Emerging antiarrhythmic agents: a personal view from the Far East.

INTRODUCTION: Arrhythmia treatments today take three different approaches. One uses electronic devices, such as electronic pacemakers or defibrillators, and this is regarded as life-saving in cases of bradyarrhythmias and ventricular fibrillation. Another is the ablation technique which eliminates abnormal pacemakers and/or conductive pathways by applying thermal or cryo-injury to pathological portions of the heart. The most classical one is the antiarrhythmic drugs, but are they effective and safe? AREAS COVERED: Recent development of the understanding of arrhythmias, cardiac ionic channels and antiarrhythmic drugs covered by papers mostly published after 2000 are discussed. EXPERT OPINION: The market size of the antiarrhythmic drugs is small, but various multichannel acting drugs may become candidates as antiarrhythmic drugs. As the cardiac ionic channels have become recognized as proteins, the molecular target for antiarrhythmic drugs has become apparent, but at the same time accurate data on clinical effectiveness and safety are required for drug approval; thus, few atrium selective drugs, such as IKur, IKACh and IKAde blocking drugs and amiodarone-like multichannel acting drugs are being developed.

Torsades de pointes liability inter-model comparisons: the experience of the QT PRODACT initiative.

Safety pharmacologists from the Japanese pharmaceutical industries and contract laboratories made a database to evaluate drug effects on the QT interval in 2005. This QT PRODACT project was a prospective study of 12 QT-prolonging (positive) drugs and 10 non-prolonging (negative) drugs to evaluate the specificity and sensitivity of several in vivo and in vitro animal models: in vitro guinea pig papillary muscle action potential recordings and in vivo ECG recordings in unanesthetized or anesthetized beagle dogs, cynomolgus monkeys and miniature pigs. In guinea pig papillary muscle action potential recordings, positive drugs showed lengthening of the action potential duration (APD). By using a new measure to detect triangulation of the action potential configuration, an IKr blocking activity of drugs with Ca channel blocking action was detected. All in vivo studies showed a QT-prolonging effect of greater than 10% for the positive drugs. These in vivo models were useful to distinguish positive from negative drugs. The QT PRODACT project showed reliability and sensitivity of the experiments to detect positive drugs. The proarrhythmic effects of these positive drugs could not be detected even though, in some animal models (e.g., unanesthetized monkey), torsades de pointes (TdP)-type arrhythmias were shown by terfenadine. We compared in vivo arrhythmia models for proarrhythmia. The halothane-anesthetized open chest coronary occlusion-reperfusion canine model, the halothane-adrenaline arrhythmia model and the chronic AV block dog models seemed to be useful to detect the arrhythmogenic potential of QT-prolonging drugs.

Cardiovascular profile of the canine torsades de pointes arrhythmia model assessed by echocardiographic and haemodynamic methods.

Chronic atrioventricular block dogs have been established as an in vivo model of drug-induced torsades de pointes arrhythmias. We compared the cardiovascular profile of the canine model with that of sham-operated animals using echocardiographic and haemodynamic methods. In the echocardiographic study, the larger diameters of the left atria, inferior vena cava and left ventricle in end-diastole in addition to greater fractional shortening, end-diastolic volume, stroke volume and ejection fraction were more often detected in the chronic atrioventricular block dogs than in the sham-operated animals. During haemodynamic examination, lower cardiac output and higher pulmonary capillary wedge pressure were detected in chronic atrioventricular block dogs more than in sham-operated animals; however, these changes were within the physiological limits, and the results suggest that the chronic atrioventricular block dogs have a pathophysiological profile of chronic compensated heart failure.

Arrhythmia models for drug research: classification of antiarrhythmic drugs.

The aim of this study was to classify antiarrhythmic drugs based on their effectiveness on 6 in vivo arrhythmia models, mainly using dogs. The models were produced by two-stage coronary ligation, digitalis, halothane-adrenaline, programmed electrical stimulation in old myocardial infarction dogs, coronary artery occlusion/reperfusion, or chronic atrioventricular block. Na(+)-channel-blocking drugs suppressed two-stage coronary ligation and digitalis arrhythmias. Ca(2+)-channel blockers and beta-blockers suppressed halothane-adrenaline arrhythmia. Positive inotropic drugs aggravated halothane-adrenaline arrhythmia, but did not aggravate digitalis arrhythmia. K(+)-channel blockers suppressed programmed electrical stimulation induced arrhythmia, but induced torsades de pointes type arrhythmia in chronic atrioventricular block dogs and aggravated halothane-adrenaline arrhythmia. Na(+)/H(+)-exchange blockers suppressed coronary artery occlusion/reperfusion arrhythmias. This classification may be useful for predicting the clinical effectiveness in the preclinical stage of drug development.

Pravastatin inhibits arrhythmias induced by coronary artery ischemia in anesthetized rats.

We have reported that chronically administered pravastatin prevented coronary artery reperfusion-induced lethal ventricular fibrillation (VF) in anesthetized rats without lowering the serum cholesterol level. The present study was undertaken to evaluate whether pravastatin prevents ischemia-induced lethal VF, simultaneously examining myeloperoxidase (MPO) activity in ischemic myocardial tissues. Anesthetized rats were subjected to 30-min ischemia and 60-min reperfusion after chronic administration of pravastatin (0.02, 0.2, and 2 mg/kg), fluvastatin (2 and 4 mg/kg), or vehicle for 22 days, orally, once daily. ECG and blood pressure were continually recorded, and MPO was measured by a spectrophotometer. Pravastatin and fluvastatin significantly (P<0.05) decreased MPO activities, but only pravastatin decreased the incidence of ischemia-induced lethal VF. Both statins had no significant effects on body weight, blood pressure, heart rate, and QT interval as we reported earlier. Our results prove further that pravastatin has benefits to decrease cardiovascular mortality beyond its cholesterol-lowering effect. Pravastatin is more potent than fluvastatin in prevention of arrhythmias. A decrease in the neutrophil infiltration may be partly involved in the inhibitory effect of pravastatin on the ischemia-induced VF.

Analysis of arrhythmogenic profile in a canine model of chronic atrioventricular block by comparing in vitro effects of the class III antiarrhythmic drug nifekalant on the ventricular action potential indices between normal heart and atrioventricular block heart.

The chronic atrioventricular block dog is a useful model for predicting the future onset of drug-induced long QT syndrome in clinical practice. To better understand the arrhythmogenic profile of this model, we recorded the action potentials of the isolated ventricular tissues in the presence and absence of the class III antiarrhythmic drug nifekalant. The action potential durations of the Purkinje fiber and free wall of the right ventricle were longer in the chronic atrioventricular block dogs than in the dogs with normal sinus rhythm. Nifekalant in concentrations of 1 and 10 microM prolonged the action potential durations of Purkinje fiber and the free wall in a concentration-dependent manner. The extent of prolongation was greater in the chronic atrioventricular block dogs than in the normal dogs. However, increase of temporal dispersion of ventricular repolarization including early afterdepolarization was not detected by nifekalant in either group of dogs, indicating lack of potential to trigger arrhythmias in vitro. These results suggest that the ventricular repolarization delay in the chronic atrioventricular block model by nifekalant may largely depend on the decreased myocardial repolarization reserve, whereas the trigger for lethal arrhythmia was not generated in the in vitro condition in contrast to the in vivo experiment.

Analysis of proarrhythmic potential of antipsychotics risperidone and olanzapine in anesthetized dogs.

In vitro electrophysiological studies have shown that second-generation antipsychotic drugs risperidone and olanzapine inhibit rapidly activating delayed rectifier K(+) currents and prolong action potential duration of the isolated ventricular myocardium. In this study, we analyzed in vivo cardiohemodynamic and electrophysiological profiles of risperidone and olanzapine using the halothane-anesthetized canine model to clarify their proarrhythmic potential. A clinically relevant dose of risperidone (0.03 mg/kg, i.v.) did not affect the ventricular repolarization process, whereas the supra-therapeutic doses (0.3 and 3 mg/kg, i.v.) prolonged the duration of monophasic action potential of the ventricle. Furthermore, the terminal repolarization period, an index of extent of electrical vulnerability, was prolonged after the supra-therapeutic doses. In contrast, therapeutic to supra-therapeutic doses of olanzapine (0.03-3 mg/kg, i.v.) hardly affected the ventricular repolarization process. Therefore, more caution has to be paid on the use of risperidone than olanzapine for patients with risks of the elevated plasma concentration.

Comparison of four rate-correction algorithms for the ventricular repolarization period in assessing net effects of IKr blockers in dogs.

The utility of corrected and uncorrected QT interval changes for assessing net repolarization delay by I(Kr) (a rapid component of delayed rectifier K(+) currents) blockers was assessed in halothane-anesthetized dogs using the electrocardiogram and monophasic action potential (MAP) recordings with electrical ventricular pacing. Intravenous administration of dl-sotalol (0.2 - 2 mg/kg) prolonged the MAP duration and RR interval, while terfenadine (3 mg/kg) increased the MAP duration but transiently shortened RR interval. The order of correlation coefficient between the MAP duration at a pacing cycle length of 400 ms and MAP duration itself or that with arithmetical correction was uncorrected > Van de Water = Matsunaga > Fridericia > Bazett. These results suggest that Matsunaga's and Van de Water's formulae would better predict the net repolarization delay in the in vivo canine model. Also, the risk of drug candidates that may prolong the QT interval should be judged by change in uncorrected QT interval as well as corrected QT interval.

Topics on the Na+/Ca2+ exchanger: involvement of Na+/Ca2+ exchange system in cardiac triggered activity.

Sodium-calcium exchange (NCX) is one of the major regulators of intracellular Ca(2+) concentration in cardiac myocytes. The bi-directional and electrogenic property of NCX raises a question about whether NCX is involved in arrhythmias. We reviewed the role of NCX in cardiac triggered activity in limited experimental conditions: the digitalis-induced arrhythmia, the arrhythmia caused from sustained opening of sodium channel, and the arrhythmia caused from the inhibition of inwardly rectifying potassium current. Effects of NCX inhibitors on ventricular arrhythmias recorded on ECG or the delayed afterdepolarizations and triggered activity recorded by the current clamp method were evaluated. As an NCX inhibitor, we preferred to use SEA0400 instead of KB-R 7943. For a precise analysis, a computational reconstruction of action potential with the Luo and Rudy model was applied. The cardiac NCX system seems to play a role only in the digitalis-induced arrhythmia and may not be involved in other arrhythmias. This review highlights the relationship between triggered activity and an NCX system and also suggests the physiologic and pathologic aspect of the NCX system in cardiac arrhythmias.

Characterization of the halothane-anesthetized guinea-pig heart as a model to detect the K+ channel blocker-induced QT-interval prolongation.

Our previous study using the urethane-anesthetized guinea-pig model has shown that an I(Ks) blocker chromanol 293B hardly affects the QT interval itself nor potentiates the I(Kr) blocker-induced QT-interval prolongation. The former is in good accordance with the previous results in the human isolated intact ventricular tissue, but the latter is in sharp contrast with them. In this study, we characterized the ventricular repolarization ability of a newly developed halothane-anesthetized guinea-pig model by using I(Kr) and I(Ks) blockers. Intravenous administration of a selective I(Kr) blocker d-sotalol (3 mg/kg) prolonged the QT interval by +27 ms. On the other hand, intravenous administration of chromanol 293B (1 mg/kg) prolonged the QT interval by +35 ms, and additional administration of the same dose of d-sotalol further prolonged the QT interval by +48 ms. These results suggest that the abundance of the repolarization reserve among the current and previous models may be in the order of the urethane-anesthetized guinea-pig heart>human intact ventricular tissue>halothane-anesthetized guinea-pig heart. Thus, the halothane-anesthetized guinea-pig model may be considered to be more sensitive than the previous models in predicting the QT-interval prolonging effects of new drugs in patients with high risks for the acquired long QT syndrome.

Acute hypokalemia may not be an effective way to sensitize the in situ canine heart for sparfloxacin-induced long QT syndrome.

Extents of the sparfloxacin (3 - 10 mg/kg, i.v.)-induced QT interval prolongation under normokalemic and hypokalemic conditions were assessed in halothane-anesthetized beagle dogs (n = 5). The hypokalemic condition was induced by an oral administration of furosemide (200 mg/kg per day) for 3 days, which decreased the serum potassium concentration from 3.65 +/- 0.13 to 2.35 +/- 0.13 mM (P < 0.05). However, the decrease of potassium concentration by itself did not affect the extent of the sparfloxacin-induced QT interval prolongation. These results indicate that acute hypokalemia may not severely sensitize the in situ heart for drug-induced long QT syndrome as previously thought.

Long-term bradycardia caused by atrioventricular block can remodel the canine heart to detect the histamine H1 blocker terfenadine-induced torsades de pointes arrhythmias.

Although a second-generation histamine H(1) blocker terfenadine induced torsades de pointes (TdP) arrhythmias in patients via the blockade of a rapid component of delayed rectifier K(+) current (I(Kr)), such action of terfenadine has not been detected in previous animal models. We analysed the potential of the canine persistent atrioventricular block heart, a new in vivo proarrhythmia model, to detect a torsadogenic effect of terfenadine of an oral dose of 3 or 30 mg kg(-1). The doses can provide therapeutic to supra-therapeutic plasma concentrations as an anti-histamine. In 2 weeks of bradycardiac heart model, there were no significant changes in any of the electrocardiogram parameters after the administration of both doses of terfenadine. In 4-6 weeks of bradycardiac heart model, the low dose of terfenadine hardly affected any of the electrocardiogram parameters except that it induced TdP in one out of six animals. The high dose significantly decreased the atrial rate and ventricular rate, prolonged the QT interval, and induced TdP in five out of six animals. Moreover, temporal variability of repolarization increased after the high-dose administration. These results suggest that long-term bradycardia caused by atrioventricular block can remodel the canine heart to detect terfenadine-induced TdP.

Effectiveness of oral magnesium in a patient with ventricular tachycardia due to hypomagnesemia.

A 12-year-old girl with occasional symptoms of chest discomfort was diagnosed with ventricular tachycardia on cardiac evaluation. No evidence of organic heart disease was apparent, but a laboratory evaluation revealed hypomagnesemia. Ventricular tachycardia disappeared after treatment with 200 mg/day of oral magnesium hydroxide, and no further chest discomfort was reported. In addition to routine cardiac evaluation for arrhythmia, serum magnesium levels should be checked in patients with suspected idiopathic benign ventricular tachycardia. Treatment with oral magnesium is a physiologic therapy and should be considered for patients with ventricular tachycardia due to hypomagnesemia.

Halothane sensitizes the guinea-pig heart to pharmacological IKr blockade: comparison with urethane anesthesia.

Potential utility of halothane-anesthetized guinea pigs for detecting drug-induced repolarization delay was analyzed in comparison with urethane-anesthesia (n = 4 for both groups). Basal QT interval was significantly greater under halothane-anesthesia than urethane-anesthesia (192 +/- 7 vs 132 +/- 5 ms, respectively), whereas the reverse was true for the heart rate (190 +/- 7 vs 248 +/- 11 beats/min, respectively). The typical I(Kr)-blocker dl-sotalol (0.1 to 3 mg/kg, i.v.) induced dose-related bradycardia and QT interval prolongation under each anesthesia. The extent of maximum prolongation in the QT interval was greater under halothane-anesthesia than urethane-anesthesia (+101 +/- 15 vs +49 +/- 3 ms, respectively), whereas that of peak change in the heart rate was smaller under the former than the latter (-49 +/- 8 vs -63 +/- 5 beats/min, respectively). Pretreatment of the animals under urethane-anesthesia with the selective I(Ks) blocker chromanol 293B (n = 6) increased the extent of the dl-sotalol-induced QT interval prolongation to +57 +/- 8 ms, which was only 0.56 times of that under the halothane-anesthesia, whereas the pretreatment increased the peak change in the heart rate to -76 +/- 12 ms. These results indicate that the halothane-anesthesia may effectively sensitize the guinea-pig heart to pharmacological I(Kr) blockade.

Practical application of guinea pig telemetry system for QT evaluation.

The purpose of this study was to evaluate a telemetry system for examining QT evaluation in the conscious free-moving guinea pig using 10 reference compounds whose effects on human QT interval are well established: 8 positive references (bepridil, terfenadine, cisapride, haloperidol, pimozide, quinidine, E-4031 and thioridazine), and 2 negative references (propranolol and nifedipine). Pharmacokinetic experiments were also performed for the 8 positive references. Telemetry transmitters were implanted subcutaneously in male Hartley guinea pigs, and the RR and QT intervals were measured. All 8 positive references prolonged QTc (QTc = k x QT/RR(1/2)) 10% or more during the 60 min observation period. When the values of the QTc changes were plotted against the serum concentrations, the resulting curves exhibited an anticlockwise hysteresis loop for all 8 references. In guinea pigs treated with haloperidol, changes of the T-wave shape from positive to flat were observed. The 2 negative references did not prolong the QTc. These findings suggest that the present telemetry guinea pig model is useful for QT evaluation in the early stages of drug development, because of the small body size of guinea pigs and their action potential configuration, which is similar to that of humans.

Effects of KB-R9032, a new Na+/H+ exchange inhibitor, on canine coronary occlusion/reperfusion-induced ventricular arrhythmias.

We investigated the effects of KB-R9032 (N-(4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl) guanidine methanesulfonate), a new Na(+)/H(+) exchange inhibitor, on a coronary artery occlusion/reperfusion-induced arrhythmia model in pentobarbital anesthetized dogs. KB-R9032 reduced the number of ventricular premature contractions seen during the coronary occlusion, while it did not alter the heart rate, mean blood pressure, or electrocardiographic parameters (PR, QRS, or QTc interval). KB-R9032 also decreased the incidence of fatal ventricular fibrillation during coronary artery occlusion and/or after reperfusion. These antiarrhythmic effects were observed not only in the pre-ischemic administration group, but also in the group given KB-R9032 at the 15th min of the 30-min occlusion. These findings support the view that Na(+)/H(+) exchanger may play an important role in inducing coronary ischemia/reperfusion arrhythmias. This suggests that the use of Na(+)/H(+) exchange inhibitors, such as KB-R9032, may be an effective clinical approach to suppress sudden cardiac death due to acute myocardial ischemia/reperfusion such as during coronary bypass surgery, cardiac valve surgery, or percutaneous transluminal coronary angioplasty.

Reduction of repolarization reserve by halothane anaesthesia sensitizes the guinea-pig heart for drug-induced QT interval prolongation.

The utility of halothane-anaesthetized guinea-pigs as an in vivo model for predicting the clinical potential of a drug to induce QT interval prolongation was assessed using the electrocardiogram and monophasic action potential (MAP) recordings with electrical ventricular pacing. Intravenous administration of D-sotalol (0.3 mg kg(-1)) and terfenadine (0.3 mg kg(-1)), blockers of a rapid component of delayed rectifier potassium currents, prolonged the QT interval by 32+/-7 and 23+/-6 ms, respectively, whereas chromanol 293B (1 mg kg(-1)), a blocker of a slow component of delayed rectifier potassium currents, lengthened it by 33+/-8 ms. The extent of the QT interval prolongation by these drugs was greater than those in previous reports using pentobarbital-anaesthetized guinea-pigs. The MAP duration at the control was shortened by decreasing the pacing cycle length from 400 to 200 ms, but the MAP duration at each cycle length was prolonged by D-sotalol. The formulas of Van de Water, Matsunaga, Fridericia and Bazett showed good correlation of the repolarization period when compared with the MAP duration at a pacing cycle length of 400 ms. The halothane-anaesthetized guinea-pig model may possess enough sensitivity to detect drug-induced QT interval prolongation, indicating that halothane anaesthesia can reduce the repolarization reserve of the heart in vivo.

A red wine vinegar beverage can inhibit the renin-angiotensin system: experimental evidence in vivo.

A new beverage made of red wine vinegar and grape juice (Budo-no-megumi) was developed for people who wish to take effective amount of both polyphenols and vinegar. Since the beverage was recently demonstrated to exert hypotensive effect in rats, we analyzed its underlying mechanisms in this study. Sprague-Dawley rats were anesthetized with pentobarbital, and the blood pressure and lead II ECG were continuously monitored (n=6). The effects of recommended volume of the beverage (3 ml/kg, p.o.) on the renin-angiotensin system were assessed in vivo. At the basal control state, the increase in the mean blood pressure induced by the angiotensin I (1 microg/kg, i.v.) and norepinephrine (0.3-3 microg/kg, i.v.) were +57+/-2 and +36+/-8 mmHg, respectively. Sixty minutes after the administration of the beverage, the angiotensin I-induced pressor response decreased to +45+/-7 mmHg at 60 min (p<0.05), whereas no significant change was detected in the norepinephrine-induced pressor response. In another parallel series of the experiment using Sprague-Dawley rats (n=6), the serum angiotensin-converting enzyme activity was 39.4+/-1.2 IU/l at basal control state, which was slightly but significantly decreased to 37.0+/-1.4 IU/l at 60 min after the administration of the beverage (p<0.01). These results suggest that previously described hypotensive action of the beverage may be partly induced by the inhibition of angiotensin-converting enzyme.

A simple in vivo atrial fibrillation model of rat induced by transesophageal atrial burst pacing.

A simple in vivo closed-chest atrial fibrillation (Af) model of rats was developed. Af was reproducibly induced by transesophageal atrial burst pacing for 30 s in each of the pentobarbital-anesthetized rats, whereas the cardiohemodynamic condition as well as the inducibility and duration of Af episode was stable over time. Moreover, the anti-Af effect of the class Ic drug pilsicainide was confirmed in this model, which was essentially the same as those reported previously in other Af animal models and clinical practice. Thus, this new model may become an alternative to current techniques.

Comparison of the direct negative dromotropic effect of a new calcium channel blocker, cilnidipine, with that of nicardipine.

We encountered a 91-year-old woman with atrial fibrillation complicating bradycardia while she was receiving therapy with an L/N-type calcium channel blocker, cilnidipine, for hypertension, which is an unusual observation for the dihydropyridine class of calcium channel blockers. Therefore, we compared the dromotropic effect of cilnidipine with that of an L-type calcium channel blocker, nicardipine, which has a similar hypotensive activity. The canine isolated, blood-perfused atrioventricular node preparation was used. Cilnidipine as well as nicardipine slowed atrioventricular nodal conduction in a dose-related manner. However, the dromotropic action of cilnidipine was about five times less potent than that of nicardipine. These experimental results may suggest that we experienced an atypical clinical event of cilnidipine in a very old woman; otherwise one can speculate that the N-type calcium channel inhibitory component of cilnidipine might have played a role in exerting the negative dromotropic effect in this patient.