INHIBITORY ACTIONS OF ZENECA-ZD7288 ON WHOLE-CELL HYPERPOLARIZATION-ACTIVATED INWARD CURRENT (I(F)) IN GUINEA-PIG DISSOCIATED SINOATRIAL NODE CELLS
INHIBITORY ACTIONS OF ZENECA-ZD7288 ON WHOLE-CELL HYPERPOLARIZATION-ACTIVATED INWARD CURRENT (I(F)) IN GUINEA-PIG DISSOCIATED SINOATRIAL NODE CELLS
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DOI：
10.1111/j.1476-5381.1993.tb13815.x
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发表时间：
1993-09-01
影响因子：
7.3
通讯作者：
STURGESS, NC
中科院分区：
文献类型：
--
作者：
BOSMITH, RE;BRIGGS, I;STURGESS, NC
1 ZENECA ZD7288（4-（N-乙基-N-苯基氨基）-1,2-二甲基-6-（甲基氨基）氯化嘧啶）是一种窦房结 (SAN) 调节剂，可选择性减慢心率。已通过标准膜片钳程序在单个新鲜分离的豚鼠 SAN 细胞中研究了其影响。2 通过从 -40 mV 的保持电位开始的超极化电压钳步骤诱发全细胞内向电流。 ZD7288 以浓度依赖性方式抑制超极化激活的阳离子电流 (If)。 “选择性心动过缓剂”alinidine 和 UL-FS 49（扎特布雷定）也能抑制 I(f)。3 在超极化步骤至不同电位以激活电流后，通过测量 + 20 mV 处的尾电流振幅来研究 I(f) 的激活。 I(f) 的减少是由于 I(f) 电流激活曲线在电压轴负方向上的移动以及激活曲线振幅的降低造成的。4 ZD7288 不会影响 I(f) 通道的离子选择性，因为尾电流反转电位在药物存在的情况下没有变化。5 ZD7288 不会抑制 I(f) 使用依赖性，而 UL-FS 49 在 I(f) 电流阻断中显示出使用依赖性。6 虽然 ZD7288 对这些细胞中的延迟整流电流 (I(k)) 没有显着影响，但 alinidine 和 UL-FS 49 在相同浓度下均显着降低 I(k)，从而降低了 If。7 数据表明，ZD7288 通过影响激活特性来降低 I(f) If 电流；这种抑制作用可能解释了该药物的选择性心动过缓特性。
1 ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride) is a sinoatrial node (SAN) modulating agent which produces a selective slowing of the heart rate. Its effects have been studied in single, freshly dissociated guinea-pig SAN cells, by standard patch clamp procedures.2 Whole-cell inward currents were evoked by hyperpolarizing voltage clamp steps from a holding potential of -40 mV. ZD7288 inhibited the hyperpolarization activated cationic current (If) in a concentration-dependent manner. The 'selective bradycardic agents' alinidine and UL-FS 49 (zatebradine) both also inhibited I(f).3 The activation of I(f) was investigated by measuring tail current amplitudes at + 20 mV after hyperpolarizing steps to different potentials to activate the current. The reduction in I(f) resulted from both a shift in the I(f) current activation curve in the negative direction on the voltage axis, and also a reduction in the activation curve amplitude.4 ZD7288 did not affect the ion selectivity of the I(f) channel, since the tail current reversal potential was unchanged in the presence of the drug.5 With ZD7288 the inhibition of I(f) was not use-dependent, whereas UL-FS 49 displayed use-dependence in the block of the I(f) current.6 Whereas ZD7288 had no significant effect on the delayed rectifier current (I(k)) in these cells, both alinidine and UL-FS 49 significantly reduced I(k) at the same concentrations which reduced If.7 The data show that ZD7288 reduces I(f) by affecting the activation characteristics of the If current; this inhibition may account for this agent's selective bradycardic properties.