Kapoor J R, Sladek C D
Department of Physiology and Biophysics, Finch University of Health Sciences, The Chicago Medical School, North Chicago, Illinois 60064, USA.
J Neurosci. 2000 Dec 1;20(23):8868-75. doi: 10.1523/JNEUROSCI.20-23-08868.2000.
The A1 catecholamine neurons of the caudal ventrolateral medulla transmit hemodynamic information to the vasopressin (VP) neurons in the hypothalamus. These neurons corelease ATP with norepinephrine. Perifused explants of the hypothalamoneurohypophyseal system were used to investigate the role of these substances on VP release. ATP (100 micrometer) increased VP release 1.5-fold (p = 0.027). The response was rapid but unsustained. It was blocked by the P(2) receptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS). The alpha(1)-adrenergic agonist phenylephrine (PE; 100 micrometer) also increased VP release by 1.5-fold (p = 0.014). Again, the response was rapid and unsustained. However, simultaneous perifusion of explants with ATP (100 micrometer) and PE (100 micrometer) resulted in a threefold to fourfold increase in VP release, which was sustained for as long as 4 hr. There was a similar synergistic effect of ATP and PE on oxytocin release. Interestingly, the synergistic response was delayed approximately 40 min relative to the response to either agent alone. Several experiments were performed to elucidate the cellular mechanisms of this synergism. The effect was blocked by PPADS, a protein kinase C inhibitor (bisindolylmaleimide I HCl), and actinomycin, an inhibitor of gene transcription. These data suggest that P(2X) receptor activation, PKC-mediated phosphorylation, and gene transcription are required for the synergistic response. The marked synergism of these coreleased agents is probably important to achieve sustained increases in plasma VP in response to prolonged hypotension. These observations may also have broad applications to CNS function, because ATP may be coreleased at noradrenergic synapses throughout the CNS.
延髓尾端腹外侧的A1儿茶酚胺能神经元将血流动力学信息传递至下丘脑的血管加压素（VP）神经元。这些神经元共释放ATP和去甲肾上腺素。采用下丘脑神经垂体系统的灌流外植体来研究这些物质对VP释放的作用。ATP（100微摩尔）使VP释放增加了1.5倍（p = 0.027）。该反应迅速但不能持续。它被P(2)受体拮抗剂磷酸吡哆醛 - 6 - 偶氮苯 - 2',4'-二磺酸（PPADS）阻断。α(1) - 肾上腺素能激动剂去氧肾上腺素（PE；100微摩尔）也使VP释放增加了1.5倍（p = 0.014）。同样，该反应迅速且不能持续。然而，用ATP（100微摩尔）和PE（100微摩尔）同时灌流外植体导致VP释放增加了三到四倍，并且这种增加可持续长达4小时。ATP和PE对催产素释放也有类似的协同作用。有趣的是，协同反应相对于单独使用任何一种药物的反应延迟了约40分钟。进行了多项实验以阐明这种协同作用的细胞机制。该作用被PPADS、蛋白激酶C抑制剂（双吲哚马来酰亚胺I盐酸盐）和基因转录抑制剂放线菌素阻断。这些数据表明，协同反应需要P(2X)受体激活、PKC介导的磷酸化和基因转录。这些共释放药物的显著协同作用可能对于在长时间低血压时实现血浆VP的持续增加很重要。这些观察结果也可能对中枢神经系统功能有广泛应用，因为ATP可能在整个中枢神经系统的去甲肾上腺素能突触处共释放。
