title: Alteration of basilar artery rho-kinase and soluble guanylyl cyclase protein expression in a rat model of cerebral vasospasm following subarachnoid hemorrhage.
abstract: OBJECTIVE
  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.
authors: Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan ; Department of Neurosurgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors: Chih-Jen
authors: CJ
authors: Wang
authors: Department of Pharmacology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors: Pei-Yu
authors: PY
authors: Lee
authors: Department of Pharmacology, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors: Bin-Nan
authors: BN
authors: Wu
authors: Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors: Shu-Chuan
authors: SC
authors: Wu
authors: Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan ; Department of Neurosurgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan ; Department of Surgery, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan.
authors: Joon-Khim
authors: JK
authors: Loh
authors: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors: Hung-Pei
authors: HP
authors: Tsai
authors: Department of Surgery, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung 812, Taiwan ; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
authors: Chia-Li
authors: 0000-0003-0224-479X
authors: CL
authors: Chung
authors: Department of Neurological Surgery, University of Virginia Health System, Charlottesville, VA 22908, USA.
authors: Neal F
authors: NF
authors: Kassell
authors: Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan ; Department of Neurosurgery, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan ; Department of Neurological Surgery, University of Virginia Health System, Charlottesville, VA 22908, USA.
authors: Aij-Lie
authors: AL
authors: Kwan
mesh_terms: D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D001522:Behavior, Animal; D000242:Cyclic AMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000097:blood; D006162:Guanylate Cyclase / Q000378:metabolism*; D008297:Male; D009928:Organ Specificity / Q000187:drug effects; D063065:Organophosphonates / Q000494:pharmacology; D051745:Protein Kinase C-delta / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071756:Soluble Guanylyl Cyclase; D013345:Subarachnoid Hemorrhage / Q000097:blood / Q000150:complications* / Q000201:enzymology; D013777:Tetrazoles / Q000494:pharmacology; D020301:Vasospasm, Intracranial / Q000097:blood / Q000201:enzymology* / Q000209:etiology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D063065:Organophosphonates; D047428:Protein Kinase Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D013777:Tetrazoles; C089987:CGS 26303; D000242:Cyclic AMP; D054460:rho-Associated Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D051745:Protein Kinase C-delta; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase