Beta-Adrenergic Receptor Stimulation Modulates the Cellular Proarrhythmic Effects of Chloroquine and Azithromycin.

Frontiers in Physiology
Henry Sutanto, Jordi Heijman

Abstract

The antimalarial drug, chloroquine (CQ), and antimicrobial drug, azithromycin (AZM), have received significant attention during the COVID-19 pandemic. Both drugs can alter cardiac electrophysiology and have been associated with drug-induced arrhythmias. Meanwhile, sympathetic activation is commonly observed during systemic inflammation and oxidative stress (e.g., in SARS-CoV-2 infection) and may influence the electrophysiological effects of CQ and AZM. Here, we investigated the effect of beta-adrenergic stimulation on proarrhythmic properties of CQ and AZM using detailed in silico models of ventricular electrophysiology. Concentration-dependent alterations in ion-channel function were incorporated into the Heijman canine and O'Hara-Rudy human ventricular cardiomyocyte models. Single and combined drug effects on action-potential (AP) properties were analyzed using a population of 1,000 models accommodating inter-individual variability. Sympathetic stimulation was simulated by increasing pacing rate and experimentally validated isoproterenol (ISO)-induced changes in ion-channel function. In the canine ventricular model at 1 Hz pacing, therapeutic doses of CQ and AZM (5 and 20 μM, respectively) individually prolonged AP duration (...Continue Reading

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Citations

Nov 19, 2020·CPT: Pharmacometrics & Systems Pharmacology·Meera VarshneyaEric A Sobie
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