequential tightly coupled extra stimuli. The results can account for the antiarrhythmic actions of disopyramide during a rapid tachycardia and prevention of its initiation by programmed electrical stimulation.     

The electrophysiological effects of disopyramide phosphate on canine ventricular muscle and Purkinje fibers in normal and low potassium

We studied the effect of lowering the extracellular potassium concentration ([K+]o) on the electrophysiological actions of disopyramide phosphate, a new antiarrhythmic drug. At low [K+]o, therapeutic concentrations of disopyramide phosphate caused significantly less depression of action potential amplitude and maximum upstroke velocity of both Purkinje fiber and ventricular muscle action potentials. The drug shifted the membrane responsiveness curve along the voltage axis to more negative membrane potentials regardless of [K+]o. However, a greater shift occurred when [K+]o was normal. Disopyramide phosphate prolonged both action potential duration and effective refractory period in all fibers but there was consistently greater prolongation of these parameters at low [K+]o. More importantly, disopyramide phosphate altered repolarization time course of action potentials in such a way that action potentials with dissimilar durations throughout the ventricular conducting system became more equal. The drug was less effective in decreasing this disparity in action potential durations throughout the ventricles in the presence of low [K+]o. These modifications of the electrophysiological actions of disopyramide by low [K+]o suggest that a therapeutic concentration of disopyramide might have less of an antiarrhythmic effect in the presence of hypokalemia.     

An analysis of the direct effect of chloridazepoxide on mammalian cardiac tissues and crayfish and squid giant axons: possible basis of antiarrhythmic activity.

Chlordiazepoxide has been found to be antiarrhythmic $\text{in vivo}$. The purpose of the present investigation is to identify the mechanism(s) of such antiarrhythmic activity. In canine heart, chlordiazepoxide effectively depressed the enhanced repetitive discharges in subendocardial Purkinje fibers surviving acute myocardial infarction. Chlordiazepoxide altered the action potential characteristics of Purkinje fiber by shortening the APD₅₀, APD₁₀₀ and effective refractory period with little effect on the resting membrane potential. The maximal rate of upstroke (dv/dt) was significantly reduced only at 1 × 10^?4M and above in Purkinje fibers and the membrane response curve was consistently shifted to the right by chlordiazepoxide. The ventricular muscle was little affected by chlordiazepoxide except for the shortened APD₅₀ and reduced dv/dt. Chlordiazepoxide exerted nerve blocking potency comparable to lidocaine in the crayfish giant axon. Voltage-clamp experiments in squid axon showed that chlordiazepoxide suppressed both components of membrane current, the transient inward sodium current being diminished far greater than the steady-state potassium current. These results demonstrate a direct action on cardiac and axonal membranes which may be partially responsible for the antiarrhythmic activity of this agent.     

Electrophysiological effects of encainide and its metabolites in normal canine Purkinje fibers and Purkinje fibers surviving infarction

In this study, we assessed the effects of O-demethyl encainide (0.5 microM), the most active metabolite of encainide, and the combination with 3-methoxy-O-demethyl encainide (0.5 microM) and encainide (0.1 microM) on cardiac action potential characteristics in normal canine Purkinje fibers and Purkinje fibers surviving 24 h of myocardial ischemia. O-demethyl encainide decreased Vmax and conduction in normal Purkinje fibers and Purkinje fibers surviving infarction. Further decreases were observed with the combination. Action potential duration at both 50 and 95% repolarization was decreased by O-demethyl encainide. The combination of O-demethyl encainide, 3-methoxy-O-demethyl encainide, and encainide had no further effect. The combination of O-demethyl encainide, 3-methoxy-O-demethyl encainide, and encainide produced a smaller change in effective refractory period than O-demethyl encainide in normal Purkinje fibers and in Purkinje fibers surviving infarction. O-demethyl encainide and the combination shifted the membrane responsiveness curve to more negative potentials in both normal Purkinje fibers and Purkinje fibers surviving infarction. It is apparent from this study that there are differences in the effects of O-demethyl encainide and the combination of O-demethyl encainide, 3-methoxy-O-demethyl encainide, and encainide in normal Purkinje fibers compared with Purkinje fibers surviving infarction. Also, the combination used in this study had different electrophysiological effects than those of O-demethyl encainide alone.     

Persistence of the electrophysiologic effects of mexiletine in canine Purkinje fibers alters the response to subsequent hypoxia

The persistence of cellular electropharmacologic effects of mexiletine on canine Purkinje fibers was studied utilizing standard microelectrode techniques and two different protocols. In the first, the tissue was exposed to hypoxic perfusion before and 30 min after perfusion with one of the following: mexiletine hydrochloride 6.25 microM solution, mexiletine hydrochloride 12.5 microM solution, or drug-free Tyrode's solution. With the higher concentration of mexiletine, depression of the maximal upstroke velocity (Vmax) persisted 30 min after drug washout and subsequent exposure to hypoxia did not result in the anticipated shortening of action potential duration but did prevent the restoration of normal Vmax. After perfusion with the lower concentration of mexiletine, Vmax was not depressed and hypoxic action potential duration shortening was not prevented. In the second protocol, Purkinje fibers were perfused with 12.5 microM mexiletine hydrochloride solution and then exposed to hypoxia after 15, 30, 45, or 60 min of perfusion with drug-free solution. Depression of maximal upstroke velocity and shortening of action potential duration persisted during washout, returning to control values by 45 min, although mexiletine was not detectable in the tissue bath after 10 min of washout. Hypoxia initiated at 15 or 30 min of washout failed to produce the anticipated shortening of action potential duration. At 45 and 60 min, action potential duration was shortened by hypoxia. We concluded that mexiletine depression of Vmax and shortening of action potential duration may persist in the absence of drug. Further shortening of action potential duration in response to hypoxia is prevented during this period. The persistence of Vmax depression is prolonged by hypoxia.     

Electromechanical characterization of the effects of racemic sotalol and its optical isomers on isolated canine ventricular trabecular muscles and Purkinje strands

In both isolated canine ventricular trabecular muscle and Purkinje strand preparations, dl-sotalol and its two optical isomers d- and l-sotalol produced a concentration-dependent increase in action potential duration while other transmembrane electrical characteristics were not significantly affected. The magnitude of the increase in action potential durations was greater in Purkinje strand preparations. In Purkinje strand preparations, the effect was rate dependent (i.e., the increase in duration was proportionately greater when stimulation frequency was slowed). From the concentration of each compound calculated to produce a 50% maximal increase in Purkinje fiber action potential durations, d-sotalol appeared to be one to three times more potent than either l-sotalol or the racemate. Each compound appeared to increase force development in ventricular trabecular muscle preparations stimulated at a frequency of 2 Hz. Increased force development was only observed in Purkinje strand preparations stimulated at slower rates (0.5-0.33 Hz). These results are unlike those produced by other beta-adrenergic blockers and suggest that the antiarrhythmic effects of sotalol are related primarily to its effect of action potential duration. The estimated potency ratios established for the effect of dl-sotalol and its optical isomers on both trabeculae and Purkinje fiber action potential durations (d greater than dl-l) may indicate that these effects are unrelated to the beta-adrenergic blocking properties of these compounds. The differential effect of sotalol on isolated trabeculae and Purkinje strand preparations may help to explain the clinically reported phenomenon of sotalol-induced torsade de pointes.     

Functional and electrophysiological effects of quinacrine on the response of ventricular tissues to hypoxia and reoxygenation

This study examined the effects of quinacrine on the functional and electrophysiological responses of isolated guinea pig hearts and isolated canine papillary muscle and Purkinje fibre preparations. A dose-response relationship for quinacrine (0.01-10.0 micrograms/mL) was studied in isolated guinea pig hearts perfused for 40 min. Quinacrine was found to exert a concentration-dependent negative inotropic effect (1.0 and 10 micrograms/mL); in the presence of the 10 micrograms/mL of the drug, hearts developed contracture, atrioventricular conduction block, and ventricular asystole. In hearts exposed to hypoxia, lactate acidosis, and glucose deprivation and then reoxygenated for 30 min, pretreatment with quinacrine (0.1 microgram/mL) for 15 min prior to the initiation of hypoxia resulted in enhanced recovery of contractile function. Administration of the drug at any other time of the hypoxia-reoxygenation protocol was without effect. However, quinacrine reduced both the incidence and duration of reoxygenation arrhythmias. To examine the possible mechanistic basis for this antiarrhythmic action, isolated canine preparations were exposed to the same conditions and then reoxygenated. Quinacrine (1 microgram/mL) significantly reduced the reoxygenation-associated loss in membrane potential and prevented inexcitability and depolarization-induced automaticity in Purkinje fibres. These results suggest that quinacrine exerts an antiarrhythmic action during reoxygenation and may do so by modifying some potential mechanisms of arrhythmia that occur in the specialized conduction system.     

Reassessment of the electrophysiological effects of the antiarrhythmic agent quinidine in canine Purkinje fibers

Microelectrode techniques were used to re-examine the direct effects of quinidine on isolated canine Purkinje fibers. Our results confirmed the previous findings that quinidine in a dose-related manner suppressed spontaneous activity, prolonged effective refractory period and depressed the maximal rate of upstroke (dv/dt). Quinidine shifted the membrane response curves to the right of the voltage axis regardless of external K⁺ concentrations. The drug diminished the phase 2 plateau of the action potential indicating a possible inhibitory effect on calcium influx. Quinidine generally lengthened the action potential duration (ADP) but the extent of the increase varied with the site of recording along the Purkinje conduction system. The shorter APDs were lengthened far more than the longer APDs, thus dissimilar APDs became more uniform. Following the alteration of external K⁺ between 2 mM and 6 mM, the effects of quinidine on transmembrane characteristics, including the depression of dv/dt, remain constant with the exception of APD.     

Electrophysiological changes induced by lysophosphatidylcholine, an ischaemic phospholipid catabolite, in rabbit atrial and ventricular cardiac cells.

The effects of palmitoyl-lysophosphatidylcholine (LPC) were studied on the cellular electrical activity of rabbit heart preparations. LPC (100 mumol/l) caused a considerable enhancement of the automaticity of the SA nodal and Purkinje fibers and frequently induced irregular firing in both supraventricular (SA node, atrium, AV junction) and ventricular (Purkinje fibers, papillary muscle) myocardial regions. The 'automatotropic' and arrhythmogenic effects of LPC were accompanied by a lengthening of the atrioventricular conduction time. In ventricular muscle fibers LPC (100 mumol/l) decreased the resting potential (RP), the maximum rate of depolarization (Vmax) and the amplitude (APA) and duration (APD) of the action potential, and often evoked action potentials of 'slow response' type. In atrial muscle cells, 100 mumol/l LPC was capable of inducing hyperpolarization, with concomitant increases in RP, Vmax, APA and APD; higher concentrations (300 and 600 mumol/l) of LPC resulted in decreases in RP, Vmax, APA and APD, i.e. phenomena similar to those observed with 100 mumol/l LPC in the ventricular myocardium. The results seem to support the assumption that lysolipids accumulating in the ischaemic myocardium may play a pathogenetic role in the development of both supraventricular and ventricular dysrhythmias accompanying coronary artery occlusion.     

The effects of acidosis and bicarbonate on action potential repolarization in canine cardiac Purkinje fibers

Studies were performed on canine cardiac Purkinje fibers to evaluate the effects of acidosis and bicarbonate (HCO3) on action potential repolarization. Extracellular pH (pHe) was reduced from 7.4 to 6.8 by increasing carbon dioxide (CO2) concentration from 4 to 15% in a HCO3-buffered solution or by NaOH titration in a Hepes-buffered solution. Both types of acidosis produced a slowing of the rate of terminal repolarization (i.e., period of repolarization starting at about -60 mV and ending at the maximum diastolic potential) with an attendant increase in action potential duration of 10--20 ms. This was accompanied by a reduction in the maximum diastolic potential of 2--8 mV. In contrast, if the same pH change was made by keeping CO2 concentration constant and lowering extracellular HCO3 from 23.7 to 6.0 mM, in addition to the slowing of terminal repolarization, the plateau was markedly prolonged resulting in an additional 50- to 80-ms increase in action potential duration. If pHe was held constant at 7.4 and HCO3 reduced from 23.7 mM to 0 (Hepes-buffered solution), the changes in repolarization were nearly identical to those seen in 6.0 mM HCO3 except that terminal repolarization was unchanged. This response was unaltered by doubling the concentration of Hepes. Reducing HCO3 to 12.0 mM produced changes in repolarization of about one-half the magnitude of those in 6.0 mM HCO3. These findings suggest that in Purkinje fibers, HCO3 either acts as a current that slows repolarization or modulates the ionic currents responsible for repolarization.     

Alterations in Extracellular and Tissue Levels of Biogenic Amines in Rat Brain Induced by the Serotonin2 Receptor Antagonist, Ritanserin

Systemic administration of ritanserin elicited rapid changes in dopamine (DA) and serotonin (5-HT) levels in both dialysate and neuronal tissue extracts. These effects occurred in both a site-selective and a dose-related manner. Increases in extracellular levels of DA and 5-HT in the nucleus accumbens were maximal at 120-140 min after treatment. A dose of 0.63 mg/kg of ritanserin elicited larger and more prolonged increases in extracellular DA and 5-HT levels than did the 0.3 mg/kg dose. By contrast, 0.63 mg/kg of ritanserin elicited no changes in either DA or 5-HT levels with dialysate collected from the striatum. Ritanserin also induced dose-related decreases in tissue levels of DA and 5-HT from the nucleus accumbens. The site specificity of action was again noted in that there were no dose-dependent decreases in tissue levels of DA or 5-HT measured from the striatum. Ritanserin exerted little effect on metabolite levels from either dialysate or tissue extracts. Taken together, these findings show that selective 5-HT2 receptor antagonism modulates DA and 5-HT neurotransmission in a specific manner. These actions appear to involve increased release of DA and 5-HT rather than significant changes in metabolism. These findings add further weight to the importance of 5-HT2 receptor interactions as an important component of antipsychotic activity.     

The Electrical Activity of Canine Cardiac Purkinje Fibers in Sodium-Free, Calcium-Rich Solutions

Propagated action potentials can be obtained in canine cardiac Purkinje fibers exposed to Na-free solutions containing no inorganic cation other than Ca and K. Essentially similar action potentials are obtained if Na is replaced by tetraethylammonium (TEA), tetramethylammonium (TMA), or choline. In a solution containing 128 mM TEA and 16.2 mM Ca the characteristics of these electrical responses were: maximum diastolic potential, -59 ± 3.3 mV; overshoot, 20 ± 6.8 mV; maximum upstroke velocity, 3.7 ± 2.3 V/s; conduction velocity, 0.1 m/s; and action potential duration, 360 ± 45 ms. The magnitude of the overshoot varied with log Ca_o with a slope of about 30 mV/10-fold concentration change. The upstroke velocity was an approximately linear function of Ca_o. The active response was greatly diminished or abolished by Mn and D-600 but was unaffected by tetrodotoxin. These Ca-dependent responses appeared in a region of transmembrane potential (about -50 mV) at which the rapid Na-dependent upstroke is abolished even when Na is present.     

Experimental studies on antiarrhythmic and antiseizure effects of polyunsaturated fatty acids in excitable tissues

It has been shown that in animals, and probably in humans, n-3 polyunsaturated fatty acids (PUFAs) are antiarrhythmic. We discuss our recent studies on the antiarrhythmic actions of PUFAs. PUFAs stabilize the electrical activity of isolated cardiac myocytes by requiring a stronger electrical stimulus to elicit an action potential and by markedly prolonging the refractory period. These electrophysiologic effects are the result of specific modulation of ion currents, particularly of the voltage-dependent sodium current and of the L-type calcium currents across sarcolemmal phospholipid membranes. This appears to be the probable major antiarrhythmic mechanism of PUFAs. However, they also similarly affect neuronal ion channels with potentially important functional effects on the nervous system.     

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.     

Effects of hirsutine and dihydrocorynantheine on the action potentials of sino-atrial node, atrium and ventricle

The effects of hirsutine, an indole alkaloid from Uncaria rhynchophylla MIQ. JACKSON with antihypertensive, negative chronotropic and antiarrhythmic activity, and its C3 structural epimer, dihydrocorynantheine, on membrane potentials of rabbit sino-atrial node and guinea-pig right ventricle and left atrium were studied with microelectrode techniques. In sino-atrial node preparations, hirsutine and dihydrocorynantheine (0.1 microM to 10 microM) concentration-dependently increased cycle length, decreased slope of the pacemaker depolarization (phase 4 depolarization), decreased maximum rate of rise and prolonged action potential duration. In atrial and ventricular preparations, both compounds (0.1 microM to 30 microM) concentration-dependently decreased maximum rate of rise and prolonged action potential duration. These results indicate that hirsutine and dihydrocorynantheine have direct effects on the action potential of cardiac muscle through inhibition of multiple ion channels, which may explain their negative chronotropic and antiarrhythmic activity.     

Strophanthidin inotropy in cardiac Purkinje fibers under conditions that vary cellular sodium or calcium

The role of sodium and calcium on strophanthidin inotropy was studied in canine cardiac Purkinje fibers perfused in vitro under conditions that vary cellular sodium and calcium. With high concentrations of strophanthidin (greater than or equal to 10(-7) M), force increases more in the presence of low [Ca]0 or high [Na]0 and less in the presence of a low sodium-calcium concentration solution than in Tyrode solution. In a solution with a low concentration of sodium-calcium containing strophanthidin, restoring [Na]0 to normal decreases and then re-increases force: when [Na]0 is decreased again, the force transiently overshoots. These effects of strophanthidin are exaggerated by metabolic inhibitors. In a low [Ca] solution, low concentrations of strophanthidin (3 X 10(-8) or 5 X 10(-8) M) re-increase force a little or not at all. On recovery, the transient force increase is not exaggerated by low strophanthidin and is absent after manganese exposure. The inotropy of low concentrations of strophanthidin is potentiated by norepinephrine, high [Ca]0 (4 mM), or by lowering [Na]0. Thus, the present results suggest that the inotropic action of high strophanthidin concentrations depends primarily on sodium and secondarily on calcium, and that the inotropic action of low concentrations of strophanthidin involves a modification of the cell response to calcium.     

Expression of skeletal muscle Na(V)1.4 Na channel isoform in canine cardiac Purkinje myocytes

BACKGROUND AND AIM: The action potential plateau of Purkinje fibers is particularly sensitive to tetrodotoxin (TTX) and this could be due to a TXX-sensitive Na(+) current. The expression of TTX-sensitive neuronal Na(V)1.1 and Na(V)1.2 isoforms has been reported in canine Purkinje myocytes. Our aim was to investigate by means of biochemical and functional techniques whether the TTX-sensitive skeletal Na(V)1.4 isoform is also expressed in canine cardiac Purkinje myocytes. METHODS AND RESULTS: Using Na(V)1.4 specific primers, a PCR product corresponding to Na(V)1.4 was amplified from canine Purkinje fibers RNA and confirmed by sequencing and megablast of the gene bank. Confocal indirect immunostaining using anti-Na(V)1.4 antibody demonstrates distinct sarcolemmal staining pattern compared to that of the cardiac isoform Na(V)1.5. Expression of Na(V)1.4 in tsA201 cells yielded a TTX-sensitive Na(+) current with an IC(50) of 10nM. CONCLUSIONS: These results demonstrate the expression of the TTX-sensitive Na(V)1.4 channel in canine cardiac Purkinje myocytes. This novel finding suggests a role of Na(V)1.4 channel in Purkinje myocytes and thus has important clinical implications for the mechanisms and management of ventricular arrhythmias originating in the Purkinje network.     

Arrhythmic effects of norepinephrine in a model of cardiac ischemia and reperfusion

The aim of this study was to assess the direct effects of norepinephrine on mechanisms of arrhythmia induced by conditions of ischemia followed by reperfusion. Isolated canine Purkinje fiber-papillary muscle preparations were studied using standard microelectrode techniques. Tissues were superfused for 40 min with a solution simulating "ischemia" (i.e., hypoxic, acidotic, elevated lactate, and zero substrate) and then "reperfused" for 60 min. Ischemia produced a moderate loss of membrane potential in both tissues. Reperfusion resulted in rapid polarization of the tissues, which was accompanied by oscillatory afterpotentials and aftercontractions in 6 of 12 and 4 of 12 Purkinje fibers, respectively. This was followed by a progressive loss of membrane potential and inexcitability in Purkinje fibers. Recovery was associated with activity resembling depolarization-induced automaticity in 4 of 12 fibers. Addition of norepinephrine (0.5 microM) to the ischemic and reperfusion solutions altered primarily the reperfusion responses. Oscillatory afterpotentials and aftercontractions were larger and occurred in 8 of 8 and 6 of 8 Purkinje fibers, respectively. Norepinephrine also prevented or blunted the progressive depolarization to inexcitability in Purkinje tissues and increased automaticity occurring at low (depolarization-induced automaticity) and more polarized membrane potentials (enhanced normal pacemaker activity). This study demonstrates that norepinephrine exacerbates several potential mechanisms of arrhythmia elicited by reperfusion in canine Purkinje tissues.     

Activity of the climbing fiber innervating various Purkinje cells

Low-amplitude potentials (10-130 microV) related to the action of a distant branch of the climbing fiber, which elicits complex spikes of the reference Purkinje cell were revealed by means of potential averaging synchronously with complex spikes of Purkinje cells in 10 out of 255 paired records of cerebellar Purkinje cells activity and extracellular field potentials at interelectrode distances of 200-1500 microns. These potential waves had a stable form in independent sets of data. In 3 out of 10 cases, the low-amplitude potentials included a slow (about 100 ms in duration) component. In one case, both test and reference electrodes recorded both simple and complex spikes of different Purkinje cells so that complex spikes of both cells were practically synchronous (conditional probability of complex spikes p = 0.97, onset time difference 0.54 ms). Thus for the first time in cerebellar physiology both simple and complex spikes activity of two Purkinje cells controlled by the same climbing fiber was recorded.     

Cardiac electrophysiologic effects of adaprolol maleate, a new beta-blocker, in closed chest dogs.

Adaprolol maleate (adaprolol) is a new beta-adrenergic receptor blocker. The cardiac electrophysiologic characteristics and the duration of action of adaprolol were studied in intact anesthetized dogs. The electrophysiologic parameters were evaluated before drug administration and 10 min after the administration of maintenance infusion of adaprolol (N = 5). The duration of action was measured during constant infusion of isoproterenol, giving the adaprolol as a single i.v. bolus in different concentrations (N = 5). Results of this study showed that adaprolol has marked electrophysiologic effects. Its major action was on sinus node; it prolonged the basic sinus cycle length and had significant effect on intrinsic automaticity as reflected by the prolonged corrected sinus node recovery time and sinuatrial conduction time. There was, also, direct effect on atrial function and AV nodal function. Adaprolol prolonged the effective refractory period of the His-Purkinje system and the ventricle. The onset of action was very rapid (within seconds) and the duration of action was relatively prolonged (3 hrs). The potency of adaprolol's electrophysiologic effects are higher compared to other widely used beta-blockers. Adaprolol appears to be a potent beta-blocker with particularly strong antiarrhythmic effect and it would be very useful in the treatment of both supraventricular and ventricular tachyarrhythmias and ectopic beats.