Cristòfol R M, Rodríguez-Farré E
Department of Pharmacology and Toxicology, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona, Spain.
Eur J Pharmacol. 1994 Feb 11;252(3):305-12. doi: 10.1016/0014-2999(94)90177-5.
The differential effects of gamma- and delta-hexachlorocyclohexane isomers on 25 mM K(+)-evoked release of [3H]noradrenaline were studied in hippocampal slices treated with selected agents to activate or block L- and N-type Ca2+ and Na+ voltage-sensitive ion channels, Cl- transport and Ca(2+)-dependent protein activity. At maximally effective concentrations, the L- and N-type Ca2+ channel blockers nifedipine and omega-conotoxin, respectively, and the Na+ channel antagonist tetrodotoxin did not modify the enhancement of K(+)-evoked [3H]noradrenaline release induced by gamma-hexachlorocyclohexane. Likewise, under activation of protein kinase C by phorbol 12,13-dibutyrate (PDB) or inhibition of calmodulin by N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), the stimulatory effect of gamma-hexachlorocyclohexane remained almost unchanged. The Cl- transport blocker 4,4-diisothiocyanato-stilbene-2,2'-disulfonic acid (DIDS) significantly reduced the effect of gamma-hexachlorocyclohexane on [3H]noradrenaline release. The enhanced release in the presence of Bay K 8644, the L-type Ca2+ channel activator, was significantly inhibited by nifedipine but not by delta-hexachlorocyclohexane. The combination of omega-conotoxin and tetrodotoxin with delta-hexachlorocyclohexane did not alter the [3H]noradrenaline release effects of each agent alone. Activation of protein kinase C in the presence of delta-hexachlorocyclohexane resulted in a reduction of the delta isomer effect and in a potentiation of the PDB effect. W-7 did not further facilitate the inhibition induced by delta-hexachlorocyclohexane alone. These data suggest that hexachlorocyclohexane isomers may modify K(+)-evoked [3H]noradrenaline release by interacting with presynaptic molecular processes involving changes in Cl- membrane permeability and intracellular Ca2+ homeostasis.
在经选定试剂处理以激活或阻断 L 型和 N 型 Ca²⁺及 Na⁺电压敏感性离子通道、Cl⁻转运和 Ca²⁺依赖性蛋白活性的海马切片中，研究了γ-和δ-六氯环己烷异构体对 25 mM K⁺诱发的[³H]去甲肾上腺素释放的不同影响。在最大有效浓度下，L 型和 N 型 Ca²⁺通道阻滞剂硝苯地平和ω-芋螺毒素，以及 Na⁺通道拮抗剂河豚毒素，均未改变γ-六氯环己烷诱导的 K⁺诱发的[³H]去甲肾上腺素释放增强。同样，在佛波醇 12,13-二丁酸酯（PDB）激活蛋白激酶 C 或 N-(6-氨基己基)-5-氯-1-萘磺酰胺（W-7）抑制钙调蛋白的情况下，γ-六氯环己烷的刺激作用几乎保持不变。Cl⁻转运阻滞剂 4,4'-二异硫氰酸根合芪-2,2'-二磺酸（DIDS）显著降低了γ-六氯环己烷对[³H]去甲肾上腺素释放的作用。L 型 Ca²⁺通道激活剂 Bay K 8644 存在时增强的释放，被硝苯地平显著抑制，但未被δ-六氯环己烷抑制。ω-芋螺毒素和河豚毒素与δ-六氯环己烷联合使用，并未改变每种试剂单独作用时对[³H]去甲肾上腺素释放的影响。在δ-六氯环己烷存在下激活蛋白激酶 C，导致δ异构体效应降低以及 PDB 效应增强。W-7 并未进一步促进δ-六氯环己烷单独诱导的抑制作用。这些数据表明，六氯环己烷异构体可能通过与涉及 Cl⁻膜通透性变化和细胞内 Ca²⁺稳态的突触前分子过程相互作用，来改变 K⁺诱发的[³H]去甲肾上腺素释放。
