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.
Inflammatory diseases including COVID-19 are associated with a cytokine storm characterized by high interleukin-6 (IL-6) titers. In particular, while recent studies examined COVID-19 associated arrhythmic risks from cardiac injury and/or from pharmacotherapy such as the combination of azithromycin (AZM) and hydroxychloroquine (HCQ), the role of IL-6 per se in increasing the arrhythmic risk remains poorly understood. The objective is to elucidate the electrophysiological basis of inflammation-associated arrhythmic risk in the presence of AZM and HCQ. IL-6, AZM and HCQ were concomitantly administered to guinea pigs in-vivo and in-vitro. Electrocardiograms, action potentials and ion-currents were analyzed. IL-6 alone or the combination AZM + HCQ induced mild to moderate reduction in heart rate, PR-interval and corrected QT (QTc) in-vivo and in-vitro. Notably, IL-6 alone was more potent than the combination of the two drugs in reducing heart rate, increasing PR-interval and QTc. In addition, the in-vivo or in-vitro combination of IL-6 + AZM + HCQ caused severe bradycardia, conduction abnormalities, QTc prolongation and asystole. These electrocardiographic abnormalities were attenuated in-vivo by tocilizumab (TCZ), a monoclonal antibody against IL-6 receptor, and are due in part to the prolongation of action potential duration and selective inhibition of Na+, Ca2+ and K+ currents. Inflammation confers greater risk for arrhythmia than the drug combination therapy. As such, in the setting of elevated IL-6 during inflammation caution must be taken when co-administering drugs known to predispose to fatal arrhythmias and TCZ could be an important player as a novel anti-arrhythmic agent. Thus, identifying inflammation as a critical culprit is essential for proper management.
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.
This study was designed to investigate the hemodynamic effect of rolipram, a phosphodiesterase type 4 (PDE4) inhibitor, in normal rat hearts both in vivo and in vitro and its underlying mechanism. The pressure-volume loop, isolated heart, and Ca 2+ transients triggered by field stimulation or caffeine were used to analyze the hemodynamic mechanism of rolipram. The results demonstrated that rolipram (3 mg/kg, ip) significantly increased the in vivo rat heart contractility by enhancing stroke work, cardiac output, stroke volume, end-systolic volume, end-diastolic volume, end-systolic pressure, heart rate, ejection fraction, peak rate of rise of left pressure (+dp/dt max ), the slopes of end-systolic pressure-volume relationship (slope of ESPVR) named as left ventricular end-systolic elastance, and reduced the slopes of end-diastolic pressure-volume relationship (slope of EDPVR). Meanwhile, the systolic blood pressure, diastolic blood pressure, and pulse pressure were significantly enhanced by rolipram. Also, rolipram deviated normal ventricular-arterial coupling without changing the arterial elastance. Furthermore, rolipram (0.1, 1, 10 μM) also exerted positive inotropic effect in isolated rat hearts by increasing the left ventricular development pressure, and +dp/dt max in non-paced and paced modes. Rolipram (10 μM) increased the SERCA2a activity, Ca 2+ content, and Ca 2+ leak rate without changing diastolic Ca 2+ level. Rolipram had significant positive inotropic effect with less effect on peripheral vascular elastance and its underlying mechanism was mediated by increasing SERCA2a activity. PDE4 inhibition by rolipram resulted in a positive inotropic effect and might serve as a target for developing agents for the treatment of heart failure in clinical settings.
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