Key result
Clarithromycin plus furosemide prolongs QT and triggers Torsades de Pointes during adrenergic stress in rats.
Why the study?
Rats typically do not respond to torsadogenic drugs unlike larger species, leaving the mechanisms underlying their resistance to drug-induced arrhythmias poorly understood.
Does the combination of clarithromycin and furosemide increase susceptibility to arrhythmias and alter cardiac ion channel gene expression during beta-adrenergic stimulation in rats?
Does the combination of clarithromycin and furosemide increase susceptibility to arrhythmias and alter cardiac ion channel gene expression during beta-adrenergic stimulation in rats?
Simultaneous administration of clarithromycin and furosemide in rats induces rapid reprogramming of cardiac ion channel genes, which may normally protect against arrhythmias but can fail and lead to Torsades de Pointes under beta-adrenergic stress.
Drug-induced long QT syndrome (LQTS) and Torsades de Pointes (TdP) are serious concerns in drug development. Although rats are a useful scientific tool, their hearts, unlike larger species, usually do not respond to torsadogenic drugs. Consequently, their resistance to drug-induced arrhythmias is poorly understood. Here, we challenged rats with rapid delayed rectifier current (Ikr)-inhibiting antibiotic clarithromycin (CLA), loop diuretic furosemide (FUR) or their combination (CLA + FUR), and examined functional and molecular abnormalities after stimulation with isoproterenol. Clarithromycin and furosemide were administered orally at 12-h intervals for 7 days. To evaluate electrical instability, electrocardiography (ECG) was recorded either in vivo or ex vivo using the Langendorff-perfused heart method under basal conditions and subsequently under beta-adrenergic stimulation. Gene expression was measured using real-time quantitative PCR in left ventricular tissue. Indeed, FUR and CLA + FUR rats exhibited hypokalemia. CLA and CLA + FUR treatment resulted in drug-induced LQTS and even an episode of TdP in one CLA + FUR rat. The combined treatment dysregulated gene expression of several ion channels subunits, including KCNQ1, calcium channels and Na+/K + -ATPase subunits, while both monotherapies had no impact. The rat with recorded TdP exhibited differences in the expression of ion channel genes compared to the rest of rats within the CLA + FUR group. The ECG changes were not detected in isolated perfused hearts. Hence, we report rapid orchestration of ion channel reprogramming of hearts with QT prolongation induced by simultaneous administration of clarithromycin and furosemide in rats, which may account for their ability to avoid arrhythmias triggered by beta-adrenergic stimulation.
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Hadová et al. (2023) studied Drug-induced long QT syndrome. Clarithromycin and Furosemide vs. Vehicle control was evaluated on QTc interval duration and incidence of arrhythmias during beta-adrenergic stimulation. Concomitant administration of clarithromycin and furosemide in rats resulted in QT prolongation and an episode of Torsades de Pointes during beta-adrenergic stimulation, associated with deregulated ion channel gene expression.
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