Lu Hua Rong, Vlaminckx Eddy, Van Ammel Karel, De Clerck Fred
Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research and Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Eur J Pharmacol. 2002 Oct 4;452(2):183-92. doi: 10.1016/s0014-2999(02)02246-x.
In the present study, we investigated three drug-induced long-QT syndromes in isolated rabbit Purkinje fibers in order to identify the relationship of action potential duration (APD), triangulation of action potentials (APD(90)-APD(40)) and early afterdepolarizations. Isolated rabbit Purkinje fibers were superperfused in Tyrode solution with solvent, indapamide (1 x 10 (-4) M, an I(ks) blocker mimicking long QT1), dofetilide (1 x 10 (-9), 1 x 10 (-8) or 1 x 10 (-7) M, an I(kr) blocker mimicking long QT2) or anthopleurin (1 x 10 (-8) M, an inhibitor of the inactivation of the I(Na(+)) current mimicking long QT3) (n=8 per group) for 25 min, and stimulated at 1 Hz for 20 min and at 0.2 Hz for another 5 min. Indapamide did not change APD and triangulation or elicit early afterdepolarizations even in the presence of beta-adrenergic stimulation with isoproterenol. Dofetilide concentration-dependently prolonged APD(90), increased triangulation and elicited early afterdepolarizations. Anthopleurin markedly increased APD(90) as well as triangulation and elicited early afterdepolarizations. The induction of early afterdepolarizations by dofetilide and anthopleurin was associated with a prolongation of APD(90) or an increase in triangulation, but not with a change in APD(40). Moreover, the degree of the increase in the triangulation was larger than that of APD(90) in long QT2 (dofetilide-induced) and long QT3 (anthopleurin-induced) models in isolated rabbit Purkinje fibers. Our present study indicates that rabbit Purkinje fibers can be used as long QT2 (dofetilide-mimicking) and LQT3 (anthopleurin-mimicking) syndrome models, and confirms that drug-induced long QT1 (indapamide-mimicking) is absent. Our present study also shows the relationship between a prolongation of APD(90) or increase in triangulation and the induction of early afterdepolarizations with dofetilide (I(kr) blocker) and anthopleurin (I(Na) modulator) in isolated rabbit Purkinje fibers.
在本研究中，我们在离体兔浦肯野纤维中研究了三种药物诱导的长QT综合征，以确定动作电位时程（APD）、动作电位三角测量（APD(90)-APD(40)）与早期后去极化之间的关系。将离体兔浦肯野纤维在泰罗德溶液中用溶剂、吲达帕胺（1×10(-4)M,一种模拟长QT1的I(ks)阻滞剂）、多非利特（1×10(-9)、1×10(-8)或1×10(-7)M,一种模拟长QT2的I(kr)阻滞剂）或海葵毒素（1×10(-8)M,一种模拟长QT3的I(Na(+))电流失活抑制剂）进行超灌注（每组n = 8）25分钟，然后以1Hz刺激20分钟，再以0.2Hz刺激5分钟。即使在存在异丙肾上腺素的β肾上腺素能刺激下，吲达帕胺也不会改变APD和三角测量，或引发早期后去极化。多非利特浓度依赖性地延长APD(90)，增加三角测量并引发早期后去极化。海葵毒素显著增加APD(90)以及三角测量并引发早期后去极化。多非利特和海葵毒素诱导的早期后去极化与APD(90)的延长或三角测量的增加有关，但与APD(40)的变化无关。此外，在离体兔浦肯野纤维的长QT2（多非利特诱导）和长QT3（海葵毒素诱导）模型中，三角测量增加的程度大于APD(90)增加的程度。我们目前的研究表明，兔浦肯野纤维可作为长QT2（多非利特模拟）和LQT3（海葵毒素模拟）综合征模型，并证实不存在药物诱导的长QT1（吲达帕胺模拟）。我们目前的研究还显示了在离体兔浦肯野纤维中，APD(90)的延长或三角测量的增加与多非利特（I(kr)阻滞剂）和海葵毒素（I(Na)调节剂）诱导的早期后去极化之间的关系。
