ABSTRACT
BACKGROUND AND PURPOSE: Several rabbit proarrhythmia models have been developed using genetic or pharmacological methods to suppress the slow component of delayed rectifier K+ currents in the ventricle, leading to reduction of the repolarization reserve. Here we have characterized a novel rabbit in vivo proarrhythmia model with severe bradycardia caused by acute atrioventricular block (AVB). EXPERIMENTAL APPROACH: Bradycardia was induced in isoflurane-anaesthetized rabbits by inducing AVB with catheter ablation, and the ventricle was electrically driven at 60 beats min-1 throughout the experiment except when extrasystoles appeared. We assessed the effects of two antiarrhythmics, two quinolone antibiotics and one antipsychotic drug, which were chosen as positive drugs (dofetilide, sparfloxacin and haloperidol) and negative drugs (amiodarone and moxifloxacin) for induction of Torsades de Pointes (TdP). KEY RESULTS: In our model, TdP arrhythmias appeared with high reproducibility after i.v. dofetilide (10-100 µg·kg-1 ) in five out of six rabbits, sparfloxacin (30 mg·kg-1 ) in three out of six rabbits and haloperidol (0.3-3 mg·kg-1 ) in two out of six rabbits. The lethal arrhythmias repeatedly appeared and were accompanied with prolongation of the QT interval and early afterdepolarization-like phenomena. Neither amiodarone (0.3-10 mg·kg-1 , n = 6) nor moxifloxacin (3-30 mg·kg-1 , n = 6) induced such arrhythmias, even when QT intervals were prolonged. CONCLUSIONS AND IMPLICATIONS: These results suggest that our model of the unremodelled and bradycardic heart of the anaesthetized rabbit is a useful test system for the detection of drug-induced TdP arrhythmias.
Subject(s)
Anesthesia , Anti-Arrhythmia Agents/adverse effects , Anti-Bacterial Agents/adverse effects , Antipsychotic Agents/adverse effects , Atrioventricular Block/chemically induced , Disease Models, Animal , Torsades de Pointes/chemically induced , Animals , Male , RabbitsABSTRACT
We assessed electrophysiological effects of an atypical antipsychotic drug paliperidone in acute atrioventricular block rabbits. Intravenous administration of paliperidone at a clinically relevant dose (0.06 mg/kg) hardly affected the QT interval or monophasic action potential (MAP) duration, and the higher doses (0.6 and 6 mg/kg) prolonged the QT interval and MAP duration. Meanwhile, premature ventricular contractions with R on T phenomenon were observed in 3 out of 6 animals at the middle dose, and torsades de pointes (TdP) episodes were detected in 2 out of 6 animals at the high dose. Intravenous administration of its chemically related compound risperidone at a clinically relevant dose (0.03 mg/kg) hardly affected the electrophysiological parameters, and the higher doses (0.3 and 3 mg/kg) prolonged the QT interval and MAP duration. Meanwhile, the premature ventricular contractions with R on T were observed in 2 out of 6 animals at the middle dose, and TdP episodes were detected in 4 out of 6 animals at the high dose. These results suggest that paliperidone showed torsadogenic potential at supra-therapeutic doses, whose potency can be estimated to be equal or slightly subordinate in comparison with that of risperidone.
Subject(s)
Antipsychotic Agents/adverse effects , Paliperidone Palmitate/adverse effects , Torsades de Pointes/chemically induced , Action Potentials/drug effects , Animals , Atrioventricular Block , Dose-Response Relationship, Drug , Male , Rabbits , Risperidone/adverse effectsABSTRACT
The pulmonary vein has a unique electrophysiological property showing an autonomic electrical activity, and this phenomenon has been further focused on as a source of triggers of atrial fibrillation. The pulmonary vein cardiomyocytes have shorter action potential duration, less negative resting membrane potential, and smaller maximum upstroke velocity than those in the left atrium, whose underlying cellular mechanisms may generate arrhythmogenic substrates such as abnormal automaticity and triggered activity. In diseased conditions including sustained atrial tachycardia or chronic volume overload, its arrhythmogenic profile can be further modified through abbreviation of action potential duration of the pulmonary vein myocardium, which may become a cause of reentry. Recently, antiarrhythmic effects of various drugs have been extensively investigated in isolated pulmonary vein preparations. The present review article highlights the recent advances in our understanding of electrophysiological and pharmacological profiles of the pulmonary vein.
Subject(s)
Anti-Arrhythmia Agents/therapeutic use , Atrial Fibrillation/drug therapy , Atrial Fibrillation/etiology , Myocytes, Cardiac/physiology , Pulmonary Veins/cytology , Pulmonary Veins/physiology , Action Potentials/drug effects , Animals , Anti-Arrhythmia Agents/pharmacology , Electrophysiological Phenomena/drug effects , Humans , In Vitro Techniques , Membrane Potentials/drug effects , Pulmonary Veins/drug effectsABSTRACT
The pulmonary vein has a unique electrophysiological property showing an autonomic electrical activity, and this phenomenon has been further focused on as a source of triggers of atrial fibrillation. The pulmonary vein cardiomyocytes have shorter action potential duration, less negative resting membrane potential, and smaller maximum upstroke velocity than those in the left atrium, whose underlying cellular mechanisms may generate arrhythmogenic substrates such as abnormal automaticity and triggered activity. In diseased conditions including sustained atrial tachycardia or chronic volume overload, its arrhythmogenic profile can be further modified through abbreviation of action potential duration of the pulmonary vein myocardium, which may become a cause of reentry. Recently, antiarrhythmic effects of various drugs have been extensively investigated in isolated pulmonary vein preparations. The present review article highlights the recent advances in our understanding of electrophysiological and pharmacological profiles of the pulmonary vein.
ABSTRACT
Cilnidipine is reported to show antihypertensive and neuroprotective actions in a rat brain ischemia model, but is barely distributed to normal brain, suggesting that its uptake into normal brain is inhibited by efflux transporter(s), such as P-glycoprotein (P-gp). Here, we investigated whether P-gp regulates the brain distribution of cilnidipine. Intracellular accumulation of cilnidipine was decreased in P-gp-overexpressing porcine kidney epithelial cells (LLC-GA5-COL150 cells) compared with control LLC-PK1 cells and the decrease was markedly inhibited by verapamil, a P-gp inhibitor. Further, cilnidipine concentration in the brain of P-gp knockout mice was significantly increased after cilnidipine administration, compared with that in wild-type mice. Moreover, when cilnidipine was administered to male spontaneously hypertensive rats (SHR) with tandem occlusion of the distal middle cerebral and ipsilateral common carotid artery, its concentration in the ischemic hemisphere was 1.6-fold higher than that in the contralateral hemisphere. This result was supported by visualization of cilnidipine distribution using matrix-assisted laser desorption/ionization-time of flight/mass spectrometry (MALDI-TOF/MS) imaging. Our results indicated that cilnidipine is normally excluded from the brain by P-gp-mediated efflux transport, but P-gp function is impaired in ischemic brain and consequently cilnidipine is distributed to the ischemic region.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Brain Ischemia/metabolism , Brain/metabolism , Dihydropyridines/metabolism , Animals , Carotid Arteries/metabolism , Cell Line , LLC-PK1 Cells , Male , Mice , Middle Cerebral Artery/metabolism , Rats , Rats, Inbred SHR , SwineABSTRACT
We assessed the effects of oseltamivir on the conduction velocity and effective refractory period in the guinea-pig atrium in comparison with those of a class Ic antiarrhythmic drug pilsicainide. The recording and stimulating electrodes were attached on the epicardium close to the sinus nodal region and on the left atrial appendage. Oseltamivir (10-100 µM) as well as pilsicainide (1-10 µM) decreased the atrial conduction velocity in a frequency-dependent manner. Both drugs also increased the effective refractory period in both atria; but the frequency-dependent property of oseltamivir was lacking in the left atrium, and it was less obvious in the right atrium compared with that of pilsicainide. These results suggest that oseltamivir can directly modify the electrophysiological functions in the guinea-pig atrium possibly via combination of Na(+) and K(+) channel-blocking actions.
Subject(s)
Antiviral Agents/pharmacology , Atrial Function/drug effects , Electrophysiological Phenomena/drug effects , Heart Atria/drug effects , Lidocaine/analogs & derivatives , Oseltamivir/pharmacology , Animals , Anti-Arrhythmia Agents/pharmacology , Antiviral Agents/therapeutic use , Atrial Fibrillation , Atrial Function, Left/drug effects , Atrial Function, Right/drug effects , Guinea Pigs , Humans , Influenza, Human/drug therapy , Lidocaine/pharmacology , Oseltamivir/therapeutic use , Potassium Channel Blockers/pharmacology , Refractory Period, Electrophysiological/drug effects , Sodium Channel Blockers/pharmacologyABSTRACT
We compared effects of the antiarrhythmic drug bepridil on the electrophysiological parameters in the isolated pulmonary vein preparation from guinea pigs with those in the left atrium. Three pairs of bipolar electrodes were attached to the left atrium, pulmonary vein and junctional region of left atrium and pulmonary vein to measure intra-atrial and intra-pulmonary vein conduction velocity and effective refractory period. Bepridil at 10 µM prolonged the effective refractory period with little effect on the conduction velocity in the pulmonary vein, whereas the drug failed to affect the electrophysiological parameters in the left atrium. Using the conventional microelectrode technique, action potential of the isolated pulmonary vein preparation and left atrium were measured. Bepridil prolonged the action potential duration of the pulmonary vein more potently than that of the left atrium. These results suggest that antiarrhythmic effects of bepridil on reentry within the pulmonary vein are estimated to be greater than within the left atrium, which may be one of the key considerations to understand its antiarrhythmic mechanisms.
Subject(s)
Anti-Arrhythmia Agents/pharmacology , Atrial Function/drug effects , Bepridil/pharmacology , Heart Atria/drug effects , Pulmonary Veins/drug effects , Action Potentials/drug effects , Animals , Electrophysiological Phenomena , Female , Guinea Pigs , In Vitro Techniques , Male , Pulmonary Veins/physiologyABSTRACT
The pulmonary vein is known as an important source of ectopic beats, initiating frequent paroxysms of atrial fibrillation. We compared effects of the class Ic antiarrhythmic drug pilsicainide on the electrophysiological parameters in the isolated pulmonary vein preparation from guinea pigs with those in the left atrium. Three pairs of bipolar electrodes were attached to the left atrium, pulmonary vein, and junctional region of the left atrium and pulmonary vein to measure intra-atrial and intra-pulmonary vein conduction velocity and effective refractory period. Pilsicainide (10 µM) decreased the conduction velocity in the pulmonary vein as well as the left atrium, whose effect on the pulmonary vein was relatively greater than that on the left atrium. The drug prolonged the effective refractory period in the pulmonary vein as well as the left atrium, and the effect of the drug on the pulmonary vein was less than that on the left atrium. The currently observed electrophysiological property of pilsicainide suggests that its effects on reentry within the pulmonary vein are estimated to be weaker than within the left atrium, which may be one of the key considerations for understanding its antiarrhythmic mechanisms in the atrium and pulmonary vein.
