In vivo characterization of anti-atrial fibrillatory potential and pharmacological safety profile of I Na,L plus I Kr inhibitor ranolazine using the halothane-anesthetized dogs

AbstractTo characterize in vivo anti-atrial fibrillatory potential and pharmacological safety profile of ranolazine havingINa,L plusIKr inhibitory actions in comparison with those of clinically available anti-atrial fibrillatory drugs; namely, dronedarone, amiodarone, bepridil anddl-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 pr essure, 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. M oreover, 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 thatINa,L suppression may attenuateIKr inhibition-associated prolongation of early repolarization in the presence of reflex-mediated increase of adrenergic tone. Thus, ranolazine alone may be less p...
Source: Heart and Vessels - Category: Cardiology Source Type: research