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 electrical properties of cardiac myocytes were investigated using the whole-cell clamp technique. 2. In isolated guinea-pig ventricular myocytes, 30 microM 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 microM tetrodotoxin and showed reverse rate-dependence. 3. Both the inward rectifier K+ current (I(KI)) and the delayed rectifier K+ current (I(K)) of guinea-pig ventricular myocytes were significantly depressed by 30 microM 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. 4. Thirty microM MTO had no direct effect on the L-type Ca2+ current (I(Ca(L))), but reversed the inhibitory effect of 1 microM carbamylcholine but not the A1-adenosine receptor agonist (-)-N6-phenylisopropyladenosine (1 microM) on I(Ca(L)) enhanced by 50 nM isoprenaline in guinea-pig ventricular myocytes. In guinea-pig atrial mycotyes, 30 microM MTO inhibited by 93% the muscarinic receptor gated K+ current (I(K,ACh)) evoked by 1 microM carbamylcholine, whereas I(K,ACh) elicited by 100 microM GTPgammaS, a nonhydrolysable GTP analogue, was only decreased by 12%. 5. The specific binding of [3H]QNB, a muscarinic receptor ligand, to human atrial membranes was concentration-dependently displaced by MTO (1-1000 microM). 6. In conclusion, MTO blocks cardiac muscarinic receptors and prolongs APD by inhibition of I(KI) and I(Kr). The occasionally observed early afterdepolarizations may signify a potential cardiac hazard of the drug.
Wang
G X
GX
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universitäts-Krankenhaus Eppendorf, Hamburg, Germany.
Zhou
X B
XB
Eschenhagen
T
T
Korth
M
M
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008942:Mitoxantrone / Q000494:pharmacology*; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D011813:Quinuclidinyl Benzilate / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects; D013779:Tetrodotoxin / Q000494:pharmacology
D000970:Antineoplastic Agents; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D015221:Potassium Channels; D011976:Receptors, Muscarinic; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013779:Tetrodotoxin; D011813:Quinuclidinyl Benzilate; D002217:Carbachol; D008942:Mitoxantrone