Alteration of basilar artery rho-kinase and soluble guanylyl cyclase protein expression in a rat model of cerebral vasospasm following subarachnoid hemorrhage.

Chih-Jen Wang,Neal F Kassell,Joon-Khim Loh,Chia-Li Chung,Shu-Chuan Wu,Bin-Nan Wu,Aij-Lie Kwan,Pei-Yu Lee,Hung-Pei Tsai

doi:10.1155/2014/531508

Abstract

Background and Purpose. The vasoconstrictor endothelin-1 (ET-1) has been implicated in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). Previous results showed that CGS 26303, an endothelin converting enzyme (ECE) inhibitor, effectively prevented and reversed arterial narrowing in animal models of SAH. In the present study, we assessed the effect of CGS 26303 on neurological deficits in SAH rats. The involvement of vasoactive pathways downstream of ET-1 signaling in SAH was also investigated. Methods. Sprague-Dawley rats were divided into five groups (n = 6/group): (1) normal control, (2) SAH, (3) SAH+vehicle, (4) SAH+CGS 26303 (prevention), and (5) SAH+CGS 26303 (reversal). SAH was induced by injecting autologous blood into cisterna magna. CGS 26303 (10 mg/kg) was injected intravenously at 1 and 24 hr after the initiation of SAH in the prevention and reversal protocols, respectively. Behavioral changes were assessed at 48 hr after SAH. Protein expression was analyzed by Western blots. Results. Deficits in motor function were obvious in the SAH rats, and CGS 26303 significantly improved the rate of paraplegia. Expressions of rho-kinase-II and membrane-bound protein kinase C-δ and rhoA were significantly increased, while those of soluble guanylyl cyclase α 1 and β 1 as well as protein kinase G were significantly decreased in the basilar artery of SAH rats. Treatment with CGS 26303 nearly normalized these effects. Conclusions. These results demonstrate that the rhoA/rho-kinase and sGC/cGMP/PKG pathways play pivotal roles in cerebral vasospasm after SAH. It also shows that ECE inhibition is an effective strategy for the treatment of this disease.

Highlights

Subarachnoid hemorrhage (SAH) is an important subcategory of stroke due to an unacceptably high mortality rate as well as the severe complications it causes, such as cerebral vasospasm, neurological deficit, and cardiopulmonary abnormality [1]
Various selective and nonselective ET-1 receptor antagonists have been evaluated in animal models of cerebral vasospasm following SAH and in humans with varying degrees of success [3, 4]
The results reported in the present study showing that an endothelin converting enzyme (ECE) inhibitor CGS 26303 significantly improved the motor function index and the rate of paraplegia in the SAH rats are significant findings

Summary

Introduction

Subarachnoid hemorrhage (SAH) is an important subcategory of stroke due to an unacceptably high mortality rate as well as the severe complications it causes, such as cerebral vasospasm, neurological deficit, and cardiopulmonary abnormality [1]. CGS 26303 is such an inhibitor [5,6,7,8], and it has been shown to prevent and reverse cerebral vasospasm in a rabbit model of SAH [9]. The vasoconstrictor endothelin-1 (ET-1) has been implicated in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). Previous results showed that CGS 26303, an endothelin converting enzyme (ECE) inhibitor, effectively prevented and reversed arterial narrowing in animal models of SAH. We assessed the effect of CGS 26303 on neurological deficits in SAH rats. These results demonstrate that the rhoA/rho-kinase and sGC/cGMP/PKG pathways play pivotal roles in cerebral vasospasm after SAH. It shows that ECE inhibition is an effective strategy for the treatment of this disease

Objectives

Methods

Discussion

Conclusion