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Effects of adriamycin on ionic currents in single cardiac myocytes of the rabbit
1Department of Physiology, Seoul National University College of Medicine, Korea.
Abstract:
Adriamycin has been widely used as an anticancer drug, but its clinical use is limited by a dose-dependent cardiac toxicity. Proposed mechanisms for the adriamycin-induced cardiomyopathy include increasing the Ca current, inhibiting the Na/Ca exchange and dysfunction of the sarcoplasmic reticulum (SR). Using the whole cell voltage clamp technique in single isolated atrial and ventricular myocytes of the rabbit, we have investigated the effect of adriamycin on various current systems which are related to regulating intracellular Ca concentration: the Ca current, the Na/Ca exchange current and [Ca2+]i-dependent currents (ouabain-induced transient inward current and the inward tail current). Adriamycin, 0.05 mg/ml, increased Ca current (L-type) by 61%. Adriamycin inhibited the inward tail current in a dose-dependent manner between 0.02 and 0.1 mg/ml and when low concentration was used the effect was reversible. Ouabain-induced transient inward current was also suppressed by 0.05 mg/ml adriamycin. Na/Ca exchange current which is partly responsible for inducing [Ca2+]i-dependent currents was, however, not affected by adriamycin, suggesting that the effect adriamycin on [Ca2+]i-dependent currents is due to inhibition of SR function. From these results it is suggested that the increase of Ca current and inhibition of SR function cause adriamycin-induced cardiac toxicity: SR dysfunction not only causes a decrease of myocardial contractility, it can also accelerate the Ca overload process which might originate from the increase of Ca current.
Insights
Adriamycin (anticancer drug) increases cardiac Ca current and inhibits sarcoplasmic reticulum (SR) function, leading to dose-dependent cardiotoxicity. This study clarifies mechanisms of adriamycin-induced cardiomyopathy.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Adriamycin is a vital anticancer drug.
- Its clinical application is limited by dose-dependent cardiac toxicity, a condition known as adriamycin-induced cardiomyopathy.
- Potential mechanisms include altered calcium (Ca) handling within heart cells.
Purpose of the Study:
- To investigate the specific effects of adriamycin on cardiac ion currents regulating intracellular Ca concentration.
- To elucidate the mechanisms underlying adriamycin-induced cardiotoxicity, focusing on the sarcoplasmic reticulum (SR) and Ca currents.
Main Methods:
- Utilized the whole-cell voltage clamp technique on isolated rabbit atrial and ventricular myocytes.
- Examined the impact of adriamycin on L-type Ca current, Na/Ca exchange current, and intracellular Ca2+-dependent currents (ouabain-induced transient inward current, inward tail current).
Main Results:
- Adriamycin (0.05 mg/ml) significantly increased L-type Ca current by 61%.
- Adriamycin inhibited inward tail currents in a dose-dependent manner (0.02-0.1 mg/ml), with reversible effects at lower concentrations.
- Ouabain-induced transient inward current was suppressed by adriamycin.
- Na/Ca exchange current remained unaffected, suggesting SR dysfunction mediates adriamycin's effect on intracellular Ca2+-dependent currents.
Conclusions:
- Adriamycin-induced cardiotoxicity results from increased Ca current and impaired SR function.
- SR dysfunction contributes to decreased myocardial contractility and may accelerate Ca overload initiated by elevated Ca current.