Bari Ferenc, Nagy Krisztina, Guidetti Paolo, Schwarcz Robert, Busija David W, Domoki Ferenc
Department of Physiology, Faculty of Medicine, University of Szeged, Dóm tér 10, H-6720 Szeged, Hungary.
Brain Res. 2006 Jan 19;1069(1):39-46. doi: 10.1016/j.brainres.2005.11.033. Epub 2006 Jan 4.
The excitatory amino acid glutamate is a potent vasodilator in the central nervous system. Glutamate-induced vasodilation is mediated primarily by N-methyl-D-aspartate (NMDA) and AMPA/kainate (KAIN) receptors. We have now tested whether two metabolites of the kynurenine pathway of tryptophan degradation acting at the NMDA receptor, the antagonist kynurenic acid (KYNA) and the agonist quinolinic acid (QUIN), are capable of modulating the dilation of pial arterioles. The closed cranial window technique was used, and changes in vessel diameter ( approximately 100 microm) were analyzed in anesthetized newborn piglets. Topical application of NMDA (10(-4) M) or KAIN (5 x 10(-5) M) resulted in marked vasodilation (44 +/- 5% and 39 +/- 4%, respectively). Neither KYNA nor QUIN (both at 10(-5) to 10(-3) M) affected the vessel diameter when applied alone. Co-application of KYNA dose-dependently reduced the vasodilation caused by 10(-4) M NMDA and also attenuated the KAIN-induced response. Ten minutes of global cerebral ischemia did not modify the interaction between KAIN and KYNA. In contrast, KYNA did not affect vasodilation to hypercapnia, elicited by the inhalation of 10% CO2. Moreover, endogenous levels of KYNA and QUIN in the cerebral cortex, hippocampus and thalamus were found to be essentially unchanged during the early reperfusion period (0.5-2 h) following an episode of cerebral ischemia. Our data are relevant for the use of drugs that target the kynurenine pathway for therapeutic interventions in cerebrovascular diseases.
兴奋性氨基酸谷氨酸是中枢神经系统中一种有效的血管舒张剂。谷氨酸诱导的血管舒张主要由N-甲基-D-天冬氨酸（NMDA）和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸/海人藻酸（AMPA/KA）受体介导。我们现在测试了色氨酸降解的犬尿氨酸途径的两种代谢产物，作用于NMDA受体的拮抗剂犬尿喹啉酸（KYNA）和激动剂喹啉酸（QUIN），是否能够调节软脑膜小动脉的舒张。采用封闭颅窗技术，在麻醉的新生仔猪中分析血管直径（约100微米）的变化。局部应用NMDA（10⁻⁴ M）或KAIN（5×10⁻⁵ M）可导致明显的血管舒张（分别为44±5%和39±4%）。单独应用时，KYNA和QUIN（均为10⁻⁵至10⁻³ M）均不影响血管直径。联合应用KYNA可剂量依赖性地减少由10⁻⁴ M NMDA引起的血管舒张，并减弱KAIN诱导的反应。10分钟的全脑缺血并未改变KAIN与KYNA之间的相互作用。相比之下，KYNA并不影响由吸入10% CO₂引起的对高碳酸血症的血管舒张。此外，发现在脑缺血发作后的早期再灌注期（0.5 - 2小时），大脑皮质、海马和丘脑内KYNA和QUIN的内源性水平基本未变。我们的数据对于使用靶向犬尿氨酸途径的药物进行脑血管疾病的治疗干预具有参考意义。
