Differential Rate and Potassium-Dependent Effects of the Class III Agents d-Sotalol and Dofetilide on Guinea Pig Papillary Muscle

The class III agents d-sotalol and dofetilide have been shown to exhibit differential effects in large controlled clinical trials. The aim of this study was to investigate the basic electrophysiological properties of these two antiarrhythmia agents in an in vitro experimental model with regard to potential antiarrhythmic and proarrhythmic action. Using standard microelectrode techniques, we evaluated the electrophysiological effects of d-sotalol and dofetilide on action potential parameters recorded from guinea pig papillary muscle at 2.5 mM, 3.5 mM, and 5.6 mM extracellular potassium concentrations. The following parameters were recorded: resting membrane potential (RMP), action potential amplitude (APA), action potential duration at 90% repolarization (APD 90), and maximum upstroke velocity (Vmax). Under all conditions studied, both d-sotalol and dofetilide exhibited highly selective reverse rate-dependent class III action. In contrast to dofetilide, the class III activity of d-sotalol was markedly influenced by changes in extracellular potassium concentrations, predominantly at low pacing rates. Hypokalemia enhanced the action potential–prolonging effects of d-sotalol, whereas hyperkalemia diminished this effect. In addition, reverse rate dependence associated with dofetilide was significantly more pronounced than reverse rate dependence associated with d-sotalol. Our observations provide a potential electrophysiological basis for differential antiarrhythmic and proarrhythmic mechanisms associated with these two drugs.     

Vascular effects of class-III antiarrhythmic drugs: chromanol 293B, but not dofetilide blocks the smooth muscle delayed rectifier K+ channel

Chromanol 293B and dofetilide are inhibitors of IK_s and IK_r, i.e., of the slow and the rapid component of the delayed rectifier potassium current. The specificity of these drugs was tested by investigating their effects on the delayed rectifier potassium current in vascular smooth muscle, regulating the tone of blood vessels. Using depolarizing step protocols with asymmetrical potassium concentrations (135/4.5 mM K⁺ in pipette/bath), voltage-dependent K⁺ currents (IK_v) of enzymatically dispersed guinea pig portal vein cells were studied in the whole-cell patch-clamp technique. Peak currents were obtained within 20 ms (at +50 mV) after activation. During a 10 s test pulse to +60 mV, these currents exhibited a relatively fast inactivation with time constants of 384 ms (τ_fast) and 4505 ms (τ_slow). Dofetilide was totally ineffective in modulating currents; in contrast, after application of chromanol 293B, a steady-state block of IK_v developed within 135 s. The block was concentration-dependent with an IC₅₀ of 7.4 μM. Chromanol did not produce any shift in the normalized steady-state activation and inactivation curves and the recovery from inactivation was not significantly changed. Chromanol 293B similarly inhibited delayed rectifier K⁺ channels whether in their closed or open state, and produced an “apparent” acceleration of inactivation, i.e., the drug accelerated the faster time constant of inactivation during a 10 s test pulse from 384 ms (control) to 149 ms (100 μM chromanol). In recent studies, chromanol was described as a specific blocker of slowly activating delayed rectifier potassium channels (IK_s) in cardiomyocytes. The results of this study, however, extend the inhibitory spectrum of the drug and demonstrate block of closed and open state delayed rectifier K⁺ currents in portal vein vascular smooth muscle. Such a block could possibly contribute to the generation of portal hypertension. Received: 2 March 2001, Returned for 1. revision: 22 March 2001, 1. Revision received: 9 May 2001, Returned for 2. revision: 16 May 2001, 2. Revision received: 3 August 2001, Accepted: 20 August 2001     

Effect of cimetidine and ranitidine on pharmacokinetics and pharmacodynamics of a single dose of dofetilide

AIMS: The aim of this open-label, placebo-controlled, randomized, four-period crossover study was to determine the effects of cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of a single dose of dofetilide. METHODS: Twenty healthy male subjects received 100 or 400 mg twice daily of cimetidine, 150 mg twice daily of ranitidine, or placebo for 4 days. On the second day, a single oral 500 microg dose of dofetilide was administered immediately after the morning doses of cimetidine, ranitidine, or placebo. Treatment periods were separated by 1-2 weeks. Pharmacokinetic parameters were determined from plasma and urinary dofetilide concentrations; prolongation of the QTc interval was determined from three-lead electrocardiograms. RESULTS: Ranitidine did not significantly affect the pharmacokinetics or pharmacodynamics of dofetilide; however, a dose-dependent increase in exposure to dofetilide was observed with cimetidine. When dofetilide was administered with 100 and 400 mg of cimetidine, the area under the plasma concentration-time curve of dofetilide increased by 11% and 48% and the maximum plasma dofetilide concentration increased by 11% and 29%, respectively. The respective cimetidine doses reduced renal clearance of dofetilide by 13% and 33% and nonrenal clearance by 5% and 21%. Dofetilide-induced prolongation of the QTc interval was enhanced by cimetidine; the mean maximum change in QTc interval from baseline was increased by 22% and 33% with 100 and 400 mg of cimetidine, respectively. However, the relationship between the prolongation of the QTc interval and plasma dofetilide concentrations was unaffected by cimetidine or ranitidine; a 1 ng ml-1 increase in plasma dofetilide concentration produced a 17-19 ms prolongation of the QTc interval. Dofetilide was well tolerated, with no treatment-related adverse events or laboratory abnormalities. CONCLUSIONS: These results suggest that cimetidine increased dofetilide exposure by inhibiting renal tubular dofetilide secretion, whereas ranitidine did not. This effect is not an H2-receptor antagonist class effect but is specific to cimetidine. If therapy with an H2-receptor antagonist is required, it is recommended that cimetidine at all doses be avoided; since ranitidine has no effect on dofetilide pharmacokinetics or prolongation of the QTc interval, it can be seen as a suitable alternative.     

新三类抗心律失常药物CPUY11018的潜在致心律失常作用

目的:考察化合物CPUY11018对心电复极的影响,评估其潜在致心律失常作用。方法:观察CPUY11018和阿奇利特对正常豚鼠心率(HR)、QT间期、校正QT间期(QTc)及校正QT间期离散度(QTcd,QTcmax～QTcm in)的影响;正常家兔连续给予异丙肾上腺素(5 mg.kg-1.d-1,sc)7 d,诱发心肌缺血性肥厚,甲氧胺法观察CPUY11018对肥厚心肌尖端扭转性室性心动过速(TdP)的诱发作用。结果:小剂量CPUY11018可浓度依赖性延长QT间期,药物剂量为0.203 mg.kg-1时,其对豚鼠心电图的影响达到平台,加大给药剂量,心电图并无明显改变,显示出明显的自限特征;甲氧胺法诱发家兔TdP模型中CPUY11018(0.15和0.3 mg.kg-1.m in-1)无诱发TdP心律失常作用。结论:CPUY11018对QT间期有限延长,诱发心肌病变家兔TdP上作用弱。此作用可能与化合物兼具钙通道阻断作用有关。     

Cellular electrophysiological effects of MS-551, a new class III antiarrhythmic agent

The cellular electrophysiological effects of MS-551, a pure class III antiarrhythmic agent lacking beta-blocking activity, were compared with those of d-sotalol and dofetilide in canine Purkinje fibers and ventricular muscles and in guinea pig atrial muscles using the standard microelectrode technique. MS-551 prolonged the action potential duration (APD) of these cardiac tissues to the same extent in a concentration-dependent manner (10^?6?10^?4 M). MS-551 did not affect other action potential parameters of these tissues except for the V_max, which was depressed approximately 10% at 10^?4 M MS-551. The extents of prolongation after 10^?5 M of MS-551 were 36, 27, and 35% for canine Purkinje and ventricular muscle and guinea pig atrial muscle, respectively. d-Stalol at a concentration 10 times higher than MS-551 produced a similar prolongation of the APD of canine cardiac tissues but only a slight prolongation of the APD of guinea pig atrial muscles. Dofetilide at a concentration 30 times lower than MS-551 produced a prolongation of the APD of canine Purkinje fibers but a relatively slight prolongation of the APD of both canine ventricular muscles and guinea pig atrial muscles. In canine Purkinje fibers, MS-551 did not prevent the APD shortening induced by high extracellular potassium (8 and 12 mM), but the APD under these conditions was lengthened compared with controls. Under simulated ischemic conditions (pO₂ 25–30 mmHg, pH 6.5, extracellular K 8 mM and no glucose) for 30 min, the APD was abruptly shortened during the first 5 min, then gradually shortened further up until 30 min. MS-551 did not prevent the abrupt APD shortening, but slowed the later gradual shortening. The APD prolonging action of MS-551 was enhanced at low frequency. These data indicate that (1) MS-551 is a pure class III antiarrhythmic agent with electrophysiological characteristics basically similar to d-sotalol and dofetilide; (2) MS-551 has a relatively greater potency in guinea pig atrial muscle than d-sotalol and dofetilide; (3) the APD prolonging action of MS-551 is preserved under high K⁺ or simulated ischemic conditions; and (4) MS-551 exhibits a reverse use-dependence in prolonging APD. © 1995 Wiley-Liss, Inc.     

Comparison in the Same Patient of Aberrant Conduction and Bundle Branch Reentry After Dofetilide, a New Selective Class III Antiarrhythmic Agent

Dofetilide may induce aberrant intraventricular conduction due to its Class III effect. This report describes an atrial fibrillation patient in whom intraventricular conduction was studied before and after dofetilide using multiple endocardial recordings. Dofetilide provoked aberrant conduction during atrial fibrillation, and aberrancy could be mimicked with programmed atrial stimulation after restoration of sinus rhythm. However, during right ventricular slimulation, isolated bundle branch reentrant beats were recorded after induction of critical retrograde conduction delays. This occurred in the setting of relatively large differences in refractoriness between the right bundle branch and the right ventricular myocardium. This favored distal retrograde bundle branch block during ventricular extrastimulation, in turn enhancing bundle branch reentry. This potendal proarrhythmic mechanism deserves close attention in the further deveiopmeni of dofetilide and also of other new "pure" Class III agents.     

Slow delayed rectifier K+ current block by HMR 1556 increases dispersion of repolarization and promotes Torsades de Pointes in rabbit ventricles

Background and purpose:

The slow delayed rectifier K⁺ current (I_Ks) contributes to ventricular repolarization when the action potential (AP) is prolonged. I_Ks block during drug-induced AP prolongation may promote Torsades de Pointes (TdP), but whether this is due to additional AP prolongation is uncertain.

Experimental approach:

In bradycardic perfused rabbit ventricles, the incidence of spontaneous TdP, monophasic AP duration at 90% repolarization (MAPD₉₀) and ECG interval between the peak and the end of T wave (T_peak−end) (index of dispersion of repolarization) were measured after the administration of veratridine (125 nM, slows Na⁺ channel inactivation), dofetilide (7.5 or 10 nM, a rapid delayed rectifier blocker) and HMR 1556 (HMR, 100 nM, an I_Ks blocker), alone or in combinations (n=6 each).

Key results:

HMR did not prolong MAPD₉₀, whereas veratridine or 7.5 nM dofetilide prolonged MAPD₉₀ (P<0.01) without inducing TdP. Veratridine+7.5 nM dofetilide additively prolonged MAPD₉₀ (P<0.05), induced 4±6 TdP per heart and prolonged T_peak−end by 12±10 ms. Subsequent addition of HMR did not further prolonged MAPD₉₀, but increased the number of TdP to 22±18 per heart and increased T_peak−end by 39±21 ms (P<0.05). Increasing dofetilide concentration from 7.5 to 10 nM (added to veratridine) produced a longer MAPD₉₀, but fewer TdP (5±5 per heart) and less T_peak−end prolongation (17±8 ms) compared to the veratridine+7.5 nM dofetilide+HMR group (P<0.05).

Conclusions and implications:

Adding I_Ks block markedly increases TdP incidence in hearts predisposed to TdP development by increasing the dispersion of repolarization, but without additional AP prolongation.