Lin Chih-Lung, Shih Huei-Chuan, Lieu Ann-Shung, Lee Kung-Shing, Dumont Aaron S, Kassell Neal F, Howng Shen-Long, Kwan Aij-Lie
Department of Neurosurgery, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
J Neurosurg. 2007 Mar;106(3):436-41. doi: 10.3171/jns.2007.106.3.436.
Impaired endothelium-dependent relaxation is present in vasospastic cerebral vessels after subarachnoid hemorrhage (SAH) and may result from deficient production of endothelial nitric oxide synthase (eNOS) or increased production and/or activity of inducible NOS (iNOS). Accumulating evidence demonstrates that adenosine A2A receptors increase the production of NO by human and porcine arterial endothelial cells, which in turn leads to vasodilation. This study was designed to examine the effects of an adenosine A2A receptor agonist, (2(4-[2-carboxyethyl]phenyl)ethylamino)-5'-N-ethylcarboxamidoadenosine (CGS 21680), in the prevention of SAH-induced vasospasm.
. Experimental SAH was induced in Sprague-Dawley rats by injecting 0.3 ml of autologous blood into the cisterna magna of each animal. Intraperitoneal injections of CGS 21680 or vehicle were administered 5 minutes and 24 hours after induction of SAH. The degree of vasospasm was determined by averaging measurements of cross-sectional areas of the basilar artery (BA) 48 hours after SAH. Expression of eNOS and iNOS in the BA was also evaluated. Prior to perfusion-fixation, there were no significant differences among animals in the control and treated groups in any physiological parameter that was recorded. The CGS 21680 treatment significantly attenuated SAH-induced vasospasm. Induction of iNOS mRNA and protein in the BA by the SAH was significantly diminished by administration of CGS 21680. The SAH-induced suppression of eNOS mRNA and protein was also relieved by the CGS 21680 treatment.
This is the first evidence that adenosine A2A receptor agonism is effective in preventing SAH-induced vasospasm without significant complications. The beneficial effect of adenosine A2A receptor agonists may be, at least in part, related to the prevention of augmented expression of iNOS and the preservation of normal eNOS expression following SAH. Adenosine A2A receptor agonism holds promise in the treatment of cerebral vasospasm following SAH and merits further investigation.
蛛网膜下腔出血（SAH）后痉挛性脑血管存在内皮依赖性舒张功能受损，这可能是由于内皮型一氧化氮合酶（eNOS）产生不足或诱导型一氧化氮合酶（iNOS）产生增加和/或活性增强所致。越来越多的证据表明，腺苷A2A受体可增加人和猪动脉内皮细胞的一氧化氮生成，进而导致血管舒张。本研究旨在探讨腺苷A2A受体激动剂（2(4-[2-羧乙基]苯基)乙氨基）-5'-N-乙基羧酰胺腺苷（CGS 21680）在预防SAH诱导的血管痉挛中的作用。
通过向每只Sprague-Dawley大鼠的大池内注射0.3 ml自体血诱导实验性SAH。在SAH诱导后5分钟和24小时腹腔注射CGS 21680或溶剂。通过SAH后48小时基底动脉（BA）横截面积测量值的平均值来确定血管痉挛程度。还评估了BA中eNOS和iNOS的表达。在灌注固定前，对照组和治疗组动物记录的任何生理参数均无显著差异。CGS 21680治疗显著减轻了SAH诱导的血管痉挛。给予CGS 21680可显著减少SAH诱导的BA中iNOS mRNA和蛋白的诱导。CGS 21680治疗也缓解了SAH诱导的eNOS mRNA和蛋白的抑制。
这是首个表明腺苷A2A受体激动在预防SAH诱导的血管痉挛且无明显并发症方面有效的证据。腺苷A2A受体激动剂的有益作用可能至少部分与预防SAH后iNOS表达增加以及维持正常eNOS表达有关。腺苷A2A受体激动在SAH后脑血管痉挛治疗中具有前景，值得进一步研究。
