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

Abstract

Abstract. 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 µM 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.

Measurements of Cardiac Ion Channel Subunits in the Chronic Atrioventricular Block Dog

“…The lower mRNA level of KvLQT1 in the chronic atrioventricular block heart may be a culprit change to enhance pharmacological or toxicological actions of I Kr blockers as observed in our previous study (7), which can be strongly supported by a previous study showing that pharmacological blockade of I Ks channels by chromanol 293B promoted prolonging action of I Kr blockers in the isolated canine myocardium (14). On the other hand, no significant change was detected in the mRNA levels of L-type, T-type, or N-type Ca 2+ channels in this study, suggesting that precise cellular mechanisms of Ca 2+ mobilization resulting in the onset of torsades de pointes in this animal model should be analyzed by a functional assay system with and without pathophysiological conditions such as an elevated plasma catecholamine level (5).…”

“…The surgical procedure using a catheter ablation technique was carried out according to previous reports (3,5,7,9). Briefly, the beagle dogs were anesthetized with sodium pentobarbital (30 mg/kg, i.v.)…”

“…Furthermore, the chronic atrioventricular block heart is known to be more sensitive to I Kr blockers than the intact heart due to the decrease of repolarization reserve (7). Excess prolongation of action potential duration occasionally induces early afterdepolarization, which is closely associated with cardiac K + -channel inhibition and Ca 2+ overload (8).…”

New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Acute Effects of Female Hormones on Cardiac Ion Channels and Cardiac Repolarization

“…The incidence of drug-induced arrhythmia is also affected by other risk factors such as gender (1 -3) or/ and sympathetic nervous system activity (10,11). Because drug-induced QT prolongation is the most common reason for withdrawal of medications from the market, pharmaceutical companies and basic researchers are striving to improve ways to predict the risk of novel agents as early as possible (8,12,13). Thus, unraveling the molecular basis for the effects of such risk factors may be beneficial for avoiding this lethal side effect.…”

Electrophysiological Effects of the Antiarrhythmic Drug Bepridil on the Guinea-Pig Pulmonary Vein Myocardium

“…[17][18][19] Since the current densities of the I K1 and I to channels were smaller in the pulmonary vein myocardium than the left atrium, 2) we speculated that such electrophysiological properties in the pulmonary vein myocardium sensitize the myocardium to the multi-K + channel blocker bepridil. [10][11][12][13] The electrophysiological features of the pulmonary vein myocardium in the diseased condition may be different from those in the normal one, since our previous study has shown that chronic volume overload to the heart abbreviated the action potential of the canine pulmonary vein myocardium, 20) which is in accordance with a clinical report that showed shorter effective refractory period of the pulmonary vein myocardium in patients with paroxysmal and persistent atrial fibrillation.…”