title: Mechanism of endothelin-1-induced contraction in rabbit basilar artery.
abstract: OBJECTIVE
  Endothelin-1 (ET-1) is suggested to be a major cause of cerebral vasospasm after subarachnoid hemorrhage. However, the mechanism of ET-1-induced contraction in cerebral arteries remains unclear. This study was undertaken to demonstrate the possible role of protein tyrosine kinase (PTK), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) in ET-1-induced contraction.
  
  
  METHODS
  PD-98059, damnacanthal, wortmannin, AG-490, genistein, calphostin C, and staurosporine were used to inhibit, or relax, the ET-1-induced contraction of basilar artery, studied with an isometric tension system. Immunoprecipitation of MAPK in ET-1-stimultated rings of basilar artery without or with the above inhibitors was studied with Western blot.
  
  
  RESULTS
  (1) ET-1 produced concentration-dependent contraction and MAPK immunoprecipitation in rabbit basilar artery by activation of ET(A) but not ET(B) receptors. (2) MAPK inhibitors PD-98059 and U-0126 produced dose-dependent inhibition of ET-1-induced contraction. (3) The Src tyrosine kinase inhibitor damnacanthal, the phosphatidylinositol-3 kinase inhibitor wortmannin, and the Janus tyrosine kinase(2) inhibitor AG-490 abolished ET-1-induced contraction. (4) The PKC inhibitor staurosporine but not calphostin C abolished ET-1-induced contraction, and the PTK inhibitor genistein partially reduced ET-1-induced contraction. (5) In arteries precontracted by ET-1, PD-98059, U-0126, wortmannin, AG-490, genistein, and staurosporine produced concentration-dependent relaxation. (6) ET-1 induced a biphasic and time-dependent MAPK immunoprecipitation. (7) PD-98059, U-0126, genistein, AG-490, and damnacanthal, but not staurosporine or wortmannin, abolished the effect of ET-1 on MAPK immunoreactivity.
  
  
  CONCLUSIONS
  This study demonstrated that MAPK may be involved in ET-1-induced contraction in rabbit basilar artery. MAPK is downstream of PTK, Src, and Janus tyrosine kinase pathways but may not be downstream of phosphatidylinositol-3 kinase pathways. The possible involvement of PKC in ET-1-induced contraction requires further investigation. Inhibition of these pathways may offer alternative treatment for ET-1-induced contraction and cerebral vasospasm.
authors.affiliation: Department of Neurosurgery, University of Mississippi Medical Center, Jackson, MS 39216-4505, USA.
authors.forename: A Y
authors.initials: AY
authors.lastname: Zubkov
authors.forename: K S
authors.initials: KS
authors.lastname: Rollins
authors.forename: A D
authors.initials: AD
authors.lastname: Parent
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: R M
authors.initials: RM
authors.lastname: Bryan
mesh_terms: D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000502:physiology*; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D019332:Endothelin-1; D004791:Enzyme Inhibitors