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Effects of mitoxantrone on action potential and membrane currents in isolated cardiac myocytes
Author(s) -
Wang GeXin,
Zhou XiaoBo,
Eschenhagen Thomas,
Korth Michael
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702547
Subject(s) - muscarinic acetylcholine receptor , medicine , chemistry , endocrinology , myocyte , afterdepolarization , carbachol , inward rectifier potassium ion channel , patch clamp , isoprenaline , agonist , guinea pig , membrane potential , biophysics , receptor , electrophysiology , biology , repolarization , ion channel , biochemistry , stimulation
The effects of mitoxantrone (MTO), an anticancer drug, on the membrane electrical properties of cardiac myocytes were investigated using the whole‐cell clamp technique. In isolated guinea‐pig ventricular myocytes, 30 μ M MTO induced a time‐dependent prolongation of action potential duration (APD) which was occasionally accompanied by early afterdepolarizations. APD prolongation was preserved in the presence of 10 μ M tetrodotoxin and showed reverse rate‐dependence. Both the inward rectifier K + current ( I K1 ) and the delayed rectifier K + current ( I K ) of guinea‐pig ventricular myocytes were significantly depressed by 30 μ M MTO. The rapidly activating component of I K ( I Kr ) seemed to be preferentially blocked by MTO. The transient outward current was not affected by MTO in rat ventricular myocytes. Thirty μ M MTO had no direct effect on the L‐type Ca 2+ current ( I Ca(L) ), but reversed the inhibitory effect of 1 μ M carbamylcholine but not the A 1 ‐adenosine receptor agonist (−)‐N 6 ‐phenylisopropyladenosine (1 μ M ) on I Ca(L) enhanced by 50 n M isoprenaline in guinea‐pig ventricular myocytes. In guinea‐pig atrial mycotyes, 30 μ M MTO inhibited by 93% the muscarinic receptor gated K + current ( I K,ACh ) evoked by 1 μ M carbamylcholine, whereas I K,ACh elicited by 100 μ M GTPγS, a nonhydrolysable GTP analogue, was only decreased by 12%. The specific binding of [ 3 H]QNB, a muscarinic receptor ligand, to human atrial membranes was concentration‐dependently displaced by MTO (1–1000 μ M ). In conclusion, MTO blocks cardiac muscarinic receptors and prolongs APD by inhibition of I K1 and I Kr . The occasionally observed early afterdepolarizations may signify a potential cardiac hazard of the drug.British Journal of Pharmacology (1999) 127 , 321–330; doi: 10.1038/sj.bjp.0702547