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.     

Effects of a novel class III antiarrhythmic agent, E-4031, on reentrant tachycardias in rabbit right atrium.

Effects of a new antiarrhythmic agent, E-4031, on reentrant types of tachycardias in rabbit right atrial preparations were studied using the microelectrode technique. E-4031 at concentrations of 0.1 and 1.0 microM prolonged the refractory period (RP) of the atrium and atrioventricular node (AVN) without affecting the intraatrial conduction time. In 13 of 17 preparations, premature stimulation repeatedly induced tachycardias lasting more than 10 beats. Twelve of 13 preparations exhibited a smooth AV conduction curve and showed activation patterns compatible with intraatrial reentry (IAR) during tachycardias, whereas the remaining preparation started tachycardia with a jump on the AV conduction curve, indicating dual AVN reentrant tachycardia (AVNRT). Application of 0.1 and 1.0 microM E-4031 completely prevented the initiation of both types of tachycardias by producing intraatrial conduction block due to prolonged effective refractory period (ERP) of the atrium. The results indicated that E-4031 exhibiting pure class III antiarrhythmic properties is effective for prevention of reentrant type of supraventricular tachycardias (SVTs).     

双苯氟嗪对异丙肾上腺素诱发人心房肌纤维迟后除极和触发活动的影响

目的研究双苯氟嗪(Dip)对异丙肾上腺素诱发人心房肌纤维迟后除极(DADs)和触发活动(TA)的影响。方法应用异丙肾上腺素诱发稳定且可重复的迟后除极和触发活动。用细胞内玻璃微电极技术记录DADs和TA诸参数。结果预先应用Dip (3 μmol·L^-1)或乙醇溶剂(3 mL·L^-1)对异丙肾上腺素引起的DADs和TA无明显影响；Dip (10 μmol·L^-1)使DADs的幅度从(13.3±2.3) mV降低到(4.0±1.0) mV，但对DADs和TA的发生率无显著影响；Dip (30 μmol·L^-1)则能抑制DADs和TA的发生。结论Dip对异丙肾上腺素诱发的人心房肌纤维DADs和TA有抑制作用，这可能与其抑制L-型钙通道和/或肌浆网钙释放从而减轻细胞内钙超载有关，并可能由此产生抗心律失常作用。     

Vascular effects of class III antiarrhythmic agents

Methanesulfonanilide Class III antiarrhythmic agents have been shown to block a specific outward delayed rectifier K⁺ current, I_kr in cardiac cells. K⁺ conductance also is recognized to be an important regular of contractile tone in vascular smooth muscle. The purpose of the present investigation was to assess the effects of the new and potent methanesulfoanilide Class III agents E-4031, UK-68,798, UK-66,914 and the Class III standard d-sotalol in vitro in phasically active and electrically quiescent vascular smooth muscle preparations. All four Class III agents augmented phasic contractile tension in spontaneously active rat portal veins at concentrations similar to those effecting significant Class III electrophysiologic activity in cardiac muscle, but failed to contract electrically quiescent rabbit aortic rings. At concentrations exceeding effective cardiac Class III electrophysiologic concentrations, E-4031 relaxed methoxamine- and histamine-contracted rabbit aortic rings, and d-sotalol relaxed methoxamine-contracted aortic rings. UK-68,798 and UK-66,914 failed to relax spasmogen-contracted aortic rings. The similarity in effective concentrations required for the four Class III agents to augment phasic contractile tension in the rat portal vein and increase myocardial refractoriness in cardiac muscle is consistent with the presence of similar K⁺ channel subtypes in the two tissues. Alternatively, the observed activities in the two tissues may be due to actions of these four Class III agents on another, non-I_kr ion channel present in rat portal vein, with an order of potency for blockade similar to block of I_kr in cardiac tissue. © 1992 wiley-Liss, Inc.     

双苯氟嗪对哇巴因诱发豚鼠乳头肌迟后除极和触发活动的影响

目的:研究双苯氟嗪(DiP)对哇巴因和高钙诱发豚鼠乳头肌迟后除极(DADs)和触发活动(TA)的影响.方法:应用哇巴因(1 μmol/L)和高钙(5.4 mmol/L)诱发稳定且可重复的迟后除极和触发活动.用细胞内玻璃微电极技术记录DADs和TA诸参数.结果:(1)预先应用DiP(10,30 μmol/L)对DADs和TA有明显的抑制作用.在DiP(30 μmol/L)作用下,DADs的幅度由(10.5±2.2)降到(3.6±0.3)mV,DADs时程由(230±19)缩短到(152±14)ms,引起DADs的时间从(21±5)延长至(66±11)min,TA未见发生.(2)诱发DADs后再给予Dip(10,30μmol/L),DADs和TA被明显抑制.在Dip(30μmol/L)作用下,DADS的幅度由(10.4±1.2)降至(3.3±0.6)mV,DADs的时程由(218±22)缩短至(159±26)ms,TA未见发生.结论:Dip对哇巴因和高钙诱发的豚鼠乳头肌迟后除极和触发活动有抑制作用,这可能与其抑制L-型钙通道和/或肌浆网钙释放从而减轻细胞内钙超载有关,并由此产生抗心律失常作用.     

Transient kinetic and dynamic interactions between verapamil and dofetilide, a class III antiarrhythmic.

Potential kinetic and dynamic interactions between the new class III antiarrhythmic dofetilide (D) and the calcium channel blocker verapamil (V) were determined in 12 young healthy male volunteers. A fixed sequence of V80 mg tid, placebo, D 0.5 mg bid, and D + V was given as matching active and placebo capsules. In steady-state conditions during combination treatment, a modest increase in mean (+/- SD) peak plasma concentration of dofetilide from 2.40 +/- 0.42 to 3.43 +/- 0.71 ng x ml(-1) (43% increase, p < 0.1) was noted. During the combination period, for the first 4 hours, mean AUC values for D increased from 7.4 +/- 1.0 (D alone) to 9.2 +/- 1.4 ng x h x ml(-1) (26% increase, p <0.1). No other significant pharmacokinetic interaction was seen. These transient changes were concurrent with trends for a dynamic interaction. The maximal mean increase in QT, over steady-state baseline values was 20 msec for D alone versus 26 msec during combination therapy. This relatively small interactive effect occurred only while peak plasma drug concentrations were developing at 1 to 3 hours after dosing and is probably caused by the known effect of verapamil to increase hepatic and portal bloodflow. In view of this interaction and the relationship between dofetilide plasma concentration and torsade, verapamil is contraindicated in patients receiving dofetilide.     

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)     

苦参碱与E-4031,多非利特和RP58866对家兔心肌I_(k1)的作用比较(英文)

目的　比较苦参碱与E 4 0 31,多非利特和RP5 886 6对家兔单个心室肌细胞的内向整流钾电流(Ik1)的效价和效能的不同 ,揭示苦参碱抗心律失常作用弱于西药的原因。方法　应用全细胞膜片钳技术记录苦参碱与E 4 0 31,多非利特和RP5 886 6对家兔Ik1的影响。结果　苦参碱 1和 10 μmol·L- 1对家兔Ik1无明显影响。在实验电压为 - 12 0mV和保持电压为 - 70mV ,苦参碱 5 0和 10 0 μmol·L- 1对Ik1分别抑制达 6 % (n =8,P <0 .0 5 )和 8% (n =8,P <0 .0 5 ) ;在实验电压为 - 5 0mV ,抑制Ik1达 4 % (n =8,P <0 .0 5 )和 8% (n =8,P <0 .0 5 )。在实验电压为 - 12 0mV ,E 4 0 311和 10 μmol·L- 1使Ik1分别降低10 % (n =6 ,P <0 .0 5 )和 4 5 % (n =6 ,P <0 .0 5 )。在 - 5 0mV ,Ik1分别降低 5 % (n =6 ,P <0 .0 5 )和35 % (n =6 ,P <0 .0 5 )。在实验电压为 - 12 0mV ,多非利特 1和 10 μmol·L- 1使Ik1降低 19% (n =8,P <0 .0 5 )及 2 5 % (n =8,P <0 .0 5 )。在 - 5 0mV ,Ik1分别降低 11%和 19% (n =8,P <0 .0 5 )。在实验电压为 - 12 0mV ,RP5 886 6 1和 10 μmol·L- 1使Ik1分别降低 2 1% (n =8,P <0 .0 5 )和 5 0 % (n =8,P <0 .0 5 )。在 - 5 0mV ,Ik1分别降低 6 % (n =8,P <0 .0 5 )和11% (n =8,P <0 .0 5     

Potentially significant drug interactions of class III antiarrhythmic drugs.

Class III antiarrhythmic drugs, especially amiodarone (a broad-spectrum antiarrhythmic agent), have gained popularity for use in clinical practice in recent years. Other class III antiarrhythmic drugs include bretylium, dofetilide, ibutilide and sotalol. These agents are effective for the management of various types of cardiac arrhythmias both atrial and ventricular in origin.Class III antiarrhythmic drugs may interact with other drugs by two major processes: pharmacodynamic and pharmacokinetic interactions. The pharmacodynamic interaction occurs when the pharmacological effects of the object drug are stimulated or inhibited by the precipitant drug. Pharmacokinetic interactions can result from the interference of drug absorption, metabolism and/or elimination of the object drug by the precipitant drug.Among the class III antiarrhythmic drugs, amiodarone has been reported to be involved in a significant number of drug interactions. It is mainly metabolised by cytochrome P450 (CYP)3A4 and it is a potent inhibitor of CYP1A2, 2C9, 2D6 and 3A4. In addition, amiodarone may interact with other drugs (such as digoxin) via the inhibition of the P-glycoprotein membrane transporter system, a recently described pharmacokinetic mechanism of drug interactions.Bretylium is not metabolised; it is excreted unchanged in the urine. Therefore the interactions between bretylium and other drugs (including other antiarrhythmic drugs) is primarily through the pharmacodynamic mechanism.Dofetilide is metabolised by CYP3A4 and excreted by the renal cation transport system. Drugs that inhibit CYP3A4 (such as erythromycin) and/or the renal transport system (such as triamterene) may interact with dofetilide.It appears that the potential for pharmacokinetic interactions between ibutilide and other drugs is low. This is because ibutilide is not metabolised by CYP3A4 or CYP2D6. However, ibutilide may significantly interact with other drugs by a pharmacodynamic mechanism.Sotalol is primarily excreted unchanged in the urine. The potential for drug interactions due to hepatic enzyme induction or inhibition appears to be less likely. However, a number of drugs (such as digoxin) have been reported to interact with sotalol pharmacodynamically.If concurrent use of a class III antiarrhythmic agent and another drug cannot be avoided or no published studies for that particular drug interaction are available, caution should be exercised and close monitoring of the patient should be performed in order to avoid or minimise the risks associated with a possible adverse drug interaction.     

New group of class III antiarrhythmic drugs: piperid-4-ylethane derivatives

A series of new piperid-4-ylethane derivatives possessing antiarrhythmic activity has been synthesized and studied. The most active compound, 1-(4-fluorophenyl)-1-(4-nitrobenzoylamino)-2-(N-ethylpiperid-4-yl)ethane (niferidyl) hydrochloride, was selected for clinical trials as a potential class III antiarrhythmic drug.     

Class III antiarrhythmic action and inotropy: effects of dofetilide in acute ischemic heart failure in dogs.

We studied the hemodynamic and metabolic effects of the novel class III antiarrhythmic agent dofetilide (UK-68,798) in acute ischemic heart failure. In pentobarbital-anesthetized dogs, heart failure was induced by microembolization of the area supplied by the main left coronary artery until a stable left ventricular (LV) end-diastolic pressure of 27 +/- 2 mm Hg was achieved. Embolization depressed LV systolic pressure, LV dP/dtmax, LV dP/dtmin, and cardiac output. None of these parameters were changed following i.v. infusion of dofetilide 5, 10, or 25 micrograms/kg, during spontaneous and paced cycle length of 300 ms (n = 9). Heart rate decreased by 12 +/- 8, 19 +/- 7, and 21 +/- 7 beats/min (p less than 0.05), while QT time increased by 23 +/- 7, 33 +/- 9, and 40 +/- 10 ms (p less than 0.05) after 5, 10, and 25 micrograms/kg, respectively. Ventricular effective refractory period increased from 128 +/- 10 to 153 +/- 11 ms after 25 micrograms/kg (n = 4). Arterial concentration and net myocardial uptake of glucose, lactate, and free fatty acids were not significantly influenced by dofetilide. In conclusion, dofetilide, at doses that prolonged repolarization, was devoid of cardiodepressive effects in acute ischemic heart failure.     

双苯氟嗪对异丙肾上腺素所致早后除极和触发活动的影响

用异丙肾上腺素(Iso)诱发豚鼠右心室乳头肌产生早后除极(EAD)和触发活动(TA), 通过细胞内微电极技术,观察双苯氟嗪(Dip)对EAD和TA的预防作用. 在0.5 Hz刺激频率下, 50 nmol·L^-1 Iso在延长动作电位时程的基础上, 可诱发豚鼠乳头肌产生EAD, 并出现TA, 有时TA会发展成持久的节律性活动, 有的还伴有EAD或迟后除极. Dip 3和10 μmol·L^-1可显著降低Iso诱发的EAD波幅及发生率和TA发生率; Dip 10 μmol·L^-1还明显延长TA潜伏期. 结果提示, Dip能预防, 减少或延迟Iso引起的豚鼠乳头肌EAD和TA.     

双苯氟嗪对异丙肾上腺素所致早后除极和触发活动的影响

用异丙肾上腺素 ( Iso)诱发豚鼠右心室乳头肌产生早后除极 ( EAD)和触发活动 ( TA) ,通过细胞内微电极技术 ,观察双苯氟嗪 ( Dip)对 EAD和TA的预防作用 .在 0 .5Hz刺激频率下 ,50 nmol· L-1Iso在延长动作电位时程的基础上 ,可诱发豚鼠乳头肌产生 EAD,并出现 TA,有时 TA会发展成持久的节律性活动 ,有的还伴有 EAD或迟后除极 . Dip 3和 1 0μmol· L-1可显著降低 Iso诱发的 EAD波幅及发生率和 TA发生率 ;Dip1 0 μmol·L-1还明显延长 TA潜伏期 .结果提示 ,Dip能预防 ,减少或延迟 Iso引起的豚鼠乳头肌 EAD和TA.     

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.     

In vivo assessment of class III agents and their antiarrhythmic activity

A variety of in vivo models have been used to detect and develop novel antiarrhythmic/antifibrillatory agents. However, most of these models primarily have identified the class I agents that block sodium ion currents during the upstroke of the cardiac action potential. Since we are interested in identifying agents with a class III electrophysiologic action, i.e. delayed repolarization of the cardiac action potential, we have focused our drug discovery process on a specific, somewhat uncommon in vivo canine model. These studies have demonstrated that class I agents such as encainide, disopyramide, or U58797, a novel benzamide, are clearly identified in the ouabain-toxic dog or the postinfarction (24–48 hr) conscious dog. In contrast, class III agents such as clofilium sotalol are identified in an acute canine model of coronary artery occlusion and reperfusion. This occlusion-reperfusion model allows us to further identify the antiarrhythmic and antifibrillatroy actions of novel class III agents.     

Differential recovery of action potential duration and HERG currents from the effects of two methanesulfonamide class III antiarrhythmic agents, KCB-328 and dofetilide

A novel pure class III antiarrhythmic agent, 1-(2-amino-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxyphen-ethyl)-N-methylamino]ethane hydrochloride (KCB-328) prolongs action potential duration (APD) by blocking the rapid component delayed rectifier K+ current (IKr). However, KCB-328 manifests little of the reverse frequency dependence (RFD) that is a general characteristic of class III antiarrhythmic agents. We have studied the onset and recovery kinetics of KCB-328 and dofetilide on APD in guinea-pig papillary muscle and on human ether-a-go-go-related gene (HERG) channel, which encodes IKr, expressed in Xenopus oocytes. KCB-328 (1 microM) and dofetilide (0.1 microM) progressively increased the duration of post-rest AP at 1-Hz stimulation, with onset time constants of 6.4 +/- 0.6 seconds and 20.7 +/- 1.8 seconds, respectively. With a 100-second resting period, the effect of KCB-328 recovered by 70% with a time constant of 13.2 +/- 4.2 seconds, whereas that of dofetilide recovered only by 25%. Both drugs blocked activated HERG channels in a biexponential decay fashion, with faster time constants for KCB-328 (3 microM) than for dofetilide (0.3 microM). After a 300-second resting period, HERG current inhibited by KCB-328 was recovered more at depolarized membrane potentials than at hyperpolarized ones, with a time constant of 179.9 seconds during the rest at -60 mV. In contrast, recovery after dofetilide was negligible at all voltages tested. These results suggest that KCB-328 binds to IKr at a preferentially open state in a use-dependent manner, but that KCB-328 unbinds from the resting state more readily than dofetilide. The less striking RFD of KCB-328 than of dofetilide might be related to the faster recovery from its effect on IKr.     

Induction and termination of afterdepolarizations and triggered arrhythmias by drugs in cat heart in vivo.

In order to investigate some anti-triggered arrhythmic drugs, the afterdepolarizations and triggered arrhythmias were induced by cesium chloride and the monophasic action potentials of the left ventricular epicardium in vivo were recorded by using a contact electrode in 58 cats. These results suggested that a) early- and afterdepolarizations, oscillatory afterpotentials and some different kinds of triggered arrhythmias were induced by cesium chloride, b) sodium valproate (150 mg/kg) could prevent CsCl-induced triggered activities, c) lidocaine (5 mg/kg), ethmozine (5 mg/kg) and sodium valproate (150 mg/kg) could terminate CsCl-induced ventricular tachycardias. The present studies provide a basically experimental evidence for treating triggered arrhythmias in clinic.     

脂布福吉宁和乙酰毒毛花甙诱发离体浦肯野氏纤维延时性后去极化及触发性心律失常的比较(英文)

用细胞外电图信号叠加技术微电极,于羊浦肯野纤维上,比较脂布福吉宁(RBG)(?)乙酰毒毛花甙元(AS)对诱发延时性后去极化(DAD)和触发性心律失常(TA)的作用,结果:1)低中毒剂量于刺激为990和690 ms时诱发出胞内和胞外的DAD;2)高中毒剂量诱发出DAD及TA,包含过早动作电位及触发性心动过速等;3)均引起动作电位振幅、静息电位及最大舒张期电位的降低、50％APD及Q-T间期的缩短,故RBG属于洋地黄类药物。     

Effects of WAY-123,398, a new class III antiarrhythmic agent, on cardiac refractoriness and ventricular fibrillation threshold in anesthetized dogs: a comparison with UK-68798, E-4031, and dl-sotalol.

Previous studies in isolated ventricular myocytes showed that WAY-123,398 is a selective blocker of the delayed rectifier K+ current (IK). In this report, we studied the electrophysiological and hemodynamic effects of WAY-123,398 in open-chest anesthetized dogs. WAY-123,398 prolonged atrial and ventricular refractoriness without affecting conduction; WAY-123,398 was as effective as UK-68798, E-4031, and dl-sotalol, but less potent than UK-68798 and E-4031. The increase in atrial refractoriness was approximately twice as large as the ventricular increase with all compounds. The hemodynamic effects of WAY-123,398 were similar to those of UK-68798; at the ED20 for increasing ventricular refractoriness, WAY-123,398 did not affect the mean arterial pressure and decreased the heart rate by 20%. In a different series of experiments, all four compounds produced large and comparable increases in the ventricular fibrillation threshold in anesthetized dogs; WAY-123,398 and UK-68798 induced defibrillation and restoration of sinus rhythm in two of six dogs each and E-4031 in one of six dogs. No episodes of drug-induced restoration to sinus rhythm were observed in dogs treated with sotalol or vehicle. In conclusion, WAY-123,398 is an effective Class III agent without Class I actions and with a favorable hemodynamic profile.     

Effects of the class III antiarrhythmic agent dofetilide (UK-68,798) on L-type calcium current from rabbit ventricular myocytes.

The methanesulphonanilide agent dofetilide (UK-68,798) exerts Class III antiarrhythmic effects by inhibiting the cardiac rapid delayed rectifier potassium current (I(Kr)) encoded by HERG. The aim of the present study was to determine whether dofetilide also exhibits Class IV (L-type calcium-channel blocking) effects. L-type calcium current (I(Ca,L)) was measured from rabbit isolated ventricular myocytes, using the whole-cell patch-clamp technique under selective recording conditions. Positive control experiments demonstrated inhibition of I(Ca,L) elicited by pulses to + 10 mV by both nifedipine and externally applied Ni2+ ions. Three concentrations of dofetilide were tested: 100 nM, 1 microM and 10 microM. I(Ca,L) magnitude was not significantly reduced by any of the concentrations tested (P > 0.05; n = minimum of seven cells per drug concentration). The inactivation time-course of I(Ca,L) was also unaffected by 10 microM dofetilide. Heterologously expressed HERG current (I(HERG)) recorded from Chinese Hamster Ovary cells was extensively inhibited by 100 nm and 1 microM dofetilide, with inhibition at 1 microM not significantly different from 100% (P > 0.1). It is concluded that dofetilide produced no I(Ca,L) blocking effects at concentrations up to and exceeding that required for maximal I(HERG) inhibition. The findings support the notion that dofetilide is a highly selective Class III antiarrhythmic agent, devoid of Class IV antiarrhythmic activity.