Yen Chun-Po, Chen Shih-Chieh, Lin Tze-Kan, Wu Shu-Chuan, Chang Chao-Yuah, Lue Sheng-I, Jeng Arco Y, Kassell Neal F, Kwan Aij-Lie
Department of Neurosurgery, Kaohsiung Medical University, Kaohsiung, Taiwan.
J Cardiovasc Pharmacol. 2004 Nov;44 Suppl 1:S474-8. doi: 10.1097/01.fjc.0000166310.71431.52.
Previous studies indicate that intravenous infusion of CGS 26303, an endothelin-converting enzyme inhibitor, prevents and reverses cerebral vasospasm after experimental subarachnoid hemorrhage. Attenuation of the vasospastic response could result from enhanced production of nitric oxide via activation of endothelial nitric oxide synthase, neuronal nitric oxide synthase, or inducible nitric oxide synthase in brain tissue. Carbon monoxide has the same attenuation effect and is synthesized by inducible heme-oxygenase- 1 or constitutive heme-oxygenase-2. In this study, we investigated the effect of endothelin-converting enzyme inhibitor on mRNA expression of endothelial nitric oxide synthase, neuronal nitric oxide synthase, inducible nitric oxide synthase, heme-oxygenase- 1 and heme-oxygenase-2 in brain tissue of rats subjected to subarachnoid hemorrhage using semi-quantitative reverse transcription-polymerase chain reaction. The results showed that gene expression of inducible nitric oxide synthase or HSP70 was not detected in all groups of rats (n = 5/group). Expression of endothelial nitric oxide synthase, neuronal nitric oxide synthase or heme-oxygenase-2 mRNA in brain tissue in the groups of subarachnoid hemorrhage or subarachnoid hemorrhage treated with endothelin-converting enzyme inhibitor appeared to be the same as compared with control rats. The subarachnoid hemorrhage rats treated with endothelin-converting enzyme inhibitor showed a significant increase in the levels of heme-oxygenase-1 mRNA expression as compared with both subarachnoid hemorrhage and control rats. These data suggest that the reduction of cerebral vasospasm by CGS 26303 in rats subjected to experimental subarachnoid hemorrhage may result from both over-expression of heme-oxygenase-1 in brain tissue and suppression of endothelin biosynthesis in basilar arteries.
先前的研究表明，静脉输注内皮素转化酶抑制剂CGS 26303可预防并逆转实验性蛛网膜下腔出血后的脑血管痉挛。血管痉挛反应的减弱可能是由于脑组织中内皮型一氧化氮合酶、神经元型一氧化氮合酶或诱导型一氧化氮合酶激活后一氧化氮生成增加所致。一氧化碳具有同样的减弱作用，它由诱导型血红素加氧酶-1或组成型血红素加氧酶-2合成。在本研究中，我们使用半定量逆转录-聚合酶链反应，研究了内皮素转化酶抑制剂对实验性蛛网膜下腔出血大鼠脑组织中内皮型一氧化氮合酶、神经元型一氧化氮合酶、诱导型一氧化氮合酶、血红素加氧酶-1和血红素加氧酶-2 mRNA表达的影响。结果显示，所有大鼠组（每组n = 5）均未检测到诱导型一氧化氮合酶或HSP70的基因表达。蛛网膜下腔出血组或经内皮素转化酶抑制剂治疗的蛛网膜下腔出血组大鼠脑组织中，内皮型一氧化氮合酶、神经元型一氧化氮合酶或血红素加氧酶-2 mRNA的表达与对照大鼠相比似乎相同。与蛛网膜下腔出血组和对照组大鼠相比，经内皮素转化酶抑制剂治疗的蛛网膜下腔出血大鼠血红素加氧酶-1 mRNA表达水平显著升高。这些数据表明，CGS 26303减轻实验性蛛网膜下腔出血大鼠的脑血管痉挛，可能是由于脑组织中血红素加氧酶-1的过度表达以及基底动脉中内皮素生物合成的抑制。
