Pentamidine-induced long QT syndrome and block of hERG trafficking

The diamidine pentamidine is used to treat leishmaniasis, trypanosomiasis, and Pneumocystis carinii pneumonia. Treatment may be accompanied by prolongation of the QT interval of the electrocardiogram and torsades de pointes tachycardias. Up to now, it has been thought that therapeutic compounds causing QT prolongation are associated with direct block of the cardiac potassium channel human ether a-go-go-related gene (hERG), which encodes the alpha subunit of cardiac I(Kr) currents. We show that pentamidine has no acute effects on currents produced by hERG, KvLQT1/mink, Kv4.3, or SCNA5. Cardiac calcium currents and the guinea pig cardiac action potential were also not affected. After overnight exposure, however, pentamidine reduced hERG currents and inhibited trafficking and maturation of hERG with IC(50) values of 5 to 8 microM similar to therapeutic concentrations. Surface expression determined in a chemiluminescence assay was reduced on exposure to 10, 30, and 100 microM pentamidine by about 30, 40, and 70%, respectively. These effects were specific for hERG since expression of hKv1.5, KvLQT1/minK, and Kv4.3 was not altered. In isolated guinea pig ventricular myocytes, 10 microM pentamidine prolonged action potential duration APD(90) from 374.3 +/- 57.1 to 893.9 +/- 86.2 ms on overnight incubation. I(Kr) tail current density was reduced from 0.61 +/- 0.09 to 0.39 +/- 0.04 pA/pF. We conclude that pentamidine prolongs the cardiac action potential by block of hERG trafficking and reduction of the number of functional hERG channels at the cell surface. We propose that pentamidine, like arsenic trioxide, produces QT prolongation and torsades de pointes in patients by inhibition of hERG trafficking.     

Cardiac ion channel effects of tolterodine

Tolterodine is a muscarinic antagonist widely used in the treatment of urinary incontinence. Although tolterodine has not been reported to alter cardiac repolarization, it is chemically related to other muscarinic antagonists known to prolong cardiac repolarization. For this reason, we studied the effects of tolterodine on cardiac ion channels and action potential recordings. Using patch-clamp electrophysiology, we found that tolterodine was a potent antagonist of the human ether-a-go-go-related gene (HERG) K(+) channel, displaying an IC(50) value of 17 nM. This potency was similar to that observed for the antiarrhythmic drug dofetilide (IC(50) of 11 nM). Tolterodine block of HERG displayed a positive voltage dependence, suggesting an interaction with an activated state. Tolterodine had little effect on the human cardiac Na(+) channel at concentrations of up to 1 microM. Inhibition of L-type Ca(2+) currents by tolterodine was frequency-dependent with IC(50) values measuring 143 and 1084 nM at 1 and 0.1 Hz, respectively. Both tolterodine and dofetilide prolonged action potential duration in single guinea pig myocytes over the concentration range of 3 to 100 nM. However, prolongation was significantly larger for dofetilide compared with tolterodine. Tolterodine seems to be an unusual drug in that it blocks HERG with high affinity, but produces little QT prolongation clinically. Low plasma levels after therapeutic doses combined with mixed ion channel effects, most notably Ca(2+) channel blockade, may serve to attenuate the QT prolonging effects of this potent HERG channel antagonist.     

QT prolongation through hERG K(+) channel blockade: current knowledge and strategies for the early prediction during drug development

Prolongation of the QT interval of the electrocardiogram is a typical effect of Class III antiarrhythmic drugs, achieved through blockade of potassium channels. In the past decade, evidence has accrued that several classes of drugs used for non-cardiovascular indications may prolong the QT interval with the same mechanism (namely, human ether-a-go-go-related gene (hERG) K(+) channel blockade). The great interest in QT prolongation is because of several reasons. First, drug-induced QT prolongation increases the likelihood of a polymorphous ventricular arrhythmia (namely, torsades de pointes, TdP), which may cause syncope and degenerate into ventricular fibrillation and sudden death. Second, the fact that several classes of drugs, such as antihistamines, fluoroquinolones, macrolides, and neuroleptics may cause the long QT syndrome (LQTS) raises the question whether this is a class effect (e.g., shared by all agents of a given pharmacological class) or a specific effect of single agents within a class. There is now consensus that, in most cases, only a few agents within a therapeutic class share the ability to significantly affect hERG K(+) channels. These compounds should be identified as early as possible during drug development. Third, QT prolongation and interaction with hERG K(+) channels have become surrogate markers of cardiotoxicity and have received increasing regulatory attention. This review briefly outlines the mechanisms leading to QT prolongation and the different strategies that can be followed to predict this unwanted effect. In particular, it will focus on the approaches recently proposed for the in silico screening of new compounds.     

Cardiac glycosides as novel inhibitors of human ether-a-go-go-related gene channel trafficking

Direct block of the cardiac potassium channel human ether-a-go-go-related gene (hERG) by a large, structurally diverse group of therapeutic compounds causes drug-induced QT prolongation and torsades de pointes arrhythmias. In addition, several therapeutic compounds have been identified more recently that prolong the QT interval by inhibition of hERG trafficking to the cell surface. We used a surface expression assay to identify novel compounds that interfere with hERG trafficking and found that cardiac glycosides are potent inhibitors of hERG expression at the cell surface. Further investigation of digitoxin, ouabain, and digoxin revealed that all three cardiac glycosides reduced expression of the fully glycosylated cell surface form of hERG on Western blots, indicating that channel exit from the endoplasmic reticulum is blocked. Likewise, hERG currents were reduced with nanomolar affinity on long-term exposure. hERG trafficking inhibition was initiated by cardiac glycosides through direct block of Na(+)/K(+) pumps and not via off-target interactions with hERG or another closely associated protein in its processing or export pathway. In isolated guinea pig myocytes, long-term exposure to 30 nM of the clinically used drugs digoxin or digitoxin reduced hERG/rapidly activating delayed rectifier K(+) current (I(Kr)) currents by approximately 50%, whereas three other cardiac membrane currents--inward rectifier current, slowly activating delayed rectifier K(+) current, and calcium current--were not affected. Importantly, 100 nM digitoxin prolonged action potential duration on long-term exposure consistent with a reduction in hERG/I(Kr) channel number. Thus, cardiac glycosides are able to delay cardiac repolarization at nanomolar concentrations via hERG trafficking inhibition, and this may contribute to the complex electrocardiographic changes seen with compounds such as digitoxin.     

In vitro cardiovascular effects of dihydroartemisin-piperaquine combination compared with other antimalarials

The in vitro cardiac properties of dihydroartemisinin (DHA) plus piperaquine phosphate (PQP) were compared with those of other antimalarial compounds. Results with antimalarial drugs, chosen on the basis of their free therapeutic maximum concentration in plasma (C(max)), were expressed as the fold of that particular effect with respect to their C(max). The following tests were used at 37 °C: hERG (human ether-à-go-go-related gene) blockade and trafficking, rabbit heart ventricular preparations, and sodium and slow potassium ion current interference (I(Na) and I(Ks), respectively). Chloroquine, halofantrine, mefloquine, and lumefantrine were tested in the hERG studies, but only chloroquine, dofetilide, lumefantrine, and the combination of artemether-lumefantrine were used in the rabbit heart ventricular preparations, hERG trafficking studies, and I(Na) and I(Ks) analyses. A proper reference was used in each test. In hERG studies, the high 50% inhibitory concentration (IC(50)) of halofantrine, which was lower than its C(max), was confirmed. All the other compounds blocked hERG, with IC(50)s ranging from 3- to 30-fold their C(max)s. In hERG trafficking studies, the facilitative effects of chloroquine at about 30-fold its C(max) were confirmed and DHA blocked it at a concentration about 300-fold its C(max). In rabbit heart ventricular preparations, dofetilide, used as a positive control, revealed a high risk of torsades de pointes, whereas chloroquine showed a medium risk. Neither DHA-PQP nor artemether-lumefantrine displayed an in vitro signal for a significant proarrhythmic risk. Only chloroquine blocked the I(Na) ion current and did so at about 30-fold its C(max). No effect on I(Ks) was detected. In conclusion, despite significant hERG blockade, DHA-PQP and artemether-lumefantrine do not appear to induce potential torsadogenic effects in vitro, affect hERG trafficking, or block sodium and slow potassium ion currents.     

Direct block of human ether-a-go-go-related gene potassium channels by caffeine

The human ether-a-go-go-related gene (hERG) potassium channel is expressed in a variety of cell types, including neurons, tumor cells, and cardiac myocytes. In the heart, it is important for repolarization of the cardiac action potential. Attenuation of hERG current can cause long QT syndrome and cardiac arrhythmias such as torsades de pointes. Caffeine is frequently used as a pharmacological tool to study calcium-dependent transduction pathways in cellular preparations. It raises cytosolic calcium by opening ryanodine receptors and may also inhibit phosphodiesterases to increase cytosolic cAMP. In this study, we show 5 mM caffeine rapidly and reversibly attenuates hERG currents expressed in human embryonic kidney 293 cells to 61.1 +/- 2.2% of control. Caffeine-dependent inhibition of hERG current is not altered by raising cAMP with forskolin, buffering cytosolic calcium with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, or inhibition of protein kinase C. Thus, the effects of caffeine are unlikely to be mediated by cAMP or intracellular calcium-dependent mechanisms. Further experiments showed caffeine directly blocks hERG in an open state-dependent manner. Furthermore, caffeine inhibition is greatly reduced by the pore mutants Y562A and F656A hERG, which disrupt block of most previously tested hERG antagonists. Thus, caffeine attenuates hERG currents by binding to a drug receptor located within the inner cavity of the channel. Dietary intake of caffeine is unlikely to cause long QT syndrome because plasma concentrations do not reach sufficiently high levels to significantly inhibit hERG currents. However, the effects of caffeine have implications for its use in examining calcium-dependent pathways in cellular preparations expressing hERG.     

Mechanism of cardiotoxicity of halofantrine

OBJECTIVES AND METHODS: To further evaluate the scope and mechanism of potential cardiotoxicity associated with the antimalarial drug halofantrine, case reports submitted to the US Food and Drug Administration Spontaneous Reporting System were examined. Because halofantrine was associated with electrocardiographic prolongation of the QT interval and ventricular arrhythmias, in vitro cardiac electrophysiologic studies (isolated perfused cardiac model and isolated ventricular myocytes) were conducted to test the hypothesis that halofantrine or its metabolite is responsible for cardiotoxicity. RESULTS: Although it is difficult to ascertain causality and to estimate overall incidence, a significant number of adverse events related to the cardiovascular system were reported, including QT interval prolongation, life-threatening arrhythmias, and sudden death. The effect of halofantrine and its active metabolite (N-desbutylhalofantrine) on repolarization were examined in an isolated perfused heart model. Results indicate that halofantrine was able to prolong the QT interval, whereas N-desbutylhalofantrine had minimal effect on the QT interval relative to baseline. In an attempt to further elucidate the mechanism of QT interval prolongation, the effects of racemic halofantrine, its stereoisomers, and N-desbutylhalofantrine on repolarizing currents in isolated ventricular myocytes were studied with use of patch-clamp techniques. Halofantrine produced a stereoselective block of the delayed rectifier potassium channel in isolated feline myocytes. CONCLUSIONS: These results indicate that halofantrine is similar to quinidine and class III antiarrhythmics in its ability to prolong repolarization. We conclude that high plasma concentrations of halofantrine should be avoided, especially in women, and that N-desbutylhalofantrine may have potential as a safer antimalarial drug.     

Stereoselective block of hERG channel by (S)-methadone and QT interval prolongation in CYP2B6 slow metabolizers

Methadone inhibits the cardiac potassium channel hERG and can cause a prolonged QT interval. Methadone is chiral but its therapeutic activity is mainly due to (R)-methadone. Whole-cell patch-clamp experiments using cells expressing hERG showed that (S)-methadone blocked the hERG current 3.5-fold more potently than (R)-methadone (IC50s (half-maximal inhibitory concentrations) at 37 degrees C: 2 and 7 microM). As CYP2B6 slow metabolizer (SM) status results in a reduced ability to metabolize (S)-methadone, electrocardiograms, CYP2B6 genotypes, and (R)- and (S)-methadone plasma concentrations were obtained for 179 patients receiving (R,S)-methadone. The mean heart-rate-corrected QT (QTc) was higher in CYP2B6 SMs (*6/*6 genotype; 439+/-25 ms; n=11) than in extensive metabolizers (non *6/*6; 421+/-25 ms; n=168; P=0.017). CYP2B6 SM status was associated with an increased risk of prolonged QTc (odds ratio=4.5, 95% confidence interval=1.2-17.7; P=0.03). This study reports the first genetic factor implicated in methadone metabolism that may increase the risk of cardiac arrhythmias and sudden death. This risk could be reduced by the administration of (R)-methadone.     

Neonatal long QT syndrome due to a de novo dominant negative hERG mutation.

A 4-day-old girl with ventricular tachyarrhythmias, sinus bradycardia, and 2:1 atrioventricular block had prolongation of the QT interval. She was symptomatic with arching, gasping, and cyanosis presumably due to a life-threatening ventricular tachyarrhythmia such as torsades de pointes. Molecular genetic studies indicated a heterozygous, de novo, dominant negative mutation in hERG, a gene that encodes a protein in a potassium ion channel. The parents do not have the mutation. The patient's clinical scenario was produced by the convergence of 3 events: a de novo mutation occurred in hERG, the mutation was dominant negative, and the action of the mutation resulted in neonatal long QT syndrome. The child was treated aggressively and is doing well at age 6 years.     

Modulation of the Electrophysiologic Actions of E-4031 and Dofetilide by Hyperkalemia and Acidosis in Rabbit Ventricular Myocytes

BACKGROUND: E-4031 and dofetilide are new class III antiarrhythmic agents that inhibit the rapid component of the delayed rectifier potassium channel (I(Kr)); however, the effectiveness of many antiarrhythmic drugs in ischemic conditions is uncertain. METHODS AND RESULTS: We modeled two components of ischemia, hyperkalemia (9.6 mM) and acidosis (pH 6.8), in voltage-clamped single rabbit ventricular myocytes to help determine the effect of ischemia on the action of these two drugs. In physiologic solution both E-4031 and dofetilide blocked I(Kr) and significantly reduced total outward current. In hyperkalemic solution, both E-4031 and dofetilide showed significantly reduced blockade of I(Kr), while in acidotic solution dofetilide showed significantly reduced blockade of I(Kr) and E-4031 showed a trend to reduced blockade. Neither drug significantly reduced total outward current in hyperkalemic or acidotic solutions. CONCLUSIONS: In these conditions, E-4031 and dofetilide demonstrate reduced blockade of I(Kr), resulting in loss of class III effect. Furthermore, the complete loss of blocking effect on total outward current during simulated ischemia suggests increases of other repolarizing currents also contribute to loss of class III effect.     

Effect of Dofetilide and d-Sotalol on the ATP-Sensitive Potassium Channel of Rabbit Ventricular Myocytes

BACKGROUND: The ability of dofetilide and d-sotalol to maintain their class III action during ischemia is uncertain. We investigated the effect of these two drugs on the ATP-sensitive potassium channel (I(KATP)), which plays a major role in ischemia-induced action potential duration shortening. METHODS AND RESULTS: The activity of I(KATP) channels was studied in excised membrane patches of single ventricular myocytes, obtained by standard enzymatic dissociation techniques from New Zealand white rabbits. Dofetilide demonstrated a dose-dependent block of I(KATP) with an EC(50) of 51 +/- 1 μM in inside-out patches, Its ability to block the channel was substantially less when applied to the external membrane surface. d-Sotalol significantly blocked I(KATP) (42% reduction) at a concentration of 10 μM but not at 1 μM. As with dofetilide, its ability to block I(KATP) was reduced when applied externally. CONCLUSIONS: We conclude that dofetilide and d-sotalol block the ATP-sensitive potassium channel, but dofetilide does so only at concentrations much greater than those required for block of the delayed rectifier potassium channel. d-Sotalol in contrast shows modest blockade of I(KATP) at concentrations in the upper range of those seen during its clinical use.     

Pharmacological activation of rapid delayed rectifier potassium current suppresses bradycardia-induced triggered activity in the isolated guinea pig heart

Recently, attention has been drawn to compounds that activate the human ether-a-go-go channel potassium channel (hERG), which is responsible for the repolarizing rapid delayed rectifier potassium current (I(Kr)) in the mammalian myocardium. The compound NS3623 [N-(4-bromo-2-(1H-tetrazol-5-yl)-phenyl)-N'-(3'-trifluoromethylphenyl) urea] increases the macroscopic current conducted by the hERG channels by increasing the time constant for channel inactivation, which we have reported earlier. In vitro studies suggest that pharmacological activation is an attractive approach for the treatment of some arrhythmias. We present here data that support that NS3623 affects native I(Kr) and report the effects that activating this potassium current have in the intact guinea pig heart. In Langendorff-perfused hearts, the compound showed a concentration-dependent shortening of action potential duration, which was also detected as concentration-dependent shorter QT intervals. There was no sign of action potential triangulation or reverse use dependence. NS3623 decreased QT variability and distinctly decreased the occurrence of extrasystoles in the acutely bradypaced hearts. Taken together, the present data strongly support the concept of using hERG activators as a treatment for certain kinds of arrhythmias and suggest further investigation of this new approach.     

QTc interval prolongation associated with intravenous methadone

Numerous medications prolong the rate-corrected QT (QTc) interval and induce arrhythmias by blocking ionic current through cardiac potassium channels composed of subunits expressed by the human ether-a-go-go-related gene (HERG). Recent reports suggest that high doses of methadone cause torsades de pointes. To date, no controlled study has described an association between methadone and QTc prolongation. The only commercial formulation of parenteral methadone available in the United States contains the preservative chlorobutanol. The objectives of this study are to determine: (1) whether the administration of intravenous (i.v.) methadone causes QTc prolongation in humans; (2) whether methadone and/or chlorobutanol block cardiac HERG potassium currents (IHERG) in vitro. Over 20 months, we identified every inpatient with at least one electrocardiogram (ECG) performed on i.v. methadone. For each patient, we measured QTc intervals for every available ECG performed on and off i.v. methadone. Concurrent methadone doses were also recorded. Similar data were collected for a separate group of inpatients treated with i.v. morphine. In a separate set of experiments IHERG was evaluated in transfected human embryonic kidney cells exposed to increasing concentrations of methadone, chlorobutanol, and the two in combination. Mean difference (+/- standard error) per patient in QTc intervals on and off methadone was 41.7 (+/- 7.8)ms, p<0.0001. Mean difference in QTc intervals on and off morphine was 9.0 (+/- 6.1)ms, p=0.15. The approximately linear relationship between QTc measurements and log-dose of methadone was significant (p<0.0001). Methadone and chlorobutanol independently block IHERG in a concentration-dependent manner with IC50 values of 20 +/- 2 microM and 4.4 +/- 0.3 mM, respectively. Chlorobutanol potentiates methadone's ability to block IHERG. Methadone in combination with chlorobutanol is associated with QTc interval prolongation. Our data strongly suggest that methadone in combination with chlorobutanol is associated with QTc interval prolongation.     

Atypical proarrhythmia with dofetilide: monomorphic VT and exercise-induced torsade de pointes

Proarrhythmia with dofetilide has most typically taken the form of torsade de pointes (TdP) and generally occurs early with therapy, such that in-hospital initiation of dofetilide with 3 days of continuous electrocardiogram monitoring is recommended. This article reports two unusual variants of ventricular proarrhythmia with dofetilide: (1) nonsustained runs of monomorphic ventricular tachycardia shortly after taking the first dose of dofetilide, confirmed by rechallenge; and (2) TdP that followed the development of isolated ventricular premature beats during an exercise test in a patient with neither excessive QT prolongation on dofetilide nor any ectopy whatsoever during in-hospital telemetric monitoring but with significant QT interval prolongation after the postectopic pause. These cases demonstrate that clinicians must be alert to the appearance of proarrhythmia with dofetilide at times other than early during drug initiation if the electrophysiological milieu is altered during nonhospital activity and/or of a pattern other than TdP.     

Class III Antiarrhythmic Effects of Dofetilide in Rabbit Atrial Myocardium

BACKGROUND: Dofetilide is a new class III antiarrhythmic agent with demonstrated efficacy in ventricular and atrial tachyarrhythmias. We investigated its class III actions and their modulation by stimulation rate in rabbit atrial myocardium. METHODS AND RESULTS: Standard microelectrode techniques were used to record action potentials from rabbit atrial tissue at varying stimulation rates. Dofetilide produced a dose-dependent prolongation of action potential duration at concentrations from 1 nM to 1 μM at an interstimulus interval of 1000 ms. Action potential duration at 90% repolarization (action potential duration) was prolonged from 116 +/- 11.7 ms in control solutions to 13.9 ms at 1 nM dofetilide and 186 +/- 49.3 ms at 1 μM dofetilide (P <.05 for 1 nM vs control; P <.01 for 1 μM vs control). Reduction of interstimulus interval to 500 ms has no significant effect on action potential duration prolongation by dofetilide (P <.05 for 1 nM vs control; P <.01 for 1 μM vs control). Reduction of interstimulus interval to 500 ms had no significant effect on action potential duration prolongation by dofetilide. At faster rates than this, and particularly at an interstimulus interval less than 330 ms, a marked "reverse rate dependence" of the class III effect was observed. Specifically, the high therapeutic concentration of 10 nM showed no effect on action potential duration at interstimulus interval of 250 ms or 200 ms, and even at a concentration of 30 nM, the small class III effect was no longer statistically significant at these rates. CONCLUSIONS: Dofetilide prolongs action potential duration in rabbit atrial myocardium, but this effect is significantly attenuated at stimulation rates above 2 Hz.     

The relationship of clinical QT prolongation to outcome in the conscious dog using a beat-to-beat QT-RR interval assessment

QT interval prolongation of the electrocardiogram has been associated with the occurrence of life-threatening fatal ventricular arrhythmias. To understand the relationship between preclinical cardiac conduction assessment to clinical outcome, comparisons of free (unbound)-plasma drug concentrations and their associated effects in the conscious mongrel dog were made to the free plasma concentrations in humans reported to produce QT prolongation. E-4031 (an experimental class III antiarrhythmic), cisapride, terfenadine, terodiline, and verapamil all affect cardiac repolarization and can produce QT prolongation in humans. In the conscious dog, the QT interval was assessed on a beat-to-beat basis in relation to each preceding RR interval at concentrations approximating the same unbound human concentrations. E-4031, cisapride and terodiline statistically increased the QT(RR1000) interval [the QT interval at a 60 beats/min (bpm) heart rate] 23, 8, and 9 ms, respectively, at concentrations 0.3 to 15.8 times their relevant clinical level. Increases were not observed for terfenadine or verapamil (p > 0.05 at all doses). Inspection of individual dog QT versus RR interval relationships showed clear QT interval responses specific to each treatment but not readily apparent when data are averaged at a heart rate of 60 bpm. For specific rectifier K(+) current (IKr) blockers, robust effects on mean QT prolongation can be detected. However, for drugs that affect repolarization through multiple channels, the effect on the mean QT interval may be more difficult to detect. Inspection of the beat-to-beat QT-RR interval relationship in an individual animal can increase the sensitivity for more accurate clinical prediction.     

Molecular Biology of the Long QT Syndrome: Impact on Management

The long QT syndrome (LQTS) is a familial disease characterized by prolonged ventricular repolarization and high incidence of malignant ventricular tachyarrhythmias often occurring in conditions ofadrenergic activation. Recently, the genes for the LQTS linked to chromosomes 3 (LQT3), 7 (LQT2), and 11 (LQTl) were identified as SCN5A, the cardiac sodium channel gene and as HERG and KvLQTl potassium channel genes. These discoveries have paved the way for the development of gene-specific therapy for these three forms of LQTS. In order to test specific interventions potentially beneficial in the molecular variants of LQTS, we developed a cellular model to mimic the electrophysiological abnormalities of LQT3 and LQT2. Isolated guinea pig ventricular myocytes were exposed to anthopleurin and dofetilide in order to mimic LQT3 and LQT2, respectively. This model has been used to study the effect of sodium channel blockade and of rapid pacing showing a pronounced action potential shortening in response to Na⁺channel blockade with mexiletine and during rapid pacing only in anthopleurin-treated cells but not in dofetilide-treated cells. Based on these results we tested the hypothesis that QT interval would shorten more in LQT3 patients in response to mexiletine and to increases in heart rate. Mexiletine shortened significantly the QT interval among LQT3 patients but not among LQT2 patients. LQT3 patients shortened their QT interval in response to increases in heart rate much more than LQT2 patients and healthy controls. These findings suggest thatLQT3 patients are more likely to benefit from Na⁺ channel blockers and from cardiac pacing because they are at higher arrhythmic risk at slow heart rates. Conversely, LQT2 patients are at higher risk to develop syncope under stressful conditions, because of the combined arrhythmogenic effect of cate-cholamines with the insufficient adaptation of their QT interval. Along the same line of development of gene-specific therapy, recent data demonstrated that an increase in the extracellular concentration of potassium shortens the QT interval in LQT2 patients suggesting that intervention aimed at increasing potassium plasma levels may represent a specific treatment for LQT2. The molecular findings on LQTS suggest the possibility of developing therapeutic interventions targeted to specific genetic defects. Until definitive data become available, antiadrenergic therapy remains the mainstay in the management of LQTS patients, however it may be soon worth considering the addition of a Na + channel blocker such as mexiletine for LQT3 patients and of interventions such as K⁺ channel openers or increases in the extracellular concentration of potassium for LQTl and LQT2 patients.     

The Influence of Specific and Nonspecific Potassium Current Blockade on the Defibrillation Energy Requirement of Biphasic Shock

Block of delayed rectifier potassium current (I_K) is known to decrease defibrillation energy requirements (DERs). We tested the hypothesis that there would be no difference in DER reduction with a nonspecific I_K (I_Kr+ I_KS) blocker, ambasilide, and a specific I_Kr blocker, dofetilide. Methods: An anesthetized canine model (n = 30) of internal transvenous defibrillation with biphasic shocks was used. Ambasilide (n = 9; dose: 4.8 mg/kg, then 9.6 mg/kg/hour), dofetilide (n = 10; dose: 10 (μg/kg, then 3.6 (μg/kg/hour), or matched placebo (n = 11) were administered. DERs (J) were determined in triplicate using an increment-decrement protocol at baseline and during each treatment. ECG intervals were measured at baseline and during each treatment. ANOVA with post-hoc Bonferroni test was used for statistical analysis. Results: Ambasilide resulted in a +23.5 ± 4.06% prolongation of the QTc interval, while dofetilide resulted in a +20.5%± 3.76% prolongation of the QTc interval. Thus, the two drugs resulted in comparable prolongation of the QTc interval (P < 0.05 compared to placebo). Both drugs significantly reduced the DER (-17.7%± 5.33% reduction by ambasilide, and -21.9%± 5.21% reduction by dofetilide, P < 0.05 compared to placebo). There was no difference in the magnitude of DER reduction between the two treatments. Conclusions: Administration of equipotent doses (as indicated by QTc changes) of ambasilide or dofetilide had comparable effects on DERs. Selectivity of I_K blockade has no significant effect on the magnitude of reduction in DERs.     

Three-dimensional quantitative structure-activity relationship for inhibition of human ether-a-go-go-related gene potassium channel

The protein product of the human ether-a-go-go gene (hERG) is a potassium channel that when inhibited by some drugs may lead to cardiac arrhythmia. Previously, a three-dimensional quantitative structure-activity relationship (3D-QSAR) pharmacophore model was constructed using Catalyst with in vitro inhibition data for antipsychotic agents. The rationale of the current study was to use a combination of in vitro and in silico technologies to further test the pharmacophore model and qualitatively predict whether molecules are likely to inhibit this potassium channel. These predictions were assessed with the experimental data using the Spearman's rho rank correlation. The antipsychotic-based hERG inhibitor model produced a statistically significant Spearman's rho of 0.71 for 11 molecules. In addition, 15 molecules from the literature were used as a further test set and were also well ranked by the same model with a statistically significant Spearman's rho value of 0.76. A Catalyst General hERG pharmacophore model was generated with these literature molecules, which contained four hydrophobic features and one positive ionizable feature. Linear regression of log-transformed observed versus predicted IC(50) values for this training set resulted in an r(2) value of 0.90. The model based on literature data was evaluated with the in vitro data generated for the original 22 molecules (including the antipsychotics) and illustrated a significant Spearman's rho of 0.77. Thus, the Catalyst 3D-QSAR approach provides useful qualitative predictions for test set molecules. The model based on literature data therefore provides a potentially valuable tool for discovery chemistry as future molecules may be synthesized that are less likely to inhibit hERG based on information provided by a pharmacophore for the inhibition of this potassium channel.     

Nicorandil, a Potassium Channel Opener, Abolished Torsades de Pointes in a Patient with Complete Atrioventricular Block

TdP is a serious complication of AV block. We report a case of complete AV block with QT prolongation who had bouts of TdP resistant to lidocaine and isoproterenol. Temporary pacing could not be performed, because insertion of a pacing lead triggered TdP that deteriorated into ventricular fibrillation. Nicorandil, a potassium channel opener, shortened the QT interval and abolished TdP. This may suggest that potassium channel opening drugs are clinically effective against TdP associated with bradycardia-dependent QT prolongation.