Sawicki G J, Arnsdorf M F
J Pharmacol Exp Ther. 1985 Dec;235(3):829-38.
The effects and interactions between an arrhythmogenic intervention and an antiarrhythmic drug on active and passive cellular properties relevant to excitability were studied with multiple microelectrode methods and rapid online data analysis in cardiac Purkinje fibers. The arrhythmogenic intervention was superfusion with lysophosphatidylcholine (LPC), a metabolite that accumulates in the ischemic myocardium; and the antiarrhythmic drug was lidocaine. LPC (10-20 microM) initially increased excitability as manifested by a decreased threshold current and, when tested, by a downward shift in nonnormalized strength- and charge-duration curves. Normalized strength- and charge-duration curves suggested altered passive properties to be primarily responsible for increased excitability. Cable analysis showed LPC to increase significantly input resistance, membrane resistance, time constant and length constant; current-voltage relationships showed LPC to decrease chord and slope conductances over the subthreshold range. Lidocaine (4 micrograms/ml) decreased excitability both by depressing the sodium system and by directly countering the effects of LPC on conductance and related properties. LPC subsequently decreased excitability by depressing the sodium system and, in this phase, the further depressant effect of lidocaine on the sodium system predominated. Lidocaine could normalize action potentials that were prolonged or had two stable steady states after LPC, at times retarded LPC-induced inexcitability and could render the tissue inexcitable to intracellular point stimulation but not to extracellular stimulation. Interactions between the arrhythmogenic and pharmacologic interventions affected net excitability by altering the matrix of active and passive cellular properties in time. The results are relevant to the development of a rational matrical approach to understanding drug action and treating arrhythmias.
运用多微电极方法和快速在线数据分析，在心脏浦肯野纤维中研究了致心律失常干预措施与抗心律失常药物对与兴奋性相关的主动和被动细胞特性的影响及相互作用。致心律失常干预措施是用溶血磷脂酰胆碱（LPC）进行灌流，LPC是一种在缺血心肌中蓄积的代谢产物；抗心律失常药物是利多卡因。LPC（10 - 20微摩尔）最初增加了兴奋性，表现为阈电流降低，并且在测试时，非标准化强度-持续时间和电荷-持续时间曲线向下移位。标准化强度-持续时间和电荷-持续时间曲线表明被动特性的改变是兴奋性增加的主要原因。电缆分析显示LPC显著增加输入电阻、膜电阻、时间常数和长度常数；电流-电压关系显示LPC在阈下范围内降低弦电导和斜率电导。利多卡因（4微克/毫升）通过抑制钠系统以及直接对抗LPC对电导和相关特性的影响来降低兴奋性。随后，LPC通过抑制钠系统来降低兴奋性，在此阶段，利多卡因对钠系统的进一步抑制作用占主导。利多卡因可以使LPC作用后延长或具有两个稳定稳态的动作电位恢复正常，有时可延缓LPC诱导的兴奋性丧失，并且可使组织对细胞内点刺激无兴奋性，但对细胞外刺激仍有兴奋性。致心律失常干预措施与药物干预措施之间的相互作用通过及时改变主动和被动细胞特性的基质来影响净兴奋性。这些结果与开发一种合理的基质方法来理解药物作用和治疗心律失常相关。
