title: Analysis of sphingosine 1-phosphate receptors involved in constriction of isolated cerebral arteries with receptor null mice and pharmacological tools.
abstract: OBJECTIVE
  Sphingosine 1-phosphate (S1P) selectively and potently constricts isolated cerebral arteries, but this response has not been pharmacologically characterized.
  
  
  METHODS
  The receptor subtype(s) involved in S1P-induced cerebrovascular constriction were characterized using genetic (S1P(2) and S1P(3) receptor null mice) and pharmacological tools (phospho-FTY720, a S1P(1/3/4/5) receptor agonist; SEW2871, a S1P(1) receptor agonist, JTE-013, a S1P(2) receptor antagonist, VPC23019, a S1P(1/3) receptor antagonist). Isolated basilar or peripheral (femoral, mesenteric resistance) arteries, from either rat or mouse, were studied in a wire myograph.
  
  
  RESULTS
  S1P concentration-dependently constricted basilar artery in rat, wild-type (WT) and S1P(2) null mice, but barely affected vascular tone in S1P(3) null mice. Vasoconstriction to U46619 (a thromboxane analogue) or to endothelin-1 did not differ between WT, S1P(2) and S1P(3) null mice. JTE-013 inhibited not only S1P-induced vasoconstriction, but also KCl-, U46619- and endothelin-1-induced constriction. This effect was observed in WT as well as in S1P(2) null mice. VPC23019 increased the concentration-dependent vasoconstriction to S1P in both rat and mouse basilar arteries with intact endothelium, but not in rat basilar artery without endothelium. Phospho-FTY720 concentration-dependently constricted rat basilar arteries, but not femoral or mesenteric resistance arteries, while SEW2871 did not induce any response in the same arteries.
  
  
  CONCLUSIONS
  S1P constricts cerebral arteries through S1P(3) receptors. The purported S1P(2) receptor antagonist JTE-013 does not appear to be selective, at least in rodents. Enhancement of S1P-induced contraction by VPC23019 might be related to blockade of S1P(1) receptors and NO generation.
authors.affiliation: Stroke and Neurovascular Regulation Laboratory, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: S
authors.initials: S
authors.lastname: Salomone
authors.forename: E M
authors.initials: EM
authors.lastname: Potts
authors.forename: S
authors.initials: S
authors.lastname: Tyndall
authors.forename: P C
authors.initials: PC
authors.lastname: Ip
authors.forename: J
authors.initials: J
authors.lastname: Chun
authors.forename: V
authors.initials: V
authors.lastname: Brinkmann
authors.forename: C
authors.initials: C
authors.lastname: Waeber
mesh_terms: D000818:Animals; D002536:Cerebral Arteries / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D000068876:Fingolimod Hydrochloride; D066298:In Vitro Techniques; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010069:Oxadiazoles / Q000494:pharmacology; D011409:Propylene Glycols / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: C471998:JTE 013; D008246:Lysophospholipids; D010069:Oxadiazoles; D011409:Propylene Glycols; D011720:Pyrazoles; D011725:Pyridines; D049349:Receptors, Lysosphingolipid; C503964:SEW2871; D013876:Thiophenes; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine