Time-dependent block of ultrarapid-delayed rectifier K+ currents by aconitine, a potent cardiotoxin, in heart-derived H9c2 myoblasts and in neonatal rat ventricular myocytes.
Aconitine (ACO), a highly toxic diterpenoid alkaloid, is recognized to have effects on cardiac voltage-gated Na(+) channels. However, it remains unknown whether it has any effects on K(+) currents. The effects of ACO on ion currents in differentiated clonal cardiac (H9c2) cells and in cultured neonatal rat ventricular myocytes were investigated in this study. In H9c2 cells, ACO suppressed ultrarapid-delayed rectifier K(+) current (I(Kur)) in a time- and concentration-dependent fashion. The IC(50) value for ACO-induced inhibition of I(Kur) was 1.4 microM. ACO could accelerate the inactivation of I(Kur) with no change in the activation time constant of this current. Steady-state inactivation curve of I(Kur) during exposure to ACO could be demonstrated. Recovery from block by ACO was fitted by a single-exponential function. The inhibition of I(Kur) by ACO could still be observed in H9c2 cells preincubated with ruthenium red (30 microM). Intracellular dialysis with ACO (30 microM) had no effects on I(Kur). I(Kur) elicited by simulated action potential (AP) waveforms was sensitive to block by ACO. Single-cell Ca(2+) imaging revealed that ACO (10 microM) alone did not affect intracellular Ca(2+) in H9c2 cells. In cultured neonatal rat ventricular myocytes, ACO also blocked I(Kur) and prolonged AP along with appearance of early afterdepolarizations. Multielectrode recordings on neonatal rat ventricular tissues also suggested that ACO-induced electrocardiographic changes could be associated with inhibition of I(Kur). This study provides the evidence that ACO can produce a depressant action on I(Kur) in cardiac myocytes.
Wang
Ya-Jean
YJ
Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan.
Chen
Bing-Shuo
BS
Lin
Ming-Wei
MW
Lin
An-An
AA
Peng
Hsung
H
Sung
Ruey J
RJ
Wu
Sheng-Nan
SN
D000157:Aconitine / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D002460:Cell Line; D004566:Electrodes; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000633:toxicity*; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012430:Ruthenium Red / Q000494:pharmacology
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D012430:Ruthenium Red; D000157:Aconitine