Analysis of sphingosine 1-phosphate receptors involved in constriction of isolated cerebral arteries with receptor null mice and pharmacological tools

Br J Pharmacol. 2008 Jan;153(1):140-7. doi: 10.1038/sj.bjp.0707581. Epub 2007 Nov 19.


Background and purpose: Sphingosine 1-phosphate (S1P) selectively and potently constricts isolated cerebral arteries, but this response has not been pharmacologically characterized.

Experimental approach: 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.

Key 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 and implications: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cerebral Arteries / drug effects*
  • Cerebral Arteries / physiology
  • Dose-Response Relationship, Drug
  • Fingolimod Hydrochloride
  • In Vitro Techniques
  • Lysophospholipids / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxadiazoles / pharmacology
  • Propylene Glycols / pharmacology
  • Pyrazoles / pharmacology
  • Pyridines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Lysosphingolipid / physiology*
  • Sphingosine / analogs & derivatives
  • Sphingosine / pharmacology
  • Thiophenes / pharmacology
  • Vasoconstriction / drug effects*


  • JTE 013
  • Lysophospholipids
  • Oxadiazoles
  • Propylene Glycols
  • Pyrazoles
  • Pyridines
  • Receptors, Lysosphingolipid
  • SEW2871
  • Thiophenes
  • sphingosine 1-phosphate
  • Fingolimod Hydrochloride
  • Sphingosine