Daunorubicin cardiotoxicity - Evidence for the importance of the quinone moiety in a free-radical-independent mechanism

Anthracyclines, such as daunorubicin (Daun), and other quinone-containing c ompounds can stimulate the formation of toxic free radicals. The present st udy tests the hypothesis that the quinone moiety of Daun, by increasing fre e-radical production, disrupts sarcoplasmic reticulum (SR) function and the reby inhibits myocardial contractility in vitro. We compared Daun with its quinone-deficient analogue, 5-iminodaunorubicin (5-ID), using experimental interventions to produce various contractile states that depend on SR funct ion. At concentrations of Daun or 5 ID that did not alter contractility (dF /dt) of steady-state contractions (1 Hz) in electrically paced atria isolat ed from adult rabbits, only Daun significantly attenuated the positive inot ropic effects on dF/dt of increased rest intervals (PRP; post-rest potentia tion) or increased stimulation frequencies. Attenuation was to 98 +/- 6% at 1 Hz, and 73 +/- 8 and 67 +/- 8% for 30 and 60 sec PRP, respectively, and 73 +/- 3 and 63 +/- 3% at 2 and 3 Hz, respectively, for 88 mu M Daun (P < 0 .05, vs pre-drug baseline values, mean +/- SEM). These effects of Daun were similar to those of caffeine (2 mM), an agent well known to deplete cardia c SR calcium. We also examined the effect of Daun in isolated neonatal rabb it atria, which lack mature, functional SR; Daun did not alter the force-fr equency relationship or PRP contractions. Additional studies in Ca2+-loaded SR microsomes indicated that both Daun and 5-ID opened Ca2+ release channe ls, with Daun being 20-fold more potent than 5-ID in this respect. Neither anthracycline, however, induced free-radical formation in SR preparations ( assayed via nicking of supercoiled DNA) prior to stimulating Ca2+ release. Thus, our results indicate that Daun impairs myocardial contractility in vi tro by selectively interfering with SR function; the quinone moiety of Daun appears to mediate this cardiotoxic effect, acting through a mechanism tha t does' not involve free radicals. (C) 2000 Elsevier Science Inc.