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

• Published in: Cardiovascular toxicology Vol. 20; no. 4; pp. 419 - 426
• Main Authors: Kondo, Yoshiki, Hagiwara-Nagasawa, Mihoko, Kambayashi, Ryuichi, Goto, Ai, Chiba, Koki, Nunoi, Yoshio, Izumi-Nakaseko, Hiroko, Matsumoto, Akio, Sugiyama, Atsushi
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.08.2020; Springer; Springer Nature B.V
• Subjects: Action Potentials - drug effects; Acyclovir - toxicity; Analysis; Anesthesia, Inhalation; Anesthetics; Anesthetics, Inhalation; Animals; Antiviral Agents - toxicity; Arrhythmia; Arrhythmias, Cardiac - chemically induced; Arrhythmias, Cardiac - diagnosis; Arrhythmias, Cardiac - physiopathology; Biomedical and Life Sciences; Biomedicine; Blood pressure; Bradycardia; Calcium; Calcium ions; Cardiology; Change detection; Conduction; Contraction; Dogs; Dosage; Dose-Response Relationship, Drug; Drug therapy; Electrocardiography; Female; Frequency dependence; Halothane; Health aspects; Heart; Heart beat; Heart Conduction System - drug effects; Heart Conduction System - physiopathology; Heart rate; Heart Rate - drug effects; Hypertension; Hypotension; Methods; Pain; Pharmacology; Pharmacology/Toxicology; Prolongation; Risk Assessment; Sympathetic nervous system; Tachycardia; Time Factors; Toxicity Tests; Ventricle; Viruses; Aciclovir; inhibition; QT prolongation; Anti-virus drug; Cardiovascular adverse events; IKr inhibition
• ISSN: 1530-7905; 1559-0259
• DOI: 10.1007/s12012-020-09568-4

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.