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% (APD) and 90% (APD) of full repolarization levels with a rectangular pattern. Azithromycin significantly suppressed the L-type Ca and Na currents from the left ventricular myocytes of guinea pig at 50% inhibiting concentrations (IC) 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 I current at an inhibition rate of 30.99 ± 5.23% with an undetectable IC. Azithromycin caused bradyarrhythmia primarily by inhibiting L-type Ca and Na currents.
It has been demonstrated that liguzinediol (2,5-dihydroxymethyl-3,6-dimethylpyrazine, LZDO), a derivative of ligustrazine from Ligusticum wallichii Franch, exerts positive inotropy in isolated rat heart mediated by the sarcoplasmic reticulum Ca-ATPase (SERCA2a). Here, we further explore the underlying mechanism of the positive inotropic effect of LZDO in rat hearts. In vivo and ex vivo rat heart experiments, biochemistry, and Western blot techniques were used to analyze the rat heart contractility, and SERCA2a activity, phospholamban (PLB) phosphorylation, and protein phosphatase (PP1 and PP2A) activities in rat left ventricular myocytes, respectively. LZDO (20 mg/kg) significantly increased the inotropy of rat heart in vivo. In isolated rat heart experiments, LZDO (100 μM) restored the decreased inotropy induced by caffeine (0.5 mM); however, calyculin A (4 nM), an inhibitor of PP1 and PP2A, eliminated the inotropic effect of LZDO (100 μM). Moreover, LZDO (1, 10, and 100 μM) significantly enhanced SERCA2a activity and increased the levels of phosphorylated PLB on both serine-16 (Ser-16) and threonine-17 (Thr-17). In addition, LZDO (100 μM) significantly inhibited the activities of PP1 and PP2A. The positive inotropic effects of LZDO on in vivo and ex vivo rat hearts seem to be mediated through inhibition of PP1/PP2A, which may suppress dephosphorylated PLB and enhance SERCA2a activity. LZDO may prove effective in treating heart failure in clinical settings based on its unique biological mechanism.
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