Barraco R A, el-Ridi M R, Ergene E, Phillis J W
Department of Physiology, Wayne State University, School of Medicine, Detroit, MI 48201.
Brain Res Bull. 1991 Jan;26(1):59-84. doi: 10.1016/0361-9230(91)90192-m.
A limited occipital craniotomy was conducted on urethane-chloralose anesthetized, spontaneously breathing rats to expose the caudal medulla in the region of the obex. Microinjections of highly selective agonists for adenosine receptor subtypes were made into the medial region of the caudal nucleus tractus solitarius (NTS) at the level of the posterior portion of the area postrema. Cardiorespiratory parameters were subsequently recorded for a 60-min test period following microinjection of drug or vehicle solutions. The following selective adenosine receptor agonists were used: the A1 agonist, N6-cyclopentyladenosine (CPA), which is 480-fold selective for A1 receptors in rat brain binding assays, and the A2 agonist, 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680), which is 170-fold selective for A2 receptors in rat brain binding studies and over 1500-fold selective in functional assays. The results showed that distinct and converse cardiovascular response patterns were elicited by these selective agonists for adenosine receptor subtypes following microinjections into the caudal NTS. Specifically, CGS 21680 selectively elicited potent dose-related decreases in mean arterial blood pressure (ED50 = 0.064 nmol/kg) and dose-related decreases in pulse pressure (ED50= 0.058 nmol/kg). Conversely, CPA selectively elicited potent dose-related increases in mean arterial blood pressure (ED50 = 0.62 nmol/kg) and dose-related increases in pulse pressure (ED50 = 0.70 nmol/kg). Additionally, the overall agonist-mediated response patterns were dramatically different wherein the CGS agonist exhibited a considerably more rapid time course in eliciting its hypotensive responses whereas CPA exhibited a more delayed and substantially longer time course to exert its hypertensive responses. Additionally, these distinct and converse cardiovascular response patterns were further shown to be receptor-selective since the depressor responses elicited by the A2 receptor agonist, CGS 21680, and the pressor responses elicited by the A1 receptor agonist, CPA, were completely and selectively blocked, respectively, by the selective A2 receptor antagonist, CGS 15943A, and the selective A1 receptor antagonist, DPCPX. Taken together, these findings provide persuasive in vivo evidence showing that pharmacologic activation of adenosine receptor subtypes in the caudal NTS of rats elicits specific response patterns with selective and opposite actions on cardiorespiratory behavior. These data also indicate that separate physiologic responses are specifically mediated by A2 receptors in the intact nervous system and thereby lend additional support to the case for using in vivo models to assess the functional role of adenosine A2 receptors in brain function.
在使用氨基甲酸乙酯-氯醛糖麻醉、自主呼吸的大鼠身上进行有限的枕骨开颅手术，以暴露闩部区域的延髓尾部。将高选择性腺苷受体亚型激动剂微量注射到最后区后部水平的孤束核（NTS）尾侧内侧区域。在微量注射药物或赋形剂溶液后的60分钟测试期内，随后记录心肺参数。使用了以下选择性腺苷受体激动剂：A1激动剂N6-环戊基腺苷（CPA），在大鼠脑结合试验中对A1受体的选择性为480倍；以及A2激动剂2-对-（2-羧乙基）苯乙氨基-5'-N-乙基羧酰胺腺苷（CGS 21680），在大鼠脑结合研究中对A2受体的选择性为170倍，在功能试验中的选择性超过1500倍。结果表明，将这些选择性腺苷受体亚型激动剂微量注射到NTS尾侧后，引发了不同且相反的心血管反应模式。具体而言，CGS 21680选择性地引起平均动脉血压的剂量相关的显著降低（ED50 = 0.064 nmol/kg）和脉压的剂量相关降低（ED50 = 0.058 nmol/kg）。相反，CPA选择性地引起平均动脉血压的剂量相关的显著升高（ED50 = 0.62 nmol/kg）和脉压的剂量相关升高（ED50 = 0.70 nmol/kg）。此外，整体激动剂介导的反应模式有显著差异，其中CGS激动剂在引发其降压反应时表现出明显更快的时间进程，而CPA表现出更延迟且持续时间长得多的时间进程来发挥其升压反应。此外，这些不同且相反的心血管反应模式进一步表明具有受体选择性，因为A2受体激动剂CGS 21680引发的降压反应和A1受体激动剂CPA引发的升压反应分别被选择性A2受体拮抗剂CGS 15943A和选择性A1受体拮抗剂DPCPX完全且选择性地阻断。综上所述，这些发现提供了有说服力的体内证据，表明大鼠NTS尾侧腺苷受体亚型的药理激活引发了对心肺行为具有选择性和相反作用的特定反应模式。这些数据还表明，在完整的神经系统中，单独的生理反应由A2受体特异性介导，从而为使用体内模型评估腺苷A2受体在脑功能中的功能作用提供了额外支持。
