Effects of idarubicin and idarubicinol on rat coronary resistance and vasoconstrictor responsiveness of isolated aorta and mesentery.

摘要: It has been hypothesized that coronary vasoconstriction is involved in the cardiotoxic action of anthracyclines. The purpose this study was to determine whether an increase resistance induced by idarubicin (IDA) or its primary circulating metabolite idarubicinol (IDOL) correlated with a decrease vascular sensitivity vasoconstrictor agonists. Coronary studied single-pass perfused rat hearts after 10-min infusion 0.5 mg IDA IDOL. In endothelium-intact thoracic aorta and mesentery we measured inhibition phenylephrine (PE)- KCl-induced contraction presence IDOL, respectively. evoked IDOL (121%) exceeded (75%). (10-100 micromol/l) concentration-dependently diminished PE KCl due reduction maximal contractile response (Emax), i.e. antagonism PE- non-competitive, indicating post-receptor cellular mechanism. These reductions efficacy elicited were significantly larger than those corresponding doses IDA. characterized IC50 estimates 44.3 30.7 mumol/l, With 10-fold lower IC50, inhibited reactivity small mesenteric arteries noradrenaline higher potency. correlation between responsiveness may suggest these anthracyclines act through common