Landa M E, Rubio M C, Jaim-Etcheverry G
Instituto de Investigaciones Farmacologicas (ININFA), Buenos Aires, Argentina.
Acta Physiol Pharmacol Latinoam. 1988;38(2):167-80.
When injected systemically to rodents, DSP4 inhibits the uptake of noradrenaline (NA) and depletes endogenous NA levels in the central nervous system and in the periphery. Pretreatment with the NA uptake blocker desipramine (DMI), with the NA precursor l-dopa or with the MAD inhibitor, pargyline, prevents the toxic effects of the compound. To investigate the mechanism of the NA depleting action of DSP4, the release of the neurotransmitter induced by nerve stimulation was studied "in vitro" in a tissue sensitive to the neurotoxic action of DSP4 such as the rat cerebral cortex previously loaded with tritiated NA. Incubation with 10 mumol/l DSP4 increased the spontaneous release of tritium from the cortex and produced a two-fold enhancement of tritium outflow during the stimulation of the cortical slices by exposure to K+ 20 mmol/l for 1 m. When the experiments were performed in a Ca++ free medium, DSP4 increased the spontaneous tritium outflow, but did not enhance the NA release by depolarization with K+. This latter effect could be due to the interaction with alpha-adrenoceptors since DSP4 did not potentiate the action of the alpha-antagonist yohimbine (1 mumol/l). DSP4, as did other uptake blockers, reduced the inhibitory effect of clonidine (0.1 mumol/l) on the NA release. Clonidine pretreatment "in vivo" (2 mg/kg), did not counteract the effect of DSP4 (25 mg/kg), suggesting that the enhanced release of NA induced by K+ does not play an important role in the depletion caused by DSP4. This is supported by the fact that DSP4 also enhanced the release of NA evoked by field stimulation of the rat vas deferens, a tissue resistant to the NA depleting action of the compound. The results indicate that the enhancement of the stimulation-induced release caused by DSP4, does not seem to play a triggering role in the NA depletion caused by the compound.
当对啮齿动物进行全身注射时，DSP4会抑制去甲肾上腺素（NA）的摄取，并降低中枢神经系统和外周组织中的内源性NA水平。用NA摄取阻滞剂地昔帕明（DMI）、NA前体左旋多巴或单胺氧化酶（MAD）抑制剂帕吉林进行预处理，可预防该化合物的毒性作用。为了研究DSP4耗竭NA作用的机制，在对DSP4神经毒性作用敏感的组织（如预先加载了氚化NA的大鼠大脑皮层）中“体外”研究了神经刺激诱导的神经递质释放。用10 μmol/L的DSP4孵育可增加皮层中氚的自发释放，并在通过暴露于20 mmol/L K+ 1分钟刺激皮层切片期间使氚流出增加两倍。当在无Ca++的培养基中进行实验时，DSP4增加了氚的自发流出，但未通过K+去极化增强NA释放。后一种效应可能是由于与α-肾上腺素能受体相互作用，因为DSP4没有增强α-拮抗剂育亨宾（1 μmol/L）的作用。与其他摄取阻滞剂一样，DSP4降低了可乐定（0.1 μmol/L）对NA释放的抑制作用。“体内”用可乐定（2 mg/kg）预处理并不能抵消DSP4（25 mg/kg）的作用，这表明K+诱导的NA释放增强在DSP4引起的耗竭中不起重要作用。这一观点得到以下事实的支持：DSP4还增强了大鼠输精管场刺激诱发的NA释放，而输精管是对该化合物的NA耗竭作用具有抗性的组织。结果表明，DSP4引起的刺激诱导释放增强，似乎在该化合物引起的NA耗竭中不发挥触发作用。
