Lengthening Of Action Potential Duration Research Articles

Investigation of the mechanism by which ketanserin prolongs the duration of the cardiac action potential.

Action potential duration (APD) lengthening is believed to underlie the cardiac arrhythmogenicity of ketanserin, a serotonin (5-HT)2A/2C receptor antagonist. We wished to determine (a) whether this activity involves blockade of 5-HT2A/2C receptors and (b) the precise mechanism of ketanserin-induced APD prolongation. APs were recorded in guinea pig isolated papillary muscles by conventional "floating" microelectrodes, and potassium currents in guinea pig isolated myocytes were recorded in the whole-cell configuration. Ketanserin (1-10 microM) increased APD (EC50 value for enhancing APD at 90% repolarization (APD90) 3.1 +/- 2.7 microM, n = 24), without affecting resting potential, maximum upstroke velocity (Vmax) or AP amplitude (APA). Pirenperone (10 microM), a ketanserin congener, similarly increased APD90 from 204 +/- 3 to 241 +/- 7 ms (p < 0.001, n = 6). No increase in APD was observed, however, with ritanserin or ICI 170809, even at high concentrations (10 microM, n = 6, respectively), two 5-HT2A/2C receptor antagonists chemically distinct from ketanserin, thereby excluding the involvement of 5-HT2A/2C receptors in mediating APD lengthening. That APD prolongation was mediated specifically by the benzolyl-piperidine moiety of ketanserin and pirenperone was confirmed by 1-propyl-4(4-fluorobenzoyl)piperidine (PFBP), which evoked APD lengthening effects remarkably similar to those produced by ketanserin and pirenperone (EC50 3.73 +/- 2.6 microM, n = 12). In isolated cardiomyocytes, ketanserin (1-32 microM) selectively and concentration-dependently reduced the IKr component of the delayed outward current (IK) without affecting the inward rectifier current, IK1. Thus, ketanserin (32 microM) significantly reduced IK at a potential value of -20 mV from 813 +/- 65 to 569 +/- 55 pA (p < 0.001, n = 6), whereas at a potential value of -110 mV, IK1 was not significantly affected (730 +/- 103 vs. 603 +/- 143 pA, respectively; n=6). The results demonstrate that APD is prolonged by ketanserin and congeners but not be chemically different 5-HT2A/2C receptor antagonists. The benzoyl-piperidine moiety appears to mediate the APD-prolonging effects of ketanserin and pirenperone specifically. Furthermore, ketanserin-induced APD lengthening does not appear to involve 5-HT2A/2C receptors but is consecutive to direct blockade of myocardial potassium channels.

Diazoxide blocks the morphine induced lengthening of action potential duration on guinea-pig papillary muscle

1. 1. Intracellular microelectrodes were used to evaluate the possible involvement of potassium currents in the action potential prolongation induced by morphine. To this purpose we investigated the electrophysiological effect of morphine on the isolated guinea pig right ventricular papillary muscle in the presence of the potassium channel opener and inhibitor diazoxide and glibenclamide respectively. 2. 2. Diazoxide (1 μM), which is devoid of effect on its own, blocks the lengthening of action potential duration (APD) induced by morphine (5 mM). 3. 3. However, in the presence of glibenclamide (1 μM), morphine (5 mM) prolonged APD in approximately the same proportion as that observed when used alone. 4. 4. These results suggest that diazoxide but not glibenclamide sensitive potassium channels could mediate the APD prolongation induced by morphine.

Cellular electrophysiological aspects of myocardial protection

Oxygen radicals (OR) generated at the time of reflow of the ischaemic myocardium may cause ‘reperfusion injury’. To protect myocardium from this injury, it is important to understand how OR cause their deleterious effects on myocytes. Here we describe the basic electrophysiological alterations caused by OR in patch-clamped ventricular myocytes isolated from the rat heart. Oxygen radicals generated by dihydroxyfumarate (DHF) caused a lengthening of action potential duration (APD) and the appearance of arrhythmogenic alterations such as early and delayed afterdepolarizations. Prolongation of APD was accompanied by a reduction in calcium and potassium currents. When intracellular calcium levels were kept constantly low by 5001μM EGTA in the pipette solution, the effects of DHF on action potential duration and the occurrence of early after depolarizations were largely prevented. It is concluded that exposure to OR may induce electrophysiological alterations in isolated myocytes. They are related to changes in specific ionic currents and in levels of intracellular calcium.

Increased dispersion of ventricular repolarization and ventricular tachyarrhythmias in the globally ischaemic rabbit heart

Contemporary concepts of ischaemic ventricular tachyarrhythmias (VTA) are based on increased electrophysiological heterogeneity of the myocardium. We developed a multi-site monophasic action potential recording system for an isolated rabbit heart to study the effects of global ischaemia on the electrophysiological properties at different ventricular sites simultaneously. The hearts were paced from the right ventricle (RV), and conduction time (CT), action potential duration (APD) and total repolarization time (TRT = [CT + APD]) were measured during normal perfusion and ischaemia. The dispersion of these parameters was calculated as the maximal difference between simultaneous recordings. Inducibility of VTA by programmed extrastimulation (ES) was investigated under normal and ischaemic conditions. During global ischaemia, CT increased progressively, showing a faster and greater increase at the left ventricle (LV) than at the RV. After 10 min the prolongation of CT reached a plateau at the LV while it continued to rise in the RV. The dispersion of CT increased from 14.5 +/- 2.7 ms during normal perfusion to a maximum of 79.8 +/- 17.2 ms after 14 min of ischaemia (P < 0.0001). APD was uniform at the three sites (190.9 +/- 10.2, 185.0 +/- 8.6 and 179.3 +/- 9.8 ms, ns) during normal perfusion but changed non-uniformly during ischaemia. There was a transient lengthening of APD until 1 and 3 min of ischaemia at the LV sites followed by a rapid shortening of APD. At the RV site, APD continued to increase until 5 min of ischaemia and then shortened gradually. Consequently, dispersion of APD showed a rapid initial rise from 17.7 +/- 2.7 ms to 77.8 +/- 10.2 ms (P < 0.0001) followed by a slower final increase. TRT was uniform during normal perfusion (210.4 +/- 10.3, 213.1 +/- 7.8, 212.1 +/- 10.3 ms, ns) but became non-uniform during global ischaemia. The dispersion of TRT increased from 15.4 +/- 4.2 ms to 92.6 +/- 23.2 ms (P < 0.0001) during 14 min of global ischaemia. Both CT and APD contributed independently to TRT and could either augment or partially compensate for the ischaemic alterations of the other parameter. ES induced VTA only during ischaemia (3.7 +/- 1.1 VTA per heart, P < 0.0001) at coupling intervals between 220 and 380 ms. The dispersion of TRT of the last regular beat preceding VTA was 67.7 +/- 17.4 ms (P < 0.001). ES which triggered VTA showed a more than two-fold increase of CT dispersion compared to the last steady state beat (122.7 +/- 29.4%, P = 0.0001).(ABSTRACT TRUNCATED AT 400 WORDS)

Increased dispersion of ventricular repolarization and ventricular tachyarrhythmias in the globally ischaemic rabbit heart

Contemporary concepts of ischaemic ventricular tachyarrhythmias (VTA) are based on increased electrophysiological heterogeneity of the myocardium. We developed a multi-site monophasic action potential recording system for an isolated rabbit heart to study the effects of global ischaemia on the electrophysiological properties at different ventricular sites simultaneously. The hearts were paced from the right ventricle (RV) andconduction time (CT), action potential duration (APD) and total repolarization time (TRT= [CT + APD]) were measured during normal perfusion and ischaemia. The dispersion of these parameters was calculated as the maximal difference between simultaneous recordings. Inducibility of VTA by programmed extrastimulation (ES) was investigated under normal and ischaemic conditions. During global ischaemia, CT increased progressivey showing a faster and greater increase at the left ventricle (LV) than at the RV. After 10 min the prolongation of CT reached a plateau at the LV while it continued to rise in the RV. The dispersion of CT increased from 14 ± 2.7 ms during normal perfusion to a maximum of 79.8 ± 17.2 ms after 14 min of ischaemnia (P<00001). APD was uniform at the three sites (190.9±02, 185.0 and 179.3±9.8 ms, ns) during normal perfusion but changed non-uniformly during ischaemia. There was a transient lengthening of APD until 1 and 3 min of ischaemia at the LV sites followed by a rapid shortening of APD. At the RV site, APD continued to increase until 5 min of ischaemia and then shortened gradually. Consequently, dispersion of APD showed a rapid initial rise from 177.8 ± 2.7 ms to 77.8 ± 10 ms (P<0.0001) followed by a slower final increase. TRT was uniform during normal perfusion (210.4 ± 10.3, 213.1±7.8, 212.1±10.3 ms, ns) but became non-uniform during global ischaemia. The dispersion of TRT increased from 15.4±4.2 ms to 92.6 ± 23.2 ms (P<0.0001) during 14 min of global ischaemia. Both CT and APD contributed independently to TRT and could either augment or partially compensate for the ischaemic alterations of the other parameter. ES induced VTA only during ischaemia (3.7±1.1 VTA per heart, P<0.0001) at coupling intervals between 220 and 380 ms. The dispersion of TRT of the last regular beat preceding VTA was 67.7±17.4 ms (P<0.001). ES which triggered VTA showed a more than two-fold increase of CT dispersion compared to the last steady state beat (122.7±29.4%, P = 0.0001). The present results show that global ischaemia results in considerable electrophysiologic heterogeneity in the intact heart. These changes may be regarded as a suitable basis of VTA, induced by ES.

Electromechanical action of dofetilide and D-sotalol during simulated metabolic acidosis in isolated guinea pig ventricular muscle.

We examined the electromechanical effects of two class III antiarrhythmic agents, dofetilide (UK-68,798) and D-sotalol, in acidic myocardium. Right ventricular papillary muscle preparations isolated from guinea pigs were divided into three groups (n = 6 per group): (a) drug-free, (b) dofetilide (10 nM), and (c) D-sotalol (30 microM). At normal extracellular pH (pH = 7.32 +/- 0.01), dofetilide and D-sotalol lengthened action potential duration (APD) to a similar extent, i.e., by 18-20%. Effective refractory period (ERP) increased in parallel, whereas membrane diastolic potential (MDP), action potential amplitude (APA), maximum velocity of depolarization (Vmax), and developed force (DF) were not significantly affected. Metabolic acidosis (pH = 6.78 +/- 0.01) was simulated by reducing the bicarbonate concentration of the Tyrode's solution from 20 to 6 mM. Superfusion with acidic solution alone for 30 min markedly decreased Vmax and DF, whereas APD and ERP were lengthened slightly. The acidosis-induced decreases in Vmax and DF were not affected by pretreatment with dofetilide or D-sotalol. In acidic superfusate, both agents still significantly increased APD and ERP to the same extent that they did at normal pH. The results indicate that metabolic acidosis, a major component of myocardial ischemia, does not attenuate the class III antiarrhythmic action of dofetilide and D-sotalol.

Prolonged propionyl-L-carnitine pre-treatment of rabbit: Biochemical, hemodynamic and electrophysiological effects on myocardium

Recently it has been reported that prolonged treatment with propionyl- l-carnitine, a carnitine derivative, results in a positive inotropic effect. To gain further insight into its mode of action, we pre-treated 253 rabbits for up to 10 days with daily doses of 1 mmol/kg propionyl- l-carnitine or l-carnitine intraperitoneally, using saline-treated animals as control. Twenty-four hours after the last injection, we isolated papillary muscles for electrophysiological investigations. Whole hearts were used in perfusion experiments for biochemical and hemodynamic measurements. In addition, mitochondria were harvested from these hearts for the analysis of their function. Plasma and cardiac levels of free carnitine, along with plasma short-chain acylcarnitines, increased at least two-fold after treatment with carnitine or its propionyl-ester, with concomitant rises in tissue long-chain acylcarnitine and long-chain acyl-CoA. At the time of animal sacrifice, treatment did not increase plasma or tissue propionyl- l-carnitine content. The studies carried out with perfused hearts and isolated mitochondria failed to show an effect of propionyl- l-carnitine pre-treatment on high-energy phosphate metabolism or respiration. Papillary muscles from animals, treated for 10 days, showed a lengthening of the action potential duration from 63 ± 4 to 102 ± 6 ms ( P<0.001) at −10 mV. Perfused hearts from these rabbits displayed positive inotropy, as indicated by an improved pressure development at higher ventricular filling volumes, e.g., from 39 ± 4 to 60 ± 3 mmHg ( P<0.05) at 3.6 ml. Pre-treatment with l-carnitine or saline failed to affect the electrophysiological and hemodynamic variables. Thus, prolonged treatment of rabbits with propionyl- l-carnitine, but not with l-carnitine, improved contractility and lengthened action potential duration in isolated muscle preparations.

Comparative Frequency-Dependent Effects of Three Class Ic Agents, Org 7797, F]ecanide, and Proprafenone, on ventricular Action Potential Duration

The frequency-dependent electrophysiological effects of three class Ic agents, Org 7797 (0.5-5 microM), flecainide (1-20 microM), and propafenone (1-10 microM), were investigated using isolated guinea pig papillary muscle. Transmembrane cellular action potentials were recorded using conventional microelectrode techniques at driving frequencies of 0.3, 1.0, and 2.0 Hz. In concentrations inducing similar frequency-dependent decreases in Vmax, both flecainide and propafenone shortened action potential duration (APD) at the two lower stimulation frequencies, whereas increasing the driving frequency to 2 Hz attenuated drug-induced APD shortening. In contrast, Org 7797 did not shorten APD at any stimulation frequency, and indeed APD lengthening was observed at 2.0 Hz. Increases in the effective refractory period (ERP) were seen at 1.0 and 2.0 Hz in the presence of Org 7797 and at 2.0 Hz in the presence of flecainide, but ERP was either unchanged (2.0 Hz) or shortened by propafenone. The rate of onset of sodium channel block was faster in response to propafenone compared to Org 7797 and flecainide. It was concluded that all three drugs may inhibit outward repolarising potassium currents, especially at higher stimulation frequencies. However, the concentrations of Org 7797 necessary to influence repolarisation may be closer to those required to induce sodium channel block compared to flecainide and especially propafenone. These differences may influence drug-induced effects on wavelength resulting in differences in antifibrillatory efficacy.

Rate and concentration‐dependent effects of UK‐68,798, a potent new class III antiarrhythmic, on canine Purkinje fibre action potential duration and Vmax

1. The frequency-dependent electrophysiological effects of UK-68,798 in concentrations of 1, 3, 10 and 30 nM were examined in isolated cardiac Purkinje fibres of the dog at both a number of constant rates of stimulation and following abrupt changes in pacing cycle length. 2. In all concentrations evaluated, UK-68,798 lengthened action potential duration in a concentration- and rate-dependent manner (e.g., at a cycle length = 500 ms, control APD90 = 234.0 +/- 3.3 ms, while after 10 nM UK-68,798, APD90 = 315.0 +/- 5.9 ms). 3. The duration of action potentials evoked following abrupt changes in pacing rate were also increased in a concentration-dependent manner at all diastolic intervals tested. 4. The fast and slow time constants for restitution of APD were not altered by UK-68,798. However, the amplitude terms for this relation were increased. 5. In addition, the maximum upstroke velocity (Vmax) was not significantly affected by exposure to UK-68,798 at any concentration or diastolic interval. The kinetics for recovery of Vmax were thus unaffected. 6. These findings are similar to those previously reported for recognized class III antiarrhythmic agents (e.g., bretylium, clofilium, and sotalol); however, UK-68,798 was 1,000 to 10,000 times more potent. 7. The combined potency and selectivity of this agent seem to make it an ideal tool for the investigation of cardiac potassium channels believed responsible for controlling the duration of the action potential. 8. This potent and highly selective compound may prove extremely useful in the control of cardiac arrhythmias.

Developmental Cellular Electrophysiologic Effects of d-Sotalol on Canine Cardiac Purkinje Fibers

d-Sotalol may be a clinically useful class III antiarrhythmic agent for controlling ventricular arrhythmias in children. Because age-related differences in repolarization currents may contribute to developmental differences in response to antiarrhythmic agents that primarily affect repolarization, the electrophysiologic effects of d-sotalol were compared in Purkinje fibers from neonatal and adult dogs. Significant age-related changes characterized the antiarrhythmic profile of d-sotalol. d-Sotalol (10(-4) M) significantly prolonged the action potential duration of adult Purkinje fibers (310 +/- 8 to 380 +/- 7 ms, p less than 0.01) and neonatal fibers (247 +/- 5 to 342 +/- 9 ms, p less than 0.01). However, the lengthening of action potential duration was significantly greater in the immature age group. d-Sotalol had no significant effect on maximum diastolic potential, action potential amplitude, or phase zero upstroke velocity in normally polarized fibers. In contrast, different electrophysiologic effects were observed in K(+)-depolarized Purkinje fibers. Superfusion of adult K(+)-depolarized fibers with d-sotalol suppressed excitability in five (38%) of 13 fibers and significantly decreased action potential amplitude (88 +/- 2 to 83 +/- 1 mV, p less than 0.05) and phase zero upstroke velocity (180 +/- 14 to 105 +/- 3 V/s, p less than 0.01) in the other eight fibers. The membrane depressant effects observed in the younger age group were significantly less [no suppression of excitability and a smaller decrease in phase zero upstroke velocity (121 +/- 22 to 101 +/- 23 V/s, p less than 0.05). The magnitude of action potential duration prolongation by d-sotalol in K(+)-depolarized fibers was less than in normally polarized fibers.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterisation of decay of frequency induced potentiation and post-extrasystolic potentiation

The aim was to elucidate the processes underlying the beat by beat decay of frequency induced and post-extrasystolic potentiation. The ventricular pacing protocol consisted of a "priming period" followed by a "decay" period of pacing at 1 s intervals, characterised by a decaying potentiation of left ventricular (LV) dP/dtmax; these were identified as test beats 1,2,3,4,5. The magnitude of potentiation of test beat 1 (P1) was increased both by increased priming frequency (frequency potentiation) and by alternately shorter priming intervals (paired pulse stimulation) at a given average frequency (post-extrasystolic potentiation). The exponential decay constant (P2) and the asymptotic value (P3) were determined and compared with the measured values and with the slope of the linear relationship between the contractility of one beat and that of the preceding beat. The lowest values after decay were related to the magnitude of preceding potentiation. Six anaesthetised dogs with induced heart block and beta adrenergic blockade were used. Beat to beat interval was controlled by ventricular pacing from a programmable stimulator. Contractility of each beat was assessed from maximum rate of rise of LV pressure (LVdP/dtmax) obtained from an intraventricular micromanometer. The asymptotic value of the exponential fit to the decay of potentiation (P3) was found to be below the measured nadir value, which was followed by an increase in LVdP/dtmax to the final steady state value P4. The decay constant (P2) was found to be equivalent to the natural logarithm of the slope of the linear relationship between the contractility of one beat and that of the preceding beat; it was unaffected by priming frequency or interval at a given average priming frequency. The asymptote P3 was inversely related to P1. P1 was interpreted as the expression of accumulation of activator in an internal release store; P3 was interpreted as a manifestation of negative feedback control of activator entry by the released activator itself, and the slow recovery to P4 as due to the slow lengthening of action potential duration and/or recovery from accumulation of an intracellular metabolite or ion.

Influence of electrogenic Na/Ca exchange on the action potential in human heart muscle

The plateau of the action potential in heart muscle is largely due to the inward Ca2+ current, ica; however, Ca2+ extrusion via Na+/Ca2+ exchange may also generate a significant current, ina/ca. The aim was to assess the influence of ina/ca on the action potential in isolated human heart muscle. Action potentials and force of isometric contractions were recorded in ventricular trabeculae. The muscle was subjected to various stimulus patterns, Ca2+ antagonists, and variations in the ionic composition of the extracellular medium. From 49 patients, aged 0.5 to 14 years, small right ventricular trabeculae were obtained during open heart surgery. The operations concerned corrections of ventricular septal defects. Data presented in this paper were from nine preparations in which action potentials were recorded during several hours. The results confirmed that: (1) the amplitude of the early part of the plateau was depressed by low [Ca2+] and by Ca2+ antagonists, showing that ica dominates this early part; and (2) that low [Na2+] and post-extrasystolic potentiation also depressed the early component of the plateau of the action potential, which can be explained by inactivation of ica due to increased levels of intracellular Ca2+. A novel observation was that post-extrasystolic potentiation led to an increase in action potential duration (APD). An explanation is that the potentiated contraction follows from an increased amount of intracellular Ca2+ which also activates an inward current, possibly ina/ca. This assumption is strengthened by the finding that lengthening of APD after extrasystoles was abolished: (a) at low [Ca2+], ie, when force was small and there was little Ca2+ to be extruded; and (b) at low [Na+], ie, when force was large but the driving force of the Na+ gradient for extrusion of Ca2+ was small. The early part of the plateau is dominated by ica, whereas ina/ca is relatively more important during the later part, and tends to lengthen the action potential.

Passive electrical properties, mechanical activity, and extracellular potassium in arterially perfused and ischemic rabbit ventricular muscle. Effects of calcium entry blockade or hypocalcemia.

The relation among passive electrical resistive properties, longitudinal conduction velocity, extracellular potassium concentration, [K+]o, and mechanical activity was investigated in the isolated rabbit papillary muscle during normal arterial perfusion and no-flow ischemia in the presence and absence of verapamil, or a reduced extracellular Ca2+ concentration [Ca2+]o. During normal arterial perfusion, verapamil (0.5 microM, free [Ca2+]o = 1.0 mM) and hypocalcemic blood perfusate (free [Ca2+]o = 0.4 mM) reduced the maximal isometric twitch tension by 48% and 78%, depolarized the resting membrane by +3 and +7 mV, decreased the extracellular longitudinal resistance (ro) by 15% and 26%, and increased conduction velocity by 4% and 6%, respectively. The changes in conduction velocity during these interventions were consistent with those predicted by linear cable theory (+3% and +9%) for the observed changes in ro. In contrast, verapamil shortened whereas a reduced [Ca2+]o lengthened action potential duration. Comparison of simultaneously measured longitudinal whole tissue resistance (rt), intracellular longitudinal resistance (ri), [K+]o, and resting tension during ischemia showed a close association between abrupt cell-to-cell electrical uncoupling, development of ischemic contracture, and the secondary rise of [K+]o, which all started to develop after approximately 15 minutes of ischemia. Electrical cell-to-cell uncoupling was completed within 15 minutes. In the presence of verapamil, the relation among the onset of electrical cell-to-cell uncoupling, secondary rise of [K+]o, and onset of ischemic contracture in ischemia was qualitatively the same as in its absence; however, these events were postponed by approximately 10 minutes, and the rates of contracture development and uncoupling were diminished. Conduction velocity decreased after 12 minutes of ischemia from 54 to 36 cm/sec in the absence of and from 61 to 46 cm/sec in the presence of verapamil. This slowing effect on impulse conduction could not be attributed to changes of electrical cell-to-cell coupling because at this time an increase in ri had not yet taken place. In the presence of a reduced [Ca2+]o, the resting tension and ri increased almost immediately after the onset of ischemia. Although the resting tension rose progressively throughout the course of ischemia, the ri showed a biphasic increase characterized by an early transient increase that reached a peak at 8 minutes (+87%) and a second, irreversible increase beginning at approximately 12 minutes. This final onset of electrical cell-to-cell uncoupling and the secondary rise of [K+]o were not different from the findings with a normal [Ca2+]o.(ABSTRACT TRUNCATED AT 400 WORDS)

Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence.

With regard to currently available class III agents, although their class III effect may reduce the likelihood of tachycardia initiation, their reverse use-dependent prolongation of action potential duration reduces their effectiveness during tachycardias and may even render them proarrhythmic, especially after long diastolic intervals. In contrast, agents that exhibit normal use-dependent prolongation of refractoriness hold great promise: While having relatively less effects on the normal heart beat, they could induce self-termination of a tachycardia. Prolongation of refractoriness can be achieved by lengthening of action potential duration and delaying recovery of excitability. Combination of these drug actions may yield important clinical applications.

The combined electrophysiological effects of lignocaine and sotalol in canine isolated cardiac Purkinje fibres are rate‐dependent

1. The frequency-dependent electrophysiological effects of lignocaine, sotalol, and their combination were studied in dog isolated cardiac Purkinje fibres, both at various constant rates of stimulation and following abrupt changes in pacing cycle length. 2. The combined effect of 18 microM lignocaine and 30 microM sotalol selectively lengthened duration of premature action potentials evoked at a diastolic interval of 40 ms (from 172.2 +/- 5.4 to 201.7 +/- 4.9 ms, n = 6, P less than 0.01) without significantly changing the durations of action potentials evoked at the basic cycle length of 500 ms (259.1 +/- 7.7 vs 251.9 +/- 3.9 ms, n = 11). 3. The combination of lignocaine with sotalol, like lignocaine alone, displayed a use-dependent depression of Vmax and revealed a slow component for a recovery of Vmax (tau = 173.5 +/- 16.0 ms, n = 5). 4. The kinetics for restitution of action potential duration were also slowed by the combination of the two dwo drugs (tau f = 173.6 +/- 16.7, before, vs 268.5 +/- 8.5 ms, after; n = 5, P less than 0.01), while the maximum action potential duration attained in this relation was not increased as it was by sotalol alone. 5. Lignocaine, therefore, appeared to inhibit the sotalol-induced lengthening of action potential duration at slow pacing rates and at long diastolic intervals. The combination of lignocaine with sotalol also completely abolished the occurrence of sotalol-induced early after depolarizations. 6. Finally, sotalol alone moderately increased the range of premature action potential durations, while the combination of the two drugs significantly decreased this parameter. 7. These findings indicate that the combination of lignocaine with sotalol may provide important, and unique, beneficial electrophysiological alterations that might be expected to provide enhanced antiarrhythmic efficacy in patients.

Effect of Altered Repolarization Course Induced by Antiarrhythmic Drugs and Constant Current Pulses on Duration of Premature Action Potentials in Canine Cardiac Purkinje Fibers

The purpose of this study was to elucidate the mechanism of the upward shift of the electrical restitution curve, i.e., the lengthening of premature action potential duration (APDt) expressed as percentage of basic APD, induced by class I antiarrhythmic drugs in dog Purkinje fibers. In this study, six class I antiarrhythmic drugs lengthened APDt at a diastolic interval of 20 ms by 2.5-14.1%. The drugs also decreased the ratio of APD at 50% to APD at 90% of repolarization from 70.8 +/- 1.8% (n = 60) to 47.4-60.8%. The relation between the decrease in the ratio of APD50 to APD90 of the basic AP and lengthening of the normalized APDt was linear (r = 0.92; p less than 0.01). We attributed the lengthening of normalized APDt to the decreased ratio of APD50 to APD90, and applied repolarizing current pulses in short (less than or equal to 2 mm) fibers to simulate the drug-induced decrease in the ratio of APD50 to APD90. The altered repolarization course of basic AP by the current pulse during late plateau and early phase 3 caused APDt lengthening. The relation between the current-induced decrease in the ratio of APD50 to APD90 of the basic AP and the lengthening of normalized APDt was linear (r = 0.91; p less than 0.01). The slope of regression line describing this relation was similar to that in the presence of drugs. These results suggest that lengthening of the normalized APDt by class I antiarrhythmic drugs results from a more rapid repolarization during phase 2 of the preceding basic AP, possibly due to lesser influence of the delayed outward rectifying current. The lengthening of APDt by class I drugs may contribute to their antiarrhythmic action.

Cardiac Electrophysiologic Effects of Fentanyl and Sufentanil in Canine Cardiac Purkinje Fibers

The electrophysiologic effects of high concentrations of the opioid agonists, fentanyl and sufentanil, on isolated canine cardiac Purkinje fibers were studied. Changes in action potential parameters were examined at the following concentrations: fentanyl 94.6 nM, 0.19 microM, and 0.95 microM; sufentanil 8.6 nM, 86.4 nM, 0.17 microM, and 0.26 microM. Naloxone 5.5 microM was administered after maximal changes were induced by fentanyl in order to explore the possibility of an opioid receptor interaction. Action potential parameters measured were Vmax of phase 0, amplitude, overshoot, maximum diastolic potential, action potential duration at 50%, and 90% repolarization and membrane responsiveness. Fentanyl 0.19 microM and sufentanil-0.17 microM caused a significant lengthening of action potential duration at 50 and 90% repolarization, 6.4% and 7.3%, and 10.2% and 12.4%, respectively, P less than 0.05. Other action potential parameters were not significantly affected by the opioids. Naloxone 5.5 microM alone did not alter action potential characteristics and failed to reverse action potential prolongation produced by fentanyl. The authors suggest that fentanyl and sufentanil prolong action potential duration in canine cardiac Purkinje fibers via direct membrane actions.

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.

Effects of propafenone on electrical and mechanical activities of single ventricular myocytes isolated from guinea-pig hearts.

1. The effects of propafenone on the transmembrane action potential and sarcomere shortening during twitch contraction were investigated in single ventricular myocytes isolated from guinea-pig hearts. 2. Propafenone at low concentrations (3-5 x 10(-7) M) slightly lengthened action potential duration (APD), but shortened it at higher concentrations. The shortening of APD was accompanied by an attenuation of sarcomere shortening during twitch contraction. 3. Propafenone (greater than 10(-6) M) caused a concentration-dependent decrease in the maximum upstroke velocity (Vmax) of the action potential. In the presence of propafenone (3 x 10(-6) M), trains of stimuli led to an exponential decline in Vmax. A time constant for the recovery of Vmax from the use-dependent block was 4.8 s. 4. In myocytes treated with propafenone (3 x 10(-6) M), the Vmax of test action potentials preceded by the conditioning clamp pulses to 0 mV was progressively decreased by increasing the duration of single clamp pulse or by increasing the number of multiple brief clamp pulses. 5. These findings suggest that propafenone has use-dependent inhibitory action on the sodium channel by binding to the channel during both activated and inactivated states, and that the unbinding rate is comparable to that of Class-I antiarrhythmic drugs with intermediate kinetics. Propafenone may also have an inhibitory action on calcium and potassium channels.

The role of potassium and sodium-calcium exchange currents in the action potential durations of normal Purkinje fibres and Purkinje fibres surviving infarction

Ventricular arrhythmias following myocardial infarction may originate from subendocardial Purkinje fibres in the infarcted area. The role of potassium and sodium-calcium exchange currents on action potential duration was therefore investigated in Purkinje fibres surviving infarction and in normal Purkinje fibres. Barium was used to reduce potassium conductance and replacement of sodium chloride by lithium chloride was used to reduce the sodium-calcium exchange current. Barium (1 x 10(-5) to 3 x 10(-5) M) produced a concentration dependent lengthening of action potential duration in normal Purkinje fibres but these concentrations had no effect in Purkinje fibres surviving infarction. The resting membrane potential, activation voltage, amplitude and Vmax were decreased in Purkinje fibres surviving infarction and in barium treated fibres v normal Purkinje fibres. These results show that action potential characteristics of barium treated normal Purkinje fibres closely resemble those seen in Purkinje fibres surviving infarction. A similar reduction of action potential duration was seen in normal Purkinje fibres, fibres surviving infarction and barium treated fibres when the sodium "window" current was decreased by lignocaine. Without any effect on the Vmax, the replacement of sodium chloride by lithium chloride resulted in a similar effect on the action potential duration in normal Purkinje fibres and fibres surviving infarction. The results show that the longer action potential duration found in Purkinje fibres surviving infarction can be explained by a decrease of the potassium conductance and not by an increase of the sodium "window" current or the sodium-calcium exchange current.