Atria selective prolongation by NIP-142, an antiarrhythmic agent, of refractory period and action potential duration in guinea pig myocardium

NIP-142 is a novel benzopyran compound that was shown to prolong the atrial effective refractory period and terminate experimental atrial fibrillation in the dog. In the present study, we examined the effects of NIP-142 on isolated guinea pig myocardium and on the G-protein-coupled inwardly rectifying potassium channel current (acetylcholine-activated potassium current; I(KACh)) expressed in Xenopus oocytes. NIP-142 (10 and 100 microM) concentration-dependently prolonged the refractory period and action potential duration in the atrium but not in the ventricle. E-4031 and 4-aminopyridine prolonged action potential duration in both left atrium and right ventricle. Prolongation by NIP-142 of the atrial action potential duration was observed at stimulation frequencies between 0.5 and 5 Hz. In contrast, the prolongation by E-4031 was not observed at higher frequencies. Tertiapin, a blocker of I(KACh), prolonged action potential duration in the atrium but not in the ventricle. NIP-142 completely reversed the carbachol-induced shortening of atrial action potential duration. NIP-142 (1 to 100 microM), as well as tertiapin (0.1 to 100 nM), concentration-dependently blocked I(KACh) expressed in Xenopus oocytes; the blockade by NIP-142 was not affected by membrane voltage. In conclusion, NIP-142 was shown to prolong atrial refractory period and action potential duration through blockade of I(KACh) which may possibly explain its previously described antiarrhythmic activity. NIP-142 has pharmacological properties that are different from classical class III antiarrhythmic agents such as atria specificity and lack of reverse frequency dependence, and thus appears promising for the treatment of supraventricular arrhythmia.     

Electrophysiologic and antiarrhythmic effects of carocainide in humans

Electrophysiologic and antiarrhythmic effects of the new benzofurane derivative carocainide given intravenously have been studied in normal patients (Group I) and in patients with paroxysmal supraventricular tachycardias (Group II). In normal patients (n = 10), carocainide increased sinoatrial conduction time, PR, PA, AH, and HV interval, QRS duration, as well as QT and QTc intervals. Sinus rate and sinus node recovery time were not influenced and refractory periods of right atrium, AV node, and right ventricle were unchanged. Like class I-C antiarrhythmic drugs, carocainide causes an increase of QRS duration without significant lengthening of the QT interval. In patients of Group II (n = 12), the ability of carocainide to interrupt supraventricular reentrant tachycardia was studied. In 11 of 12 patients (11 patients with regular atrioventricular reentrant tachycardia incorporating an accessory pathway, one patient with AV node reentry), sustained tachycardia was stopped by intravenous injection of carocainide in a dose of 3.5 mg/kg body weight. No major adverse effects were seen during or after administration of the drug. Carocainide was effective in the short-term treatment of supraventricular tachycardias. Further studies must show whether these promising effects can also be obtained during long-term oral treatment.     

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.     

Effects of the new class III antiarrhythmic drug E-4031 on myocardial contractility and electrophysiological parameters.

The effects of the new class III antiarrhythmic agent E-4031 were investigated in different guinea pig cardiac preparations. In left atria, E-4031 (10(-8)-10(-5) M) prolonged the functional refractory period up to 45% and reduced the frequency of spontaneously beating right atria by 32%. In papillary muscles, E-4031 (3 x 10(-8)-3 x 10(-7) M) reversibly prolonged the action potential duration (APD70) of fast and slow APs by 68 and 51%, respectively. Vmax, resting potential, and AP amplitude (APA) were not altered. In isolated ventricular myocytes, E-4031 reversibly prolonged the APD90 from 275 ms (control) to 1,496 ms (10(-6) M), pD2 value 6.5. The current changes that underlie the AP-prolonging effect were also studied in ventricular myocytes: in concentrations up to 10(-5) M), E-4031 did not affect the Na+ or Ca2+ inward current but reduced the delayed rectifier (IK) tail current by 76% (10(-7) M). Contractility was enhanced by E-4031 in isolated atria by 20% (3 x 10(-7) M) and increased cell shortening in ventricular myocytes. Thus, the class III antiarrhythmic action of E-4031 is due to a selective reduction of outward currents.     

Electrophysiologic effects and efficacy of cibenzoline in patients with supraventricular tachycardia.

Electrophysiologic effects of intravenous (i.v.) cibenzoline were evaluated in 18 patients with accessory pathways or dual atrioventricular (AV) nodal pathways (12 men and 6 women with a mean age of 44 +/- 18 years). Twelve patients had accessory AV pathways, including 6 patients with a manifest accessory pathway. Six patients had AV nodal reentrant tachycardia (AVNRT). Electrophysiologic studies were performed before and after cibenzoline (1.4 mg/kg i.v.) infusion for 5 min. Sinus cycle length did not change significantly after cibenzoline administration. Cibenzoline increased both the AH (85 +/- 20 vs. 91 +/- 21 ms, p less than 0.05) and HV intervals (41 +/- 10 ms vs. 53 +/- 11 ms, p less than 0.001). Neither the atrial nor ventricular effective refractory period (ERP) was altered by cibenzoline. Complete block in the accessory pathway occurred antegradely in 4 patients and retrogradely in 1 patient. Cibenzoline prevented induction of AV reentrant tachycardia (AVRT) in 3 of 8 patients with sustained orthodromic AVRT by abolishing retrograde accessory pathway conduction or prolonging the retrograde accessory pathway ERP. Of 5 patients who continued to have inducible AVRT before and after cibenzoline administration, the tachycardia cycle length was increased in 3, mainly due to the increase in retrograde accessory pathway conduction time. Cibenzoline prevented induction of sustained AVNRT in 4 of 5 patients by prolonging the minimum pacing cycle length, maintaining 1:1 ventriculoatrial (VA) conduction through the retrograde fast AVN pathway or shortening the antegrade fast AVN pathway ERP equal to the slow AVN pathway. In one patient who had an uncommon type of AVNRT, sustained tachycardia was induced by cibenzoline.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of pentisomide and E-4031 on canine atrial flutter due to reentry: a comparative study with disopyramide and propafenone.

Effects of new antiarrhythmic drugs, pentisomide [3.5 +/- 0.5 mg/kg intravenously (i.v.) n = 8], and E-4031 (5.6 +/- 1.0 micrograms/kg, n = 8), a class III drug, on atrial flutter (AF) caused by reentry were compared with those of disopyramide (1.6 +/- 0.2 mg/kg, n = 8) and propafenone (2.2 +/- 0.2 mg/kg, n = 8). AF was induced with burst atrial pacing after we made an intercaval crush in anesthetized, open-chest dogs. Termination of AF did not differ among test drugs (8 of 8 with disopyramide, 7 of 8 with propafenone, 6 of 8 with pentisomide, and 8 of 8 with E-4031). Cycle length (CL) of AF was prolonged more with propafenone (57 +/- 10%) and pentisomide (41 +/- 5%) than with E-4031 (12 +/- 3%, p less than 0.05). This was also true for increase in interatrial conduction time determined at a pacing CL of 150 ms. Increase in atrial effective refractory period (ERP) determined at a basic pacing CL of 300 ms did not differ among test drugs. Changes in CL of AF correlated significantly with those in interatrial conduction time (r = 0.84, p less than 0.001), but not with those of ERP (r = 0.10, NS). Reinitiation of AF was significantly greater in propafenone (7 of 7) and pentisomide (5 of 6) groups than in disopyramide (1 of 8) and E-4031 (0 of 8) groups (p less than 0.001). Pentisomide and E-4031 were effective in terminating canine AF due to reentry, as were disopyramide and propafenone. Reinitiation of AF was greater in dogs treated with antiarrhythmic drugs that had more prominent effects on conduction time than on ERP.     

Clinico-electrophysiologic studies on the action of the anti-arrhythmic substance 3-carbethoxyamino-5-dimethylamino-acetyl-10,11-dihydro-5H- dibenz[b,f]azepine hydrochloride (Bonnecor, AWD 19-166, GS 015)

The effects of the new antiarrhythmic drug 3-carbethoxy-amino-5-dimethyl-amino-acetyl-iminodibenzyl-hydroc hlorid (Bonnecor) (B.) were investigated by means of clinical-electrophysiologic methods (His-bundle electrography, programmed electrical stimulation) in 11 patients with normal cardiac output and paroxysmal supraventricular tachycardias. In a maximal dosage of 0.24 mg/kg body mass. B. affects several compartments of the impulse initiation and conduction. B. has positive chronotropic actions on the sinus node automaticity, negative dromotropic effects on the sinu-atrial, intraatrial, AV nodal and intraventricular conduction and finally negative bathmotropic actions on the myocardium of the atria and ventricles. B. suppress the artificial induction of paroxysmal supraventricular tachycardias in patients with AV nodal reentry. These results help to recognize indications (supraventricular and ventricular premature beats or tachycardias) and contraindications (sick sinus syndrome, atrio-ventricular block of higher degreé and bifascicular blocks).     

Mechanism of antifibrillatory action of Org 7797 in regionally ischemic pig heart.

Org 7797 is effective against ventricular fibrillation (VF) induced during ischemia. In Langendorff-perfused pig hearts, application of three premature stimuli to nonischemic myocardium between 3 and 5 min after coronary occlusion always resulted in VF in the absence of drug. In no instance when Org 7797 was present (2-10 microM) could VF be induced, although sustained and nonsustained ventricular tachycardias (VTs) could still be initiated in about two thirds of treated hearts. We determined the effects of Org 7797 on wavelength in normal and ischemic myocardium during regular driving at a cycle length of 350 ms. Wavelength, the algebraic product of conduction velocity and refractory period, is considered a useful parameter in assessing efficacy of antiarrhythmic agents in preventing reentrant arrhythmias. Conduction velocity was obtained by analyzing the spread of activation under 121 unipolar electrodes (1 mm apart) placed around a central stimulus electrode. Refractory periods were determined with premature test stimuli at an intensity of twice diastolic threshold. Both in normal and ischemic myocardium Org 7797 (5-10 microM) produced a marked shortening of wavelength. This should predispose to reentry. However, Org 7797 prolonged the refractory period at the fastest possible driving rate from 154 to 247 ms and attenuated (5 microM) or prevented (10 microM) shortening of the refractory period during application of subsequent premature stimuli. The antifibrillatory effect of the drug may be explained by prolongation of wavelength at very short cycles.     

Three thiadiazinone derivatives, EMD 60417, EMD 66430, and EMD 66398, with class III antiarrhythmic activity but different electrophysiologic profiles

The thiadiazinone derivatives EMD 60417, EMD 66430, and EMD 66398 were developed as class III antiarrhythmic agents. Their chemical structure is closely related to that of their calcium-sensitizing congener [+]-EMD 60263, and EMD 66398 possesses the methylsulfonylaminobenzoyl moiety present in the prototypical IKr blocker E-4031. We compared the electrophysiologic effects of these compounds with standard drugs (almokalant, E-4031, quinidine) in cardiac myocytes from guinea-pig ventricle and human atrium by whole-cell patch-clamp technique. The test compounds' class III action, which is related to impairment of K+ channel function, was confirmed by action potential measurements. EMD 60417, EMD 66430, EMD 66398, and almokalant (1 microM each) reversibly prolonged the action potential duration in guinea-pig myocytes. In the same cells, the rapidly activating component IKr of the delayed rectifier K+ current, which has been defined by its sensitivity to E-4031, was reduced by EMD 60417, EMD 66430, EMD 66398, and almokalant. Inhibition of IKr was concentration-dependent as determined by attenuation of tail currents. The slowly activating component IKs of the delayed rectifier K+ current was not affected. The inward rectifier K+ current IK1 was not influenced at potentials close to the reversal potential. Transient and sustained outward K+ currents (Ito, Iso) measured in human atrial myocytes were not altered by any EMD compound. L-type Ca2+ current was hardly affected at concentrations of 1-10 microM, but sodium current was decreased. Action potential prolongation by EMD 60417, EMD 66430, and EMD 66398 is due to block of IKr. INa is inhibited at higher concentrations by EMD 66430 and EMD 60417. EMD 66398 is more potent and selective for IKr than EMD 60417 and EMD 66430, and thus resembles E-4031 in structure and function.     

Metoprolol in the treatment and prophylaxis of paroxysmal reentrant supraventricular tachycardia

The effect of metoprolol on paroxysmal reentrant supraventricular tachycardia was studied in 30 patients. In 16 cases (12 accessory pathway, 4 pure AV nodal reentry) programmed stimulation was performed before and after 0.1 mg/kg intravenous metoprolol. When administered during sustained tachycardia, metoprolol terminated the arrhythmia in 4 out of 12 cases. Metoprolol prolonged the AV nodal functional and effective refractory period and the A-H interval but had no effect on refractory periods and conduction intervals of accessory pathways. Following metoprolol no tachycardia could be initiated in five patients. Premature atrial pacing revealed widened tachycardia zones in 10 cases; premature ventricular pacing showed varying responses to the drug. Twenty two patients (13 accessory pathway, 9 pure AV nodal reentry) received two times 50 to two times 100 mg metoprolol orally per day and were followed for 4 weeks. Five patients did not complete the entire term, four because of frequent tachycardia and one because of side effects. Ten patients were free of arrhythmia, most over several months, and seven continued to have attacks. Plasma levels were higher on oral metoprolol. Intravenous testing had correctly predicted the response to oral metoprolol in seven out of eight patients. Higher plasma concentrations, suppression of premature beats, or the different patient population may explain the more favorable prophylactic action of oral metoprolol.     

Effect of tiapamil in the Wolff-Parkinson-White syndrome

The effect of tiapamil was studied in 9 patients with the Wolff-Parkinson-White syndrome using programmed stimulation of the heart. Before the drug, sustained orthodromic tachycardias could be initiated in 7 patients and antidromic tachycardia in 2 by premature atrial and/or ventricular stimulation. An intravenous bolus of tiapamil, 2 mg/kg, terminated the tachycardia in 7 out of 8 cases by a block in the atrioventricular (AV) node. Tiapamil lengthened the effective refractory period of the AV node in the only patient in whom it could be measured and the atrial effective refractory period in 1 out of 9 cases, but the drug had no influence on antegrade or retrograde refractory periods of the accessory pathway or on that of the ventricle. The AV nodal conduction time (A-H interval) was prolonged. Following tiapamil, it was not possible to initiate the tachycardia in 4 cases, in 2 patients the tachycardia zone widened, and in 3 it was unaltered. In the latter cases, the cycle length of the tachycardia was increased. Tiapamil appears to be useful for the termination of tachycardia and also for its prevention in some cases. In others, it may facilitate the inhibition of tachycardia. The delayed AV nodal conduction during sinus rhythm augments the area of ventricular preexcitation, which may facilitate the electrocardiographic localization of the accessory pathway.     

In vitro electrophysiological mechanisms for antiarrhythmic efficacy of resveratrol, a red wine antioxidant

Resveratrol (trans-3, 4', 5-trihydroxystilbene), a natural antioxidant derived from grapes, has beneficial effects against coronary heart disease. Its electrophysiological characteristics for antiarrhythmic efficacy are largely unknown; thus, this study aims to explore the resveratrol's antiarrhythmic effects and conduction system in isolated hearts as well as its electrophysiological effects on cardiac myocytes. In the experiment, resveratrol suppressed the ischemia/reperfusion-induced ventricular arrhythmias in Langendorff-perfused rat hearts. In the current clamp study of the experiment, resveratrol prolonged the action potential duration (APD(50) and APD(90)) and suppressed the upstroke velocity of the action potential (V(max)). In the voltage clamp study, resveratrol inhibited sodium inward current (I(Na)) in a concentration-dependent manner and negative-shifted the voltage-dependent inactivation curve. Resveratrol also reduced the calcium inward current (I(Ca), 51.2+/-13.3% at 100 microM). Furthermore, the transient (I(to)) and sustained (I(ss)) outward potassium currents were decreased 60.2+/-5.7% and 42.3+/-5.2% after exposure to resveratrol (100 microM), respectively. The inward rectifier potassium current (I(K1)) was also reduced 24.2+/-7.0% in the presence of resveratrol (100 microM). In the isolated heart perfusion model, resveratrol (100 microM) prolonged AV nodal refractory period, the Wenckebach cycle length and the conduction through AV node and His-Purkinje system. In conclusion, resveratrol increased the cardiac effective refractory period mainly through inhibiting the ionic channels including I(Na), I(to) and I(ss) which could contribute to the conversion of ischemia/reperfusion-induced lethal arrhythmias.     

Electrophysiologic effects and antiarrhythmic efficacy of recainam in patients with supraventricular tachycardia.

Recainam is a new antiarrhythmic agent with class Ic properties. To evaluate its electrophysiologic effects and antiarrhythmic efficacy in patients with recurrent supraventricular tachycardia (SVT), programmed electrical stimulation was performed in 10 patients before and after intravenous recainam (loading dose 0.8 mg/kg, infusion 1 mg/kg/h), and in four patients on oral recainam 1,200 mg/day. Five patients had atrioventricular (AV) node reentrant tachycardia; five had AV-reciprocating tachycardia. There were no significant changes in electrocardiographic and intracardiac intervals after either intravenous or oral recainam. After intravenous recainam, the ventricular effective refractory period (ERP) shortened (231 +/- 14-219 +/- 9 ms, p less than 0.05). The antegrade ERP of all three bidirectional accessory pathway markedly prolonged, but the effect on retrograde accessory pathway and AV node ERPs was unremarkable. SVT induction was prevented in three of 10 patients and SVT cycle length increased modestly in seven (357 +/- 44-374 +/- 42 ms, p = 0.07). On oral recainam, an increase in the frequency of spontaneous SVT occurred in two patients. At the doses given, recainam caused less electrophysiologic change than expected, had modest antiarrhythmic efficacy, and might have significant arrhythmogenic potential.     

Electrophysiology and antiarrhythmic actions of E-4031 in the experimental animal model of sudden coronary death.

The Class III agent E-4031 was evaluated for its antiarrhythmic and antifibrillatory actions in conscious dogs 3-5 days after anterior myocardial infarction that were responsive to the induction of tachyarrhythmia by programmed electrical stimulation. The administration of E-4031 as an intravenous loading dose (100 micrograms/kg) followed by an infusion for 90 min (10 micrograms/kg/min) suppressed the induction of ventricular tachycardia by programmed electrical stimulation in 6 of 12 dogs and prolonged the cycle length of the induced arrhythmia in 5 of the 6 remaining animals. Continued administration of E-4031 in a dose regimen of 1,000 microgram/kg every 2 h provided significant protection (8 of 10 dogs) against the development of ventricular fibrillation (sudden coronary death) within the first hour after the onset of myocardial ischemia in a region of the ventricle remote from the infarct-related vessel. The incidence of sudden coronary death was 80% in a comparable control group of electrically inducible postinfarcted dogs. Increases in ventricular myocardial refractoriness in the paced QT and QTc intervals suggest that Class III electrophysiologic actions contribute to the antiarrhythmic and antifibrillatory actions of E-4031. The findings suggest that E-4031 may be of clinical utility in the prevention of life-threatening arrhythmias in the setting of myocardial ischemia in the postinfarcted heart.     

The effects of indecainide, a new antidysrhythmic drug, on nodal tissues in the isolated rabbit heart

The effects of indecainide, previously shown to be a class 1c antiarrhythmic drug restricting fast inward current, have been studied on rabbit sinoatrial (SA) node and atrioventricular (AV) node. Indecainide at concentrations up to 2.9 mumol/L in 5 preparations did not produce a sinus bradycardia, nor reduce the maximum rate of rise of the intracellular action potential of sinus node cells, but it did antagonize the tachycardia induced by increasing the extracellular calcium concentration. Indecainide slightly prolonged AV conduction time [from 49.07 +/- 4.43 ms to 57.37 +/- 0.90 ms at 2.9 mumol/L (means +/- SEM in four preparations)], but this small delay could be attributed to slowing of conduction in atrial fibres leading to the node, rather than to an effect on the AV nodal cells themselves. It is concluded that indecainide does not block channels carrying inward calcium current in nodal tissues.     

Effect of E-4031, a class III antiarrhythmic agent, on experimental infarct size in a canine model of myocardial ischemia-reperfusion injury.

Class III antiarrhythmic agents such as E-4031 have demonstrated efficacy in preventing and/or terminating malignant ventricular arrhythmias in experimental models. It has recently been suggested that Class III agents might possess additional antiischemic properties that may translate into a reduction in the frequency or severity of arrhythmia. The potential for the Class III antiarrhythmic agent E-4031 to limit the extent of developing myocardial infarction was assessed in a barbiturate-anesthetized canine model of ischemic-reperfusion injury. Untreated control (n = 13) and E-4031-treated animals (n = 8, 300 micrograms/kg, i.v., immediately preceding myocardial ischemia) were subjected to a 90-min period of left circumflex coronary artery occlusion followed by a 5-h period of reperfusion. The predominant hemodynamic effect displayed by E-4031 was a reduction in heart rate throughout the period of coronary artery occlusion and early reperfusion. Areas at risk of infarction, expressed as percentages of left ventricle, were equivalent in the control and E-4031 treatment groups (38.5 +/- 1.0 and 34.6 +/- 1.9%, respectively). Posterolateral myocardial infarct sizes, expressed either as percentages of risk area or of total left ventricle, were reduced slightly but not significantly in the E-4031 treatment group compared to the control group (35.2 +/- 5.6 and 45.4 +/- 3.0% of risk area, respectively; 12.7 +/- 2.4 and 17.6 +/- 1.4% of left ventricle, respectively). Regional myocardial blood flows in nonischemic and central ischemic zones of myocardium did not differ significantly between the control and E-4031 treatment groups before and during the period of coronary artery occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of semotiadil (SD-3211), a benzothiazine calcium antagonist, on blood pressure and atrioventricular conductivity in anesthetized dogs.

We investigated the effects of semotiadil (SD-3211), a novel calcium antagonist, on blood pressure and the atrioventricular (AV) conduction time and functional refractory period (FRP) of the AV conduction system (AV conductivity) in anesthetized open-chest dogs. The heart was electrically stimulated at a constant rate. In dogs with an intact nerve supply to the heart, i.v.-injections of semotiadil (0.03 to 0.3 mg/kg) produced a fall of blood pressure in a dose-dependent manner. AV conduction time and FRP were prolonged by rather higher doses (0.3 mg/kg), and second-degree AV block occurred only with the highest dose (1 mg/kg). In dogs with the nerve supply to the heart interrupted, the vasodepressor effects and suppressant effects of semotiadil on AV conductivity were slightly enhanced. The suppressant effects on AV conductivity became marked as pacing rates were increased. These results suggest that semotiadil at appropriate doses produces a vasodepressor effect without affecting AV conductivity even in the heart deprived of nervous control, e.g., the heart with beta-adrenoceptors blocked. The frequency-dependent suppressant effect on FRP of semotiadil is also noteworthy in the treatment of reentrant supraventricular tachycardia that involves the AV node.     

Differences in the cardiac actions of the calcium antagonists verapamil and nifedipine.

1. It was investigated whether the calcium antagonistic coronary drugs verapamil and nifedipine have similar antiarrhythmic properties. Their effects on functional refractory period and contractile force in the isolated left guinea pig atrium were compared. To assess their influence on myocardial excitability the relation between threshold voltage and pulse duration was studied in the left guinea pig atrium. Furthermore, the influence on AV conduction was investigated in the conscous dog in haemodynamically equieffective dose ranges. 2. Verapamil as well as nifedipine cause a dose-dependent prolongation of the functional refractory period in the isolated left guinea pig atrium. The slope of the dose-response curve of nifedipine is, however, significantly less steep than that of verapamil. Maximum prolongation of refractory period which can be induced by nifedipine is significantly inferior to that occurring after verapamil; under nifedipine this prolongation is, however, accompanied by a significantly greater reduction in contractility. 3. In the isolated left guinea pig atrium the voltage-duration curve is shifted to the right and the chronaxia value is significantly increased by verapamil. Even in the highest dose possible nifedipine has no effect on atrial excitability. 4. In the conscious dog verapamil considerably prolongs AV conduction time whereas a moderate yet dose-dependent shortening of PQ duration is observed with equieffective nifedipine doses regarding the decrease in blood pressure and increase in heart rate. 5. The results indicate that nifedipine does not exert antiarrhythmic effects comparable to those of verapamil.     

Functional effects of the late sodium current inhibition by AZD7009 and lidocaine in rabbit isolated atrial and ventricular tissue and Purkinje fibre

AZD7009 (tert-Butyl-2-(7-[(2S)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)ethylcarbamate) is an antiarrhythmic agent that increases atrial refractoriness, shows high antiarrhythmic efficacy and has low proarrhythmic potential. This study was primarily undertaken to determine the effects of AZD7009 on the late sodium current and to examine the impact of late sodium current inhibition on action potential duration in various myocardial cells. AZD7009 inhibited the late sodium current in Chinese Hamster Ovary K1 (CHO K1) cells expressing hNa(v)1.5 with an IC(50) of 11+/-2 microM. The late sodium current in isolated rabbit atrial and ventricular myocytes was also concentration dependently inhibited by AZD7009. Action potentials were recorded during exposure to 5 microM E-4031 (1-[2-(6-methyl-2pyridyl)ethyl]-4-(4-methylsulfonyl aminobenzoyl)piperidine), a compound that selectively inhibits the rapid delayed rectifier potassium current (I(Kr)), and to E-4031 in combination with AZD7009 or lidocaine in rabbit atrial and ventricular tissue and Purkinje fibres. In Purkinje fibres, but not in ventricular tissue, AZD7009 and lidocaine attenuated the E-4031-induced action potential duration prolongation. In atrial cells, AZD7009, but not lidocaine, further prolonged the E-4031-induced action potential duration. E-4031 induced early afterdepolarisations (EADs) in Purkinje fibres, EADs that were totally suppressed by AZD7009 or lidocaine. In conclusion, excessive action potential duration prolongation induced by E-4031 was attenuated by AZD7009 and lidocaine in rabbit Purkinje fibre, but not in atrial or ventricular tissue, most likely by inhibiting the late sodium current. Furthermore, the opposite effect by AZD7009 on action potential duration in atrial tissue suggests that AZD7009, in addition to inhibiting I(Kr), also inhibits other repolarising currents in the atria.