title: Combined argatroban and anti-oxidative agents prevents increased vascular contractility to thrombin and other ligands after subarachnoid haemorrhage.
abstract: OBJECTIVE
  Increased vascular contractility plays a fundamental role in cerebral vasospasm in subarachnoid haemorrhage (SAH). We investigated the role of thrombin and its receptor, proteinase-activated receptor 1 (PAR1), and other G protein-coupled receptors in the increased contractility, and examined the preventive effects of the thrombin inhibitor, argatroban, and anti-oxidative agents, vitamin C and tempol.
  
  
  METHODS
  A rabbit model of SAH was utilized. Contractile responses of the isolated basilar artery and the level of oxidative stress of brain tissues were evaluated.
  
  
  RESULTS
  Contractile responses to thrombin and PAR1-activating peptide (PAR1-AP) were enhanced and prolonged after SAH. The thrombin-induced contraction persisted even after terminating thrombin stimulation. When sequentially stimulated with PAR1-AP, the second response was maintained in SAH, while it was substantially attenuated in the control. Only a combination of argatroban with vitamin C or tempol prevented both the enhancement and prolongation of the contractile response to PAR1-AP and restored the reversibility of the thrombin-induced contraction. The responses to angiotensin II, vasopressin and PGF(2α) were enhanced and prolonged after SAH to varying degrees, and responded differently to the treatment. The response to vasopressin exhibited a similar phenomenon to that seen with PAR1-AP. Oxidative stress was increased in SAH, and normalized by the treatment with argatroban, vitamin C or their combination.
  
  
  CONCLUSIONS
  Increased vascular reactivity to agonists in SAH was attributable to the enhancement and prolongation of the contractile response. A combination of argatroban and anti-oxidative agents was required to prevent both the enhancement and prolongation of the contractile response.
authors.affiliation: Division of Molecular Cardiology, Research Institute of Angiocardiology, Graduate School of Medical Sciences, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Japan.
authors.forename: Katsuharu
authors.initials: K
authors.lastname: Kameda
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Kikkawa
authors.forename: Mayumi
authors.initials: M
authors.lastname: Hirano
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsuo
authors.forename: Tomio
authors.initials: T
authors.lastname: Sasaki
authors.forename: Katsuya
authors.initials: K
authors.lastname: Hirano
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives; D001205:Ascorbic Acid / Q000494:pharmacology; D004359:Drug Therapy, Combination; D008297:Male; D010875:Pipecolic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D044463:Receptor, PAR-1 / Q000819:agonists; D015398:Signal Transduction; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy*; D013449:Sulfonamides; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology*; D013927:Thrombosis; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D010875:Pipecolic Acids; D044463:Receptor, PAR-1; D013449:Sulfonamides; D017392:Thiobarbituric Acid Reactive Substances; D001120:Arginine; D013917:Thrombin; C031942:argatroban; D001205:Ascorbic Acid