Effects of mitoxantrone on action potential and membrane currents in isolated cardiac myocytes

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