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

1 The effects of mitoxantrone (MTO), an anticancer drug, on the membrane el ectrical properties of cardiac myocytes were investigated using the whole-c ell clamp technique. 2 In isolated guinea-pig ventricular myocytes,30 mu M MTO induced a time-de pendent prolongation of action potential duration (APD) which was occasiona lly accompanied by early afterdepolarizations. APD prolongation was preserv ed in the presence of 10 mu M tetrodotoxin and showed reverse rate-dependen ce. 3 Both the inward rectifier K+ current (I-K1) and the delayed rectifier Kcurrent (I-K) Of guinea-pig ventricular myocytes were significantly depress ed by 30 mu M MTO. The rapidly activating component of I-K (I-Kr) Seemed to be preferentially blocked by MTO. The transient outward current was not af fected by MTO in rat ventricular myocytes. 4 Thirty mu M MTO had no direct effect oil the L-type Ca2+ current (I-Ca(L) ), but reversed the inhibitory effect of 1 mu M carbamylcholine but not the A(1)-adenosine receptor agonist (-)-N-6- phenylisopropyladenosine (1 mu M) on I-Ca(L) enhanced by 50 nM isoprenaline in guinea-pig ventricular myocyt es. In guinea-pig atrial mycotyes, 30 mu M MTO inhibited by 93% the muscari nic receptor gated K+ current (I-K,I-ACh) evoked by 1 mu M carbamylcholine, whereas I-K,I-ACh elicited by 100 mu M GTP gamma S, a nonhydrolysable GTP analogue, was only decreased by 12%. 5 The specific binding of [H-3]QNB, a muscarinic receptor ligand, to human atrial membranes was concentration-dependently displaced by MTO (1-1000 mu M). 6 In conclusion, MTO blocks cardiac muscarinic receptors and prolongs APD b y inhibition of I-Kl and IKr The occasionally observed early afterdepolariz ations may signify a potential cardiac hazard of the drug.