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[Effects on anthracycline antibiotics on ionic currents and contraction of frog atrial fibrils associated with
Abstract:
The action of the anthracycline antibiotics rubomycin and its nitroxyl analogue ehoxyl(ruboxyl) at the concentration 100 mg/l was studied in the experiments, have been carried out with the isolated bundles of frog atrium using simultaneous registration of the ionic currents (or the active potentials) and the contraction. It has been shown, that rubomycin caused an action of potential shortening, membrane depolarization, increasing of the background outward current IKI, slowing of the muscle relaxation and the growth of the ionic contraction, associated with the Na/Ca exchange. Nitroxyl derivative of the rubomycin ruboxyl, exhibited small toxicity, did not change the ionic currents and the parameters of the mechanical activity. It is assumed, that cardiotoxicity of anthracyclines is in the great degree due to their ability to block the elimination of the Ca++ from the cell via the Na/Ca exchange, that results in the disturbance of the Ca-homeostasis of the cardiomyocyte and its calcium overload.
Insights
Rubomycin, an anthracycline antibiotic, disrupts frog heart cell function by affecting ion currents and contraction. Its derivative, ruboxyl, shows minimal toxicity, suggesting a potential therapeutic advantage.
Area of Science:
- Cardiology
- Pharmacology
- Cell Physiology
Background:
- Anthracycline antibiotics, like rubomycin, are used in cancer therapy.
- Cardiotoxicity is a significant side effect of anthracycline treatment.
- The precise mechanisms underlying anthracycline-induced cardiotoxicity require further elucidation.
Purpose of the Study:
- To investigate the cellular effects of rubomycin and its nitroxyl analogue, ruboxyl, on cardiac muscle.
- To determine the impact of these compounds on ionic currents and mechanical activity in isolated frog atrium.
- To explore the role of Na/Ca exchange in rubomycin-induced cardiotoxicity.
Main Methods:
- Experiments were conducted on isolated frog atrium bundles.
- Simultaneous registration of ionic currents (action potentials) and muscle contraction was performed.
- Specific concentrations (100 mg/l) of rubomycin and ruboxyl were applied.
Main Results:
- Rubomycin induced action potential shortening, membrane depolarization, and increased outward potassium current (IKI).
- Rubomycin also slowed muscle relaxation and increased ionic contraction, linked to Na/Ca exchange.
- Ruboxyl demonstrated low toxicity, with no significant changes in ionic currents or mechanical activity.
Conclusions:
- Anthracycline cardiotoxicity may stem from blocking Ca++ elimination via Na/Ca exchange.
- This blockade leads to cardiomyocyte calcium overload and disrupted Ca-homeostasis.
- Ruboxyl's reduced toxicity suggests potential for safer anthracycline-based therapies.