Effects of idarubicin and idarubicinol on rat coronary resistance and vasoconstrictor responsiveness of isolated aorta and mesentery.
It has been hypothesized that coronary vasoconstriction is involved in the cardiotoxic action of anthracyclines. The purpose of this study was to determine whether an increase in coronary resistance induced by idarubicin (IDA) or its primary circulating metabolite idarubicinol (IDOL) is correlated with a decrease in vascular sensitivity to vasoconstrictor agonists. Coronary vasoconstriction was studied in single-pass perfused rat hearts after a 10-min infusion of 0.5 mg IDA or IDOL. In the endothelium-intact rat thoracic aorta and mesentery we measured the inhibition of phenylephrine (PE)- and KCl-induced contraction in the presence of IDA and IDOL, respectively. The increase in coronary vascular resistance evoked by IDOL (121%) exceeded that of IDA (75%). IDA (10-100 micromol/l) concentration-dependently diminished vascular sensitivity to PE and KCl due to a reduction in maximal contractile response (Emax), i.e. the antagonism by IDA of PE- or KCl-induced vasoconstriction was non-competitive, indicating a post-receptor cellular mechanism. These reductions of PE or KCl efficacy elicited by IDOL were significantly larger than those elicited by the corresponding doses of IDA. The decrease in efficacy of PE in the presence of IDA and IDOL was characterized by IC50 estimates of 44.3 and 30.7 mumol/l, respectively. With a 10-fold lower IC50, IDA inhibited the reactivity of small mesenteric arteries to noradrenaline with 10-fold higher potency. The correlation between the increase in coronary resistance and the decrease in vasoconstrictor responsiveness may suggest that these anthracyclines act through a common cellular mechanism.
Weiss
Michael
M
Section of Pharmacokinetics, Martin Luther University Halle-Wittenberg, Halle, Germany. michael.weiss@medizin.uni-halle.de
Giessler
Christine
C
Kang
Wonku
W
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003630:Daunorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects*; D015255:Idarubicin / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014655:Vascular Resistance / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D011189:Potassium Chloride; C054440:idarubicinol; D009638:Norepinephrine; D015255:Idarubicin; D003630:Daunorubicin