This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, Y.-X. Articles by Korth, M. Search for Related Content PubMed PubMed Citation Articles by Wang, Y.-X. Articles by Korth, M.

(Circulation Research. 1995;76:645-653.)
© 1995 American Heart Association, Inc.

Articles

Effects of Doxorubicin on Excitation-Contraction Coupling in Guinea Pig Ventricular Myocardium

Yong-Xiao Wang, Michael Korth

From the Institut für Pharmakologie und Toxikologie der Technischen, Universität München (Germany).

Correspondence to Dr Michael Korth, Institut für Pharmakologie und Toxikologie der Technischen, Universität München, Biedersteiner Str 29, D-80802 München, Germany.

Abstract Doxorubicin, an anticancer drug, was recently shown to release Ca²⁺ from cardiac sarcoplasmic reticulum (SR) by increasing the open probability of Ca²⁺ release channels. In the present study, we investigated the effects of doxorubicin on excitation-contraction coupling of guinea pig heart preparations. In papillary muscles contracting at 0.5 Hz, 100 µmol/L doxorubicin produced within 3 hours the following effects: it increased the force of contraction by 269.3±19.8% (n=6) and prolonged the time to peak force by 75.1±8.7% (n=6), relaxation time by 54.7±8.7% (n=6), and action potential duration (APD) at 90% repolarization (APD₉₀) by 38.6±2.9% (n=3). Despite its positive inotropic effect, doxorubicin depressed the early contraction component by increasing the latency between stimulus and the onset of force development. In single myocytes, 100 µmol/L doxorubicin prolonged APD₉₀ by 62.1% (n=18) and blocked time-dependent delayed rectifier K⁺ current (I_K) by 44% (n=9). Ca²⁺ inward current and inward rectifier K⁺ current were not affected by doxorubicin. Ca²⁺ transients elicited in myocytes loaded with the fluorescent Ca²⁺ indicator fura 2 were strongly suppressed by doxorubicin in their initial rising phase. Thereafter, doxorubicin produced a delayed rise in intracellular Ca²⁺, which reached a late peak exceeding that of the control peak by 52±8% (n=5). The results suggest that doxorubicin decreases Ca²⁺-induced Ca²⁺ release from cardiac SR, probably by increasing the SR Ca²⁺ leak. On the other hand, prolongation of APD due to inhibition of I_K allows more Ca²⁺ to enter the cell. After being only temporarily buffered by the SR, Ca²⁺ may accumulate in the cytosol as long as depolarization is maintained and lead to a more complete activation of contractile proteins.

Key Words: doxorubicin • ventricular myocytes • positive inotropic effect • sarcoplasmic reticulum Ca²⁺ release • action potential

This article has been cited by other articles:

				H. J. Choi, M. R. Seon, S. S. Lim, J.-S. Kim, H. S. Chun, and J. H. Y. Park Hexane/Ethanol Extract of Glycyrrhiza uralensis Licorice Suppresses Doxorubicin-Induced Apoptosis in H9c2 Rat Cardiac Myoblasts Experimental Biology and Medicine, December 1, 2008; 233(12): 1554 - 1560. [Abstract] [Full Text] [PDF]

				S. Deng, B. Kulle, M. Hosseini, G. Schluter, G. Hasenfuss, L. Wojnowski, and A. Schmidt Dystrophin-deficiency increases the susceptibility to doxorubicin-induced cardiotoxicity Eur J Heart Fail, October 1, 2007; 9(10): 986 - 994. [Abstract] [Full Text] [PDF]

				T. Rudzinski, M. Ciesielczyk, W. Religa, Z. Bednarkiewicz, and M. Krzeminska-Pakula Doxorubicin-induced ventricular arrhythmia treated by implantation of an automatic cardioverter-defibrillator Europace, May 1, 2007; 9(5): 278 - 280. [Abstract] [Full Text] [PDF]

				A. L. De Jongh, V. Ramanathan, B. K. Hoffmeister, and R. A. Malkin Left ventricular geometry immediately following defibrillation: shock-induced relaxation Am J Physiol Heart Circ Physiol, March 1, 2003; 284(3): H815 - H819. [Abstract] [Full Text] [PDF]

				Y.-X. Wang, Y.-M. Zheng, I. Abdullaev, and M. I. Kotlikoff Metabolic inhibition with cyanide induces calcium release in pulmonary artery myocytes and Xenopus oocytes Am J Physiol Cell Physiol, February 1, 2003; 284(2): C378 - C388. [Abstract] [Full Text] [PDF]

				T. Nakamura, Y. Ueda, Y. Juan, S. Katsuda, H. Takahashi, and E. Koh Fas-Mediated Apoptosis in Adriamycin-Induced Cardiomyopathy in Rats : In Vivo Study Circulation, August 1, 2000; 102(5): 572 - 578. [Abstract] [Full Text] [PDF]

				G.-X. Wang, X.-B. Zhou, and M. Korth Effects of Mitoxantrone on Excitation-Contraction Coupling in Guinea Pig Ventricular Myocytes J. Pharmacol. Exp. Ther., May 1, 2000; 293(2): 501 - 508. [Abstract] [Full Text]

				P Venditti, M Balestrieri, T De Leo, and S Di Meo Free radical involvement in doxorubicin-induced electrophysiological alterations in rat papillary muscle fibres Cardiovasc Res, June 1, 1998; 38(3): 695 - 702. [Abstract] [Full Text] [PDF]

				R. Zucchi and S. Ronca-Testoni The Sarcoplasmic Reticulum Ca2+ Channel/Ryanodine Receptor: Modulation by Endogenous Effectors, Drugs and Disease States Pharmacol. Rev., March 1, 1997; 49(1): 1 - 52. [Abstract] [Full Text] [PDF]