title: Effects of doxorubicinol on excitation--contraction coupling in guinea pig ventricular myocytes.
abstract: The cardiotoxicity of the anticancer drug doxorubicin may be related to its main metabolite doxorubicinol. In this study, the acute effects of doxorubicinol on excitation-contraction coupling in isolated guinea pig ventricular myocytes were investigated and compared with doxorubicin using the whole-cell patch-clamp-, fura-2 fluorescence- and cell-edge tracking techniques. Both drugs were applied intracellularly by diffusion from the patch electrode for 15--20 min. Doxorubicin (100 microM) prolonged the action potential duration (APD) by 31% and enhanced cell shortening by 26%. Contrary to doxorubicin, doxorubicinol (10 microM) shortened APD by 25% and decreased cell shortening by 31%. APD shortening by doxorubicinol was due to an increase of the delayed rectifier K(+) current. Neither the inward rectifier K(+) current nor the L-type Ca(2+) current was influenced by doxorubicinol. The decline in cell shortening induced by doxorubicinol was not exclusively due to APD shortening because doxorubicinol reduced the peak Ca(2+) transient by 23% in cells clamped with an action potential of constant duration. Despite opposite effects on APD and contractility, both doxorubicin and doxorubicinol produced a considerable delay in the activation and inactivation of contraction and Ca(2+) transient, compatible with an impaired function of the sarcoplasmic reticulum. It is suggested that doxorubicinol-induced APD shortening may amplify the detrimental effects of both doxorubicin and doxorubicinol on sarcoplasmic reticulum Ca(2+) load and hence on contractile function. The accumulation of doxorubicinol in the cardiac myocytes may play an important role in the time-dependent development of doxorubicin-induced ventricular dysfunction.
authors.affiliation: Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Abteilung Pharmakologie für Pharmazeuten, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.
authors.forename: G X
authors.initials: GX
authors.lastname: Wang
authors.forename: Y X
authors.initials: YX
authors.lastname: Wang
authors.forename: X B
authors.initials: XB
authors.lastname: Zhou
authors.forename: M
authors.initials: M
authors.lastname: Korth
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology; D048429:Cell Size / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004558:Electric Stimulation; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D016276:Ventricular Function
chemical_list: D020746:Calcium Channels, L-Type; D015221:Potassium Channels; D004317:Doxorubicin; C010013:adriamycinol; D002118:Calcium