Neuroprotective use-dependent blockers of Na+ and Ca2+ channels controlling presynaptic release of glutamate.
Neuroprotective use-dependent blockers of Na+ and Ca2+ channels controlling presynaptic release of glutamate.
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神经保护性使用依赖的 Na 和 Ca2 通道阻滞剂控制突触前谷氨酸的释放。
DOI：
10.1111/j.1749-6632.1995.tb16578.x
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发表时间：
1995
影响因子：
5.2
通讯作者：
Magar,S
中科院分区：
文献类型：
--
作者：
Goldin,SM;Subbarao,K;Sharma,R;Knapp,AG;Fischer,JB;Daly,D;Durant,GJ;Reddy,NL;Hu,LY;Magar,S
我们发明了一系列 N,N'-二取代胍，可阻断控制谷氨酸释放的电压激活 Ca2+ 和 Na+ 通道。这些化合物，CNS 1237（N-苊基-N'-甲氧基萘基胍）及其类似物，在减弱神经递质释放的能力方面具有“使用依赖性”：相对于其阻断由更具有正常特征的短暂、短暂去极化引起的谷氨酸释放的能力，它们在持续或重复去极化条件下（如在病理生理情况下会遇到的情况）更有效地阻断谷氨酸释放非缺血脑中的生理释放事件。利用电生理学和快速动力学方法，我们将控制神经递质释放的相关 Na+ 和 Ca2+ 通道的依赖性阻断与分别由取代的胍 Na+ 通道阻断剂河豚毒素 (TTX) 和毒液肽 Ca2+ 拮抗剂所表现出的通道拮抗机制区分开来。为了表征 CNS 1237 的使用依赖性 Na+ 通道阻断，我们采用了表达克隆哺乳动物 II 型 Na+ 通道的中国仓鼠卵巢 (CHO) 细胞系的全细胞电压钳记录。这些实验表明，与相同条件下 TTX 的作用相比，CNS 1237 对 Na+ 通道的阻断效力通过以频率依赖性方式去极化刺激而大大增强。使用快速灌注技术，在 5 秒的高 K (+) 去极化周期内，以约 300 毫秒的时间分辨率测量 Ca2+ 通道激活的谷氨酸从脑神经末梢制剂中的释放。 1-3 µM 的 CNS 1237 和类似物可加速谷氨酸释放的衰减 40-70%，反映出去极化诱导的阻滞增强。相比之下，Ca2+通道拮抗剂肽毒素omega-aga IV-A（来自蜘蛛毒液）和omega-芋螺毒素M-VII-C（来自锥形蜗牛毒液）对谷氨酸释放的阻断表现出“反向使用依赖性”：在0.3μM的浓度下，谷氨酸释放的初始幅度被阻断40-60%，谷氨酸释放的衰减时间常数显着增加，表明去极化诱导的块的浮雕。这些发现证实 CNS 1237 和该化合物系列的其他成员是控制谷氨酸释放的电压激活离子通道的依赖于使用的阻断剂。 CNS 1237 在大鼠大脑中动脉闭塞 (MCAO) 局灶性中风模型中的研究表明，梗塞面积缩小程度与同一研究人员观察到的谷氨酸释放阻滞剂 (BW 619C89 (Burroughs-Wellcome，现正处于临床开发阶段) 所观察到的结果相当。通过推注 3 mg/kg，然后 4 小时输注 0.75 毫克/千克，可实现最大程度的梗塞面积缩小。毫克/公斤/小时。（摘要截断为 400 字）
We have originated a family of N, N'-disubstituted guanidines that block the voltage-activated Ca2+ and Na+ channels governing glutamate release. These compounds, CNS 1237 (N-acenaphthyl-N'-methoxynaphthyl guanidine) and its analogues, are" use dependent" in their ability to attenaute neurotransmitter release: they block glutamate release with greater efficacy under conditions of persistent or repetitive depolarization, as would be encountered under pathophysiological circumstances, relative to their ability to block glutamate release elicited by brief, transient depolarizations more characteristic of normal physiological release events in nonischemic brain. Using electrophysiological and rapid kinetic methods, we have differentiated the use-dependent block of the relevant Na+ and Ca2+ channels governing neurotransmitter release from the mechanism of channel antagonism exhibited by, respectively, the substituted guanidine Na+ channel blocker tetrodotoxin (TTX) and venom peptide Ca2+ antagonists. To characterize use-dependent Na+ channel block by CNS 1237, we have employed whole-cell voltage-clamp recordings from a Chinese hamster ovary (CHO) cell line expressing cloned mammalian type II Na+ channels. These experiments demonstrated that, in contrast to the actions of TTX under the same conditions, the potency of Na+ channel block by CNS 1237 is greatly enhanced by depolarizing stimuli in a frequency-dependent manner. Ca2+ channel-activated glutamate release from brain nerve terminal preparations was measured with approximately 300 msec time resolution over a 5-second period of high K (+)-depolarization, using a rapid superfusion technique. CNS 1237 and analogues, at 1-3 microM, accelerated the decay of glutamate release by 40-70%, reflecting depolarization-induced enhancement of block. In contrast, blockade of glutamate release by the Ca2+ channel antagonist peptide toxins omega-aga IV-A (from spider venom) and omega-conotoxin M-VII-C (from cone snail venom) exhibited" reverse-use-dependence:" at concentrations of 0.3 microM, which blocked the initial amplitude of glutamate release by 40-60%, the decay time constant for glutamate release was significantly increased, indicating depolarization-induced relief of block. These findings establish that CNS 1237 and other members of this compound series are use-dependent blockers of the voltage-activated ion channels governing glutamate release. Studies of CNS 1237 in the rat middle cerebral artery occlusion (MCAO) focal stroke model have indicated infarct size reduction comparable to that observed by the same investigators for the glutamate release blocker (BW 619C89 (Burroughs-Wellcome, now in clinical development). Maximal infarct size reduction is achieved with a 3-mg/kg bolus followed by a 4-hour infusion of 0.75 mg/kg/hr.(ABSTRACT TRUNCATED AT 400 WORDS)
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脊椎动物肌肉的细胞内 pH 调节。
影响因子：
18.2
作者：
C. Aickin
通讯作者：
C. Aickin
兔肾髓质集合管细胞的细胞内pH调节。
DOI：
10.1172/jci112486
发表时间：
1986
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
Zeidel,ML;Silva,P;Seifter,JL
通讯作者：
Seifter,JL
DOI：
10.1073/pnas.81.23.7436
发表时间：
1984-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
PARADISO, AM;TSIEN, RY;MACHEN, TE
通讯作者：
MACHEN, TE
影响因子：
64.8
作者：
COHEN, SM;OGAWA, S;WILLIAMSON, JR
通讯作者：
WILLIAMSON, JR
DOI：
10.1172/jci112948
发表时间：
1987-04
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
M. Soleimani;S. M. Grassi;P. Aronson
通讯作者：
M. Soleimani;S. M. Grassi;P. Aronson