title: Electrophysiologic Studies on the Risks and Potential Mechanism Underlying the Proarrhythmic Nature of Azithromycin.
abstract: The mechanisms underlying arrhythmia induced by the clinical use of azithromycin are poorly understood. We aimed to investigate the proarrhythmic effects of azithromycin using electrocardiogram (ECG) and ion channel models. In vivo and in vitro guinea pig ECG and current and voltage clamp recordings were carried out. Azithromycin at 114.6 mg/kg (three times the clinically relevant dose) reduced heart rate (HR) and prolonged the PR, QRS and rate-corrected QT (QTc) intervals of guinea pig ECG in vivo. In vitro technique revealed that azithromycin at 207.5 and 415 mg/L [five and ten times clinically relevant concentration (CRC)] reduced HR and prolonged the PR, QRS and QTc intervals in the isolated guinea pig heart ECG. Both arrhythmias presented bradyarrhythmic features, mainly with reduced HR and prolonged PR interval. Action potential analysis from the guinea pig cardiomyocytes indicated that azithromycin at 830 mg/L (20 times CRC) significantly prolonged the action potential durations at 50% (APD50) and 90% (APD90) of full repolarization levels with a rectangular pattern. Azithromycin significantly suppressed the L-type Ca2+and Na+currents from the left ventricular myocytes of guinea pig at 50% inhibiting concentrations (IC50) of 942.5 ± 68.4 mg/L (22.7 times CRC) and 1123.0 ± 87.7 mg/L (27.1 times CRC), respectively. However, azithromycin at 50 times CRC (2075 mg/L) inhibited IKrcurrent at an inhibition rate of 30.99 ± 5.23% with an undetectable IC50. Azithromycin caused bradyarrhythmia primarily by inhibiting L-type Ca2+and Na+currents.
authors.affiliation: National Standard Laboratory of Pharmacology for Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, China.
authors.forename: Mengdan
authors.initials: M
authors.lastname: Zhang
authors.affiliation: National Standard Laboratory of Pharmacology for Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Xie
authors.affiliation: National Standard Laboratory of Pharmacology for Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Li
authors.affiliation: National Standard Laboratory of Pharmacology for Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gao
authors.affiliation: National Standard Laboratory of Pharmacology for Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, China.
authors.forename: Shuyin
authors.initials: S
authors.lastname: Xue
authors.affiliation: National Standard Laboratory of Pharmacology for Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, China.
authors.forename: Huili
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Respiratory, Inpatient Wards for Senior Cadres, Nanjing General Hospital of Nanjing Military Command Region, Nanjing, 210002, China.
authors.forename: Kesu
authors.initials: K
authors.lastname: Chen
authors.affiliation: First Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, 210029, China. liufuming@medmail.com.cn.
authors.forename: Fuming
authors.initials: F
authors.lastname: Liu
authors.affiliation: National Standard Laboratory of Pharmacology for Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, China. longchen@njucm.edu.cn.|Institute of Chinese Medicine of Taizhou China Medical City, Taizhou, 225300, China. longchen@njucm.edu.cn.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology*; D017963:Azithromycin / Q000633:toxicity*; D002121:Calcium Channel Blockers / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D022062:Electrophysiologic Techniques, Cardiac / Q000379:methods; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D012307:Risk Factors
chemical_list: D000900:Anti-Bacterial Agents; D002121:Calcium Channel Blockers; D017963:Azithromycin
keywords: Arrhythmia; Azithromycin; Cardiac myocyte; Ion channel