Effects of doxorubicin on excitation-contraction coupling in guinea pig ventricular myocardium.
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 mumol/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 mumol/L doxorubicin prolonged APD90 by 62.1% (n = 18) and blocked time-dependent delayed rectifier K+ current (IK) 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. There-after, 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 Ca(2+)-induced Ca2+ release from cardiac SR, probably by increasing the SR Ca2+ leak. On the other hand, prolongation of APD due to inhibition of IK 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.
Wang
Y X
YX
Institut für Pharmakologie und Toxikologie der Technischen, Universität München, Germany.
Korth
M
M
D000200:Action Potentials; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D011188:Potassium / Q000378:metabolism; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects; D013997:Time Factors
D012433:Ryanodine; D004317:Doxorubicin; D011188:Potassium; D002118:Calcium