Schechter L E
Wyeth-Ayerst Research, CNS Disorders, Princeton, New Jersey 08543-8000, USA.
J Pharmacol Exp Ther. 1997 Jul;282(1):262-70.
Previous investigations have demonstrated that compounds capable of blocking presynaptic potassium channels can stimulate neurotransmitter release at both peripheral and central synapses. This study examined the in vitro effects of the "classical" potassium channel blockers 4-aminopyridine (4-AP) and tetraethylammonium (TEA) on the spontaneous basal release of [3H]5-hydroxytryptamine ([3H]5-HT) from rat hippocampal slices using an automated superfusion apparatus. 4-AP and structural analogs increased the spontaneous basal release of [3H]5-HT in a concentration-related manner. The rank order of potencies from the estimated EC50 values indicated that 3,4-diaminopyridine (0.88 mM) approximately 4-AP (1.2 mM) > 2-AP (89 mM) > 3-AP (100 mM) > pyridine (256 mM). TEA stimulated [3H]5-HT release with an estimated EC50 value of 63 mM and was less efficacious than the pyridine congeners. The enhancement of release induced by 1 mM 4-AP was additive with 100 mM TEA and 5 microM veratridine but not with 3,4-diaminopyridine or KCl (25 and 50 mM). The release induced by 4-AP (0.3, 1 and 10 mM) and TEA (30, 100 and 300 mM) was significantly attenuated in a calcium-free buffer containing 1 mM ethylene glycol-bis(b-aminoethyl ether N,N,N',N'-tetraacetic acid. Tetrodotoxin (1 microM), a sodium channel blocker, was unable to block the response to 4-AP (1 mM) and TEA (100 mM). Notably, this concentration of tetrodotoxin reduced the stimulation of [3H]5-HT release produced by the sodium channel opener veratridine (5 microM). Taken together, the results demonstrate that potassium channel blockade can enhance the spontaneous basal release of [3H]5-HT in rat hippocampal slices. These effects are at least partly dependent on extracellular calcium and do not appear to be mediated by modulating sodium channel function.
先前的研究表明，能够阻断突触前钾通道的化合物可刺激外周和中枢突触处的神经递质释放。本研究使用自动灌流装置，检测了“经典”钾通道阻滞剂4-氨基吡啶（4-AP）和四乙铵（TEA）对大鼠海马切片中[3H]5-羟色胺（[3H]5-HT）自发基础释放的体外影响。4-AP及其结构类似物以浓度相关的方式增加了[3H]5-HT的自发基础释放。根据估计的EC50值得出的效价顺序表明，3,4-二氨基吡啶（0.88 mM）＞4-AP（1.2 mM）＞2-AP（89 mM）＞3-AP（100 mM）＞吡啶（256 mM）。TEA刺激[3H]5-HT释放，估计的EC50值为63 mM，且效力低于吡啶同系物。1 mM 4-AP诱导的释放增强与100 mM TEA和5 μM藜芦定相加，但与3,4-二氨基吡啶或KCl（25和50 mM）不相加。在含有1 mM乙二醇双（β-氨基乙基醚）N,N,N',N'-四乙酸的无钙缓冲液中，4-AP（0.3、1和10 mM）和TEA（30、100和300 mM）诱导的释放显著减弱。钠通道阻滞剂河豚毒素（1 μM）无法阻断对4-AP（1 mM）和TEA（100 mM）的反应。值得注意的是，该浓度的河豚毒素降低了钠通道开放剂藜芦定（5 μM）对[3H]5-HT释放的刺激。综上所述，结果表明钾通道阻断可增强大鼠海马切片中[3H]5-HT的自发基础释放。这些作用至少部分依赖于细胞外钙，且似乎不是通过调节钠通道功能介导的。
