Attenuation of Endothelin-1 Regulates Rho-kinase And Soluble Guanylyl Cyclase Pathways After Subarachnoid Hemorrhage

• Main Authors: Pei-Yu Lee, 李佩育
• Other Authors: Aij-Lie Kwan
• Format: Others
• Language: zh-TW
• Published: 2008
• Online Access: http://ndltd.ncl.edu.tw/handle/53796213428227148629

碩士 === 高雄醫學大學 === 藥理學研究所 === 96 === Subarachnoid hemorrhage (SAH) is an important subcategory of stroke, because of its unacceptably high levels of mortality, as well as severe complications, such as cerebral vasospasm, neurological deficit and cardiopulmonary abnormality. Many evidences have shown that endothelin-1 (ET-1), a potent vasoconstrictor, plays a pivotal role in cerebral vasospasm following SAH. Previous researches have shown that blocking ET-1 biosynthesis with CGS 26303, an endothelin-converting enzyme (ECE) inhibitor, could effectively prevent and reverse arterial narrowing in SAH animal model; however, the vasorelaxation mechanism is still uncertain. Vascular smooth muscle tone is regulated by NO-dependent soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG), RhoA/Rho-kinase (ROCK) and protein kinase C (PKC) pathways. Many researches have shown that ET-1 could activate PKC pathway in SAH animal model, while RhoA/ROCK and sGC/cGMP/PKG pathway is discussed rarely. The aim of the study is to exam wherether attenuating ET-1 synthesis in SAH with CGS 26303, could alleviate vasoconstriction through altering RhoA/ROCK and sGC/cGMP/PKG protein expression. Sprague-Dawley (SD) rats were divided into five groups：(1) normal control, (2) SAH, (3) SAH + vehicle, (4) SAH + prevention and (5) SAH + reverse. CGS 26303 (1 mg/ml/kg, i.v.) was injected into rats at 1 h and 24 h after SAH for the preventive and reverse protocols, respectively. SAH was simulated by single injection of autologous blood into cisterna magna. CGS 26303 could significantly reverse cerebral vasospasm and ET-1 elevation after SAH. The expression of RhoA/ROCK elevated and sGC/cGMP/PKG attenuated in SAH basilar artery. However, CGS 26303 significantly reversed both RhoA/ROCK-II and sGC/cGMP/PKG proteins to control level. In conclusion, RhoA/ROCK-II and sGC/cGMP/PKG pathways play pivotal roles in cerebral vasospasm after SAH. Inhibit ET-1 biosynthesis with CGS 26303, could alleviate cerebral vasospasm and neurological deficit after SAH through downregulating of RhoA/ROCK-II expression and upregulating of sGC/cGMP/PKG expression. Besides, unwanted blood pressure and heart rate changes did not occur after vasorelaxation with CGS 26303. Moreover, ROCK-II and sGC expression were not affected either. With this study, we found that CGS 26303 is a potential drug for prevention and reverse vasospasm after SAH. Adverse effects were rarely found in our experiments, therefore, CGS 26303 could be expected to use in SAH patients in the future.