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To characterize in vivo anti-atrial fibrillatory potential and pharmacological safety profile of ranolazine having I Na,L plus I Kr inhibitory actions in comparison with those of clinically available anti-atrial fibrillatory drugs; namely, dronedarone, amiodarone, bepridil and dl-sotalol in our previous studies, ranolazine dihydrochloride in sub-therapeutic (0.3 mg/kg) and supra-therapeutic (3 mg/kg) doses was intravenously infused over 10 min to the halothane-anesthetized dogs (n = 5). The low dose increased the heart rate, cardiac output and atrioventricular conduction velocity possibly via vasodilator action-induced, reflex-mediated increase of adrenergic tone. Meanwhile, the high dose decreased the heart rate, ventricular contraction, cardiac output and mean blood pressure, indicating that drug-induced direct actions may exceed the reflex-mediated compensation. In addition, it prolonged the atrial and ventricular effective refractory periods, of which potency and selectivity for the former were less great compared with those of the clinically-available drugs. Moreover, it did not alter the ventricular early repolarization period in vivo, but prolonged the late repolarization with minimal risk for re-entrant arrhythmias. These in vivo findings of ranolazine suggest that I Na,L suppression may attenuate I Kr inhibition-associated prolongation of early repolarization in the presence of reflex-mediated increase of adrenergic tone. Thus, ranolazine alone may be less promising as an anti-atrial fibrillatory drug, but its potential risk for inducing torsade de pointes will be small. These information can be used as a guide to predict the utility and adverse effects of anti-atrial fibrillatory drugs having multi-channel modulatory action.

Poyendarone, a deuterated analogue of dronedarone, is expected to reduce the onset of cardiovascular adverse events of dronedarone, including congestive heart failure and excessive QT-interval prolongation. Since information is still lacking on the anti-atrial fibrillatory property of poyendarone, we assessed it along with effects on the inter-atrial conduction time (IACT) and atrial effective refractory period (AERP) using the canine paroxysmal atrial fibrillation model. Poyendarone hydrochloride (n = 4) and dronedarone hydrochloride (n = 4) in intravenous doses of 0.3 and 3 mg/kg/30 s were cumulatively administered. Poyendarone hardly altered sinoatrial rate, but dronedarone decreased it in a dose-related manner, whereas both drugs slightly but significantly reduced idioventricular rate. Poyendarone shortened duration of burst pacing-induced atrial fibrillation, whereas such abbreviation was not observed by dronedarone. Poyendarone and dronedarone similarly prolonged IACT in a frequency-dependent manner, indicating that their I Na inhibitory actions may be similar. The high dose of poyendarone prolonged AERP in a reverse frequency-dependent manner, extent of which at basic pacing cycle lengths of 300 and 400 ms was comparable to that of dronedarone. However, the extent at a basic pacing cycle length of 200 ms was tended to be greater in poyendarone than in dronedarone, suggesting greater I Ks inhibitory action of poyendarone. The deuteration of dronedarone attenuated the inhibition of sinus automaticity and prolonged the AERP with keeping the blood pressure and ventricular rate stable. Thus, poyendarone may have both more potent anti-atrial fibrillatory action and wider cardiovascular safety margin than dronedarone.

While vanoxerine (GBR-12909) is a synaptosomal dopamine uptake inhibitor, it also suppresses I Kr , I Na and I Ca,L in vitro. Based on these profiles on ionic currents, vanoxerine has been developed as a candidate compound for treating atrial fibrillation. To investigate electropharmacological profiles, vanoxerine dihydrochloride was intravenously administered at 0.03 and 0.3 mg/kg to halothane-anesthetized dogs (n = 4), possibly providing subtherapeutic and therapeutic concentrations, respectively. The low dose increased the heart rate and cardiac output, whereas it prolonged the ventricular refractoriness. The high dose decreased the heart rate but increased the total peripheral vascular resistance, whereas it delayed the ventricular repolarization and increased the atrial refractoriness in addition to further enhancing the ventricular refractoriness. The extent of increase in the refractoriness in the atrium was 0.8 times of that in the ventricle. The high dose also prolonged the early and late repolarization periods of the ventricle as well as the terminal repolarization period. Meanwhile, no significant change was detected in the mean blood pressure, ventricular contraction, preload to the left ventricle, or the intra-atrial, intra-ventricular or atrioventricular conductions. The high dose can be considered to inhibit I Kr , but it may not suppress I Na or I Ca in the in situ heart, partly explaining its poor atrial selectivity for increasing refractoriness. The prolongation of early repolarization period may reflect enhancement of net inward current, providing potential risk for intracellular Ca 2+ overload. Thus, vanoxerine may provide both trigger and substrate toward torsade de pointes, which would make the drug less promising as an anti-atrial fibrillatory drug.

AVE0118, an inhibitor of I Kur , I to and I K,ACh , was in the drug pipeline for atrial fibrillation. To investigate the limitation of AVE0118 as an anti-atrial fibrillatory drug, we studied its electropharmacological effects particularly focusing on the anti-atrial fibrillatory action as reverse translational research. We adopted the chronic atrioventricular block beagle dogs (n = 4), having a pathophysiology of bradycardia-associated, volume overload-induced chronic heart failure, in which the atrial fibrillation was induced by 10 s of burst pacing on atrial septum. AVE0118 in doses of 0.24 and 1.2 mg/kg, i.v. over 10 min hardly altered electrophysiological variables. Meanwhile, AVE0118 in a dose of 6 mg/kg, i.v. over 10 min delayed the inter-atrial conduction in a frequency-dependent manner and prolonged the atrial effective refractory period in a reverse frequency-dependent manner, whereas it did not significantly alter the duration of atrial fibrillation or its cycle length. The increment of atrial effective refractory period was 3.3 times greater compared with that of ventricular one at a basic cycle length of 400 ms. Torsade de pointes was not induced during the experimental period. Thus, AVE0118 may possess a favorable cardiac safety pharmacological profile, but its weak anti-atrial fibrillatory effect would indicate the limitation of atrial repolarization-delaying agents for suppressing atrial fibrillation.

To characterize in vivo anti-atrial fibrillatory potential and pharmacological safety profile of ranolazine having INa,L plus IKr inhibitory actions in comparison with those of clinically available anti-atrial fibrillatory drugs; namely, dronedarone, amiodarone, bepridil and dl-sotalol in our previous studies, ranolazine dihydrochloride in sub-therapeutic (0.3 mg/kg) and supra-therapeutic (3 mg/kg) doses was intravenously infused over 10 min to the halothane-anesthetized dogs (n = 5). The low dose increased the heart rate, cardiac output and atrioventricular conduction velocity possibly via vasodilator action-induced, reflex-mediated increase of adrenergic tone. Meanwhile, the high dose decreased the heart rate, ventricular contraction, cardiac output and mean blood pressure, indicating that drug-induced direct actions may exceed the reflex-mediated compensation. In addition, it prolonged the atrial and ventricular effective refractory periods, of which potency and selectivity for the former were less great compared with those of the clinically-available drugs. Moreover, it did not alter the ventricular early repolarization period in vivo, but prolonged the late repolarization with minimal risk for re-entrant arrhythmias. These in vivo findings of ranolazine suggest that INa,L suppression may attenuate IKr inhibition-associated prolongation of early repolarization in the presence of reflex-mediated increase of adrenergic tone. Thus, ranolazine alone may be less promising as an anti-atrial fibrillatory drug, but its potential risk for inducing torsade de pointes will be small. These information can be used as a guide to predict the utility and adverse effects of anti-atrial fibrillatory drugs having multi-channel modulatory action. [ABSTRACT FROM AUTHOR]

Oseltamivir has been shown to prolong the atrial conduction time and effective refractory period, and to suppress the onset of burst pacing-induced atrial fibrillation in vitro. To better predict its potential clinical benefit as an anti-atrial fibrillatory drug, we performed translational studies by assessing in vivo anti-atrial fibrillatory effect along with in vivo and in vitro electropharmacological analyses. Oseltamivir in intravenous doses of 3 (n = 6) and 30 mg/kg (n = 7) was administered in conscious state to the persistent atrial fibrillation model dogs to confirm its anti-atrial fibrillatory action. The model was prepared by tachypacing to the atria of chronic atrioventricular block dogs for > 6 weeks. Next, oseltamivir in doses of 0.3, 3 and 30 mg/kg was intravenously administered to the halothane-anesthetized intact dogs to analyze its in vivo electrophysiological actions (n = 4). Finally, its in vitro effects of 10–1,000 μM on IK,ACh, IKur, IKr, INa and ICaL were analyzed by using cell lines stably expressing Kir3.1/3.4, KV1.5, hERG, NaV1.5 or CaV1.2, respectively (n = 3 for IK,ACh and IKr or n = 6 for IKr, INa and ICaL). Oseltamivir in doses of 3 and 30 mg/kg terminated the atrial fibrillation in 1 out of 6 and in 6 out of 7 atrial fibrillation model dogs, respectively without inducing any lethal ventricular arrhythmia. Its 3 and 30 mg/kg delayed inter-atrial conduction in a frequency-dependent manner, whereas they prolonged atrial effective refractory period in a reverse frequency-dependent manner in the intact dogs. The current assay indicated that IC50 values for IK,ACh and IKr were 160 and 231 μM, respectively, but 1,000 µM inhibited INa, ICaL and IKur by 22, 19 and 13%, respectively. The extent of INa blockade was enhanced at faster beating rate and more depolarized resting membrane potential. Oseltamivir effectively terminated the persistent atrial fibrillation, which may be largely due to the prolongation of the atrial effective refractory period and inter-atrial conduction time induced by IK,ACh and IKr inhibitions along with INa suppression. Thus, oseltamivir can exert a powerful anti-atrial fibrillatory action through its ideal multi-channel blocking property; and oseltamivir would become a promising seed compound for developing efficacious and safe anti-atrial fibrillatory drugs. [ABSTRACT FROM AUTHOR]