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.

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).

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

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).

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.

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.

The endothelium-dependent vasodilator action of a new beverage made of red wine vinegar and grape juice.

A new non-alcoholic beverage made of red wine vinegar and grape juice (Budo-no-megumi) has been recently demonstrated to lower the blood pressure of human as well as rats. In this study, we pharmacologically analyzed the mechanism of its hypotensive action. The thoracic aorta with intact endothelium was isolated from Sprague-Dawley rats, and incubated with a Tyrode's solution.

Antiarrhythmic properties of a prior oral loading of amiodarone in in vivo canine coronary ligation/reperfusion-induced arrhythmia model: comparison with other class III antiarrhythmic drugs.

Amiodarone, which is generally classified as class III antiarrhythmic drug in the Vaughan Williams classification, is widely used for the treatments of refractory arrhythmias. However, we previously reported that intravenous infusion of amiodarone (6.67 mg/kg per hour) did not suppress arrhythmias induced by coronary ligation/reperfusion in dogs.

Halothane sensitizes the canine heart to pharmacological IKr blockade.

The effects of halothane and pentobarbital on the cardiovascular system were compared using the in vivo canine models. The ventricular repolarization process was longer under the halothane-anesthesia than pentobarbital-anesthesia. Intravenous administration of a selective blocker of rapidly activating delayed rectifier K+ currents (I(Kr)) sematilide prolonged the ventricular repolarization period without affecting the intraventricular conduction under both anesthesia; however, the potency was about 1.

The antipsychotic and antiemetic drug prochlorperazine delays the ventricular repolarization of the in situ canine heart.

Electropharmacological effect of the antipsychotic and antiemetic drug prochlorperazine was assessed using the halothane-anesthetized in vivo canine model (n = 5). Up to 10 times higher than the clinically relevant doses of prochlorperazine (< or = 3 mg/kg, i.v.

Effects of SEA0400, a Na+/Ca2+ exchange inhibitor, on ventricular arrhythmias in the in vivo dogs.

SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy]-5-ethoxyaniline), a novel and selective inhibitor of Na+/Ca2+ exchanger, was investigated for its possible antiarrhythmic effects on arrhythmias of Ca2+ overload induced by coronary ligation/reperfusion and by digitalis in the dog. SEA0400 (1.0 mg/kg) did not change the hemodynamics but slightly prolonged the QRS duration (P<0.