Shi Yanrong, Liu Xiaoguang, Gebremedhin Debebe, Falck John R, Harder David R, Koehler Raymond C
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland 21287-4961, USA.
J Cereb Blood Flow Metab. 2008 Jan;28(1):111-25. doi: 10.1038/sj.jcbfm.9600511. Epub 2007 May 23.
Adenosine, astrocyte metabotropic glutamate receptors (mGluRs), and epoxyeicosatrienoic acids (EETs) have been implicated in neurovascular coupling. Although A(2A) and A(2B) receptors mediate cerebral vasodilation to adenosine, the role of each receptor in the cerebral blood flow (CBF) response to neural activation remains to be fully elucidated. In addition, adenosine can amplify astrocyte calcium, which may increase arachidonic acid metabolites such as EETs. The interaction of these pathways was investigated by determining if combined treatment with antagonists exerted an additive inhibitory effect on the CBF response. During whisker stimulation of anesthetized rats, the increase in cortical CBF was reduced by approximately half after individual administration of A(2B), mGluR and EET antagonists and EET synthesis inhibitors. Combining treatment of either a mGluR antagonist, an EET antagonist, or an EET synthesis inhibitor with an A(2B) receptor antagonist did not produce an additional decrement in the CBF response. Likewise, the CBF response also remained reduced by approximately 50% when an EET antagonist was combined with an mGluR antagonist or an mGluR antagonist plus an A(2B) receptor antagonist. In contrast, A(2A) and A(3) receptor antagonists had no effect on the CBF response to whisker stimulation. We conclude that (1) adenosine A(2B) receptors, rather than A(2A) or A(3) receptors, play a significant role in coupling cortical CBF to neuronal activity, and (2) the adenosine A(2B) receptor, mGluR, and EETs signaling pathways are not functionally additive, consistent with the possibility of astrocytic mGluR and adenosine A(2B) receptor linkage to the synthesis and release of vasodilatory EETs.
腺苷、星形胶质细胞代谢型谷氨酸受体（mGluRs）和环氧二十碳三烯酸（EETs）与神经血管耦合有关。虽然A(2A)和A(2B)受体介导大脑对腺苷的血管舒张作用，但每种受体在脑血流量（CBF）对神经激活的反应中的作用仍有待充分阐明。此外，腺苷可增强星形胶质细胞的钙信号，这可能会增加花生四烯酸代谢产物如EETs。通过确定拮抗剂联合治疗是否对CBF反应产生累加抑制作用来研究这些途径之间的相互作用。在对麻醉大鼠的触须进行刺激期间，单独给予A(2B)、mGluR和EET拮抗剂以及EET合成抑制剂后，皮质CBF的增加减少了约一半。将mGluR拮抗剂、EET拮抗剂或EET合成抑制剂与A(2B)受体拮抗剂联合治疗，并未使CBF反应进一步降低。同样，当EET拮抗剂与mGluR拮抗剂或mGluR拮抗剂加A(2B)受体拮抗剂联合使用时，CBF反应也仍然降低约50%。相比之下，A(2A)和A(3)受体拮抗剂对触须刺激引起的CBF反应没有影响。我们得出结论：（1）腺苷A(2B)受体而非A(2A)或A(3)受体在将皮质CBF与神经元活动耦合中起重要作用；（2）腺苷A(2B)受体、mGluR和EETs信号通路在功能上并非累加的，这与星形胶质细胞mGluR和腺苷A(2B)受体与血管舒张性EETs的合成和释放相联系的可能性一致。
