AUTOINHIBITION OF HISTAMINE SYNTHESIS MEDIATED BY PRESYNAPTIC H-3 RECEPTORS
AUTOINHIBITION OF HISTAMINE SYNTHESIS MEDIATED BY PRESYNAPTIC H-3 RECEPTORS
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DOI：
10.1016/0306-4522(87)90279-x
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发表时间：
1987-10-01
期刊：
影响因子：
3.3
通讯作者：
SCHWARTZ, JC
中科院分区：
文献类型：
--
作者：
ARRANG, JM;GARBARG, M;SCHWARTZ, JC
研究了L-[3H]组氨酸标记的大鼠脑切片或突触体对组胺合成的调控作用。细胞外K+浓度的增加使大脑皮层中[3H]组胺的形成增加了约两倍。这种刺激也被观察到，尽管在较小程度上，在大脑皮层的突触体和下丘脑后部的切片中，大多数组胺能细胞体位于那里，这表明它可能发生在神经末梢以及核周围。在外源组胺浓度增加的情况下，K+诱导的刺激逐渐减少高达60 - 70%。外源性组胺的作用似乎是受体介导的，表现为其饱和特性、高药理学特异性和组胺拮抗剂的竞争性逆转。合成还原组胺的EC50值为(0.34 +-。0.03 .mu。M)与其已知由h3受体介导的释放抑制的EC50值相似。此外，甲皮拉米和噻替丁这两种强效拮抗剂分别在H1和h2受体上效果较差，而h3受体拮抗剂布里马胺和丙咪嘧啶则以明显的竞争方式逆转组胺的作用。这些效应在大脑皮层或下丘脑后部切片以及皮质突触体中观察到。此外，即使在没有添加组胺的情况下，h3受体拮抗剂也增强了去极化诱导的[3H]组胺合成的刺激，表明释放的内源性组胺参与了合成控制过程。h3受体拮抗剂对突触前自受体控制[3H]组胺释放的效力与这些药物相似。由此可见，h3受体不仅在神经末梢水平上控制组胺的释放，而且还控制组胺的合成。两种调节过程之间的关系，可能通过细胞内钙，似乎是可能的，但仍需在分子水平上进行研究。
The regulation of histamine synthesis was studied on rat brain slices or synaptosomes labeled with L-[3H]histidine. Depolarization by increased extracellular K+ concentration enhanced by about twofold the [3H]histamine formation in slices of cerebral cortex. This stimulation was also observed, although to a lesser extent, in synaptosomes from cerebral cortex and slices from the posterior hypothalamus where most histaminergic cell-bodies are located, suggesting that it may occur in nerve endings as well as in perikarya. In the presence of exogenous histamine in increasing concentrations the K+-induced stimulation was progressively reduced by up to 60 70%. The effect of exogenous histamine appears to be receptor-mediated as shown by its saturable character, high pharmacological specificity and competitive reversal by histamine antagonists. The EC50 value of histamine for synthesis reduction (0.34 .+-. 0.03 .mu.M) was similar to its EC50 value for release inhibition known to be mediated by H3-receptors. In addition, whereas mepyramine and tiotidine, two potent antagonists, at H1- and H2-receptors, respectively, were poorly effective, the H3-receptor antagonists burimamide and impromidine reversed the histamine effect in an apparently competitive manner. These effects were observed in slices of cerebral cortex or posterior hypothalamus as well as in cortical synaptosomes. Furthermore, even in the absence of added histamine, H3-receptor antagonists enhanced the depolarization-induced stimulation of [3H]histamine synthesis, indicating a participation of released endogenous histamine in the synthesis control process. The potencies of H3-receptor antagonists were similar to those of the these agents at presynaptic autoreceptors controlling [3H]histamine release. It is concluded that H3-receptors control not only release but also synthesis of histamine at the level of nerve endings and also, presumably, of perikarya. A relationship between the two regulatory processes, possibly via intracellular calcium, seems likely but remains to be investigated at the molecular level.