Comparison of acute effects of anthracyclines on cardiac electrophysiological parameters of isolated guinea-pig hearts

• Published in: Cancer chemotherapy and pharmacology 1990-01, Vol.26 (6), p.415-418
• Main Authors: STARK, G, STARK, U, SAMONIGG, H, KASPAREK, K, LUEGER, A, NAGL, S, BERTUCH, H, PILGER, E, TRITTHART, H. A
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; Antineoplastic agents; Biological and medical sciences; Cardiac Pacing, Artificial; Dose-Response Relationship, Drug; Doxorubicin - analogs & derivatives; Doxorubicin - pharmacology; Electrocardiography - drug effects; Electrophysiology; Female; General aspects; Guinea Pigs; Heart - drug effects; Heart - physiology; Heart Rate - drug effects; Heart Rate - physiology; In Vitro Techniques; Male; Medical sciences; Pharmacology. Drug treatments; Time Factors
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/BF02994091

This study was performed to evaluate the acute effects of two anthracycline derivatives, doxorubicin and 4'O-tetrahydropyranyl-doxorubicin [(THP)-doxorubicin], on the conduction intervals, heart rate and refractoriness of isolated spontaneously beating guinea-pig hearts using a high-resolution ECG recording technique (SST-ECG). Doxorubicin as well as (THP)-doxorubicin were added to the perfusate in increasing concentrations of 0.1, 1 and 10 microM. Doxorubicin did not significantly alter the heart rate or conduction intervals. Only the rate-dependent QT interval was significantly shortened under the influence of 10 microM doxorubicin. In contrast, 10 microM (THP)-doxorubicin led to a significant reduction in the heart rate (-13% +/- 3%; P less than 0.01, n = 7) and to a prolongation of atrioventricular conduction time (24% +/- 10%; P less than 0.05, n = 7). The rate-dependent repolarization period (QT interval) was only insignificantly shortened in the presence of 10 microM (THP)-doxorubicin. The maximal following frequencies of each part of the conduction system were not changed by 10 microM doxorubicin. In the presence of (THP)-doxorubicin, the maximal following frequency of the ventricular myocardium was increased by as much as 36% +/- 8% (P less than 0.01, n = 7), indicating a shortening of the effective refractory period of the ventricular myocardium (V-ERP). These results show that the activation of (THP)-doxorubicin resembles the effects of Ca-antagonistic compounds on the heart (i.e. decrease in the spontaneous sinus rate and prolongation of the AV-nodal conduction interval). Changes in the QT interval exerted by doxorubicin and the shortening of the ventricular effective refractory period by (THP)-doxorubicin may indicate an alteration of the K(+)-conductance of the membrane. As the acute electrophysiological effects of doxorubicin and (THP)-doxorubicin are modest and occur only at excessive concentrations (10 microM), a direct influence on the generation of arrhythmias in healthy hearts is unlikely.