Electropharmacological Characterization of Aciclovir in the Halothane-Anesthetized Dogs: A Proposal of Evaluation Method for Cardiovascular Safety Pharmacology of Anti-virus Drugs

Given limited information regarding the pathophysiology underlying aciclovir-associated, clinically observed cardiovascular adverse events including chest pain, tachycardia, bradycardia, palpitation, arrhythmia, hypertension and hypotension, we investigated its electropharmacological effects using the halothane-anesthetized beagle dogs. Aciclovir in doses of 2 and 20 mg/kg was sequentially infused over 10 min with an interval of 20 min ( n = 4), which would achieve sub-therapeutic to supra-therapeutic levels of plasma concentrations. Aciclovir decreased the total peripheral vascular resistance along with the blood pressure in a dose-related manner, which increased the heart rate, ventricular contraction and atrioventricular nodal conduction speed probably via a reflex-mediated increase of sympathetic tone. No significant change was detected in the intra-atrial or intra-ventricular conduction, indicating that aciclovir may not inhibit atrial or ventricular I Na . Aciclovir prolonged the repolarization period in a dose-related as well as in a reverse frequency-dependent manners, indicating that aciclovir may inhibit I Kr , which was supported by the T peak − T end prolongation. Aciclovir transiently prolonged the J − T peak c possibly through a reflex-mediated increase of sympathetic tone, indicating an increase of net inward current in the early repolarization phase. Thus, aciclovir may directly inhibit I Kr , and also have the potential to indirectly induce Ca 2+ overload leading to early afterdepolarization. These in vivo electropharmacological profile of aciclovir would partly explain the onset mechanism of clinical adverse events.