Ehrlich Joachim R, Cha Tae-Joon, Zhang Liming, Chartier Denis, Villeneuve Louis, Hébert Terence E, Nattel Stanley
Department of Medicine, University of Montral, Montreal, Quebec, Canada.
J Physiol. 2004 Jun 1;557(Pt 2):583-97. doi: 10.1113/jphysiol.2004.061119. Epub 2004 Mar 12.
Cardiomyocytes from the pulmonary vein sleeves (PVs) are known to play an important role in atrial fibrillation. PVs have been shown to exhibit time-dependent hyperpolarization-induced inward currents of uncertain nature. We observed a time-dependent K(+) current upon hyperpolarization of PV and left atrial (LA) cardiomyocytes (I(KH)) and characterized its biophysical and pharmacological properties. The activation time constant was weakly voltage dependent, ranging from 386 +/- 14 to 427 +/- 37 ms between -120 and -90 mV, and the half-activation voltage averaged -93 +/- 4 mV. I(KH) was larger in PV than LA cells (e.g. at -120 mV: -2.8 +/- 0.3 versus-1.9 +/- 0.2 pA pF(-1), respectively, P < 0.01). The reversal potential was approximately -84 mV with 5.4 mmK(+) and changed by 55.7 +/- 2.4 mV per decade K(+) change. I(KH) was exquisitely Ba(2+) sensitive, with a 50% inhibitory concentration (IC(50)) of 2.0 +/- 0.3 microm (versus 76.0 +/- 17.9 microm for instantaneous inward-rectifier current, P < 0.01), and showed similar Cs(+) sensitivity to instantaneous current. I(KH) was potently blocked by tertiapin-Q, a selective Kir3-subunit channel blocker (IC(50) 10.0 +/- 2.1 nm), was unaffected by atropine and was significantly increased by isoproterenol (isoprenaline), carbachol and the non-hydrolysable guanosine triphosphate analogue GTPgammaS. I(KH) activation by carbachol required GTP in the pipette and was prevented by pertussis toxin pretreatment. Tertiapin-Q delayed repolarization in atropine-exposed multicellular atrial preparations studied with standard microelectrodes (action potential duration pre- versus post-tertiapin-Q: 190.4 +/- 4.3 versus 234.2 +/- 9.9 ms, PV; 202.6 +/- 2.6 versus 242.7 +/- 6.2 ms, LA; 2 Hz, P < 0.05 each). Seven-day atrial tachypacing significantly increased I(KH) (e.g. at -120 mV in PV: from -2.8 +/- 0.3 to -4.5 +/- 0.5 pA pF(-1), P < 0.01). We conclude that I(KH) is a time-dependent, hyperpolarization-activated K(+) current that likely involves Kir3 subunits and appears to play a significant role in atrial physiology.
已知肺静脉袖套（PVs）中的心肌细胞在心房颤动中起重要作用。PVs已被证明表现出性质不确定的时间依赖性超极化诱导内向电流。我们观察到PV和左心房（LA）心肌细胞超极化时出现时间依赖性钾电流（I(KH)），并对其生物物理和药理学特性进行了表征。激活时间常数对电压的依赖性较弱，在-120至-90 mV之间，范围为386±14至427±37 ms，半激活电压平均为-93±4 mV。PV细胞中的I(KH)大于LA细胞（例如在-120 mV时：分别为-2.8±0.3与-1.9±0.2 pA pF(-1)，P<0.01）。在细胞外钾离子浓度为5.4 mmol/L时，反转电位约为-84 mV，每十倍细胞外钾离子浓度变化，反转电位变化55.7±2.4 mV。I(KH)对钡离子极为敏感，50%抑制浓度（IC(50)）为2.0±0.3 μmol（瞬时内向整流电流的IC(50)为76.0±17.9 μmol，P<0.01），对铯离子的敏感性与瞬时电流相似。I(KH)被选择性Kir3亚基通道阻滞剂特律平-Q有效阻断（IC(50)为10.0±2.1 nmol），不受阿托品影响，异丙肾上腺素、卡巴胆碱和不可水解的鸟苷三磷酸类似物GTPγS可使其显著增加。卡巴胆碱激活I(KH)需要移液管中有GTP，百日咳毒素预处理可阻止其激活。在用标准微电极研究的阿托品处理的多细胞心房制剂中，特律平-Q延迟了复极化（PV的动作电位持续时间在特律平-Q处理前与处理后：190.4±4.3与234.2±9.9 ms；LA：202.6±2.6与242.7±6.2 ms；2 Hz，每组P<0.05）。七天的心房快速起搏显著增加了I(KH)（例如在PV中-120 mV时：从-2.8±0.3增加到-4.5±0.5 pA pF(-1)，P<0.01）。我们得出结论，I(KH)是一种时间依赖性、超极化激活的钾电流，可能涉及Kir3亚基，似乎在心房生理学中起重要作用。
