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

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Abstract
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 (S1P2 and S1P3 receptor null mice) and pharmacological tools (phospho‐FTY720, a S1P1/3/4/5 receptor agonist; SEW2871, a S1P1 receptor agonist, JTE‐013, a S1P2 receptor antagonist, VPC23019, a S1P1/3 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 S1P2 null mice, but barely affected vascular tone in S1P3 null mice. Vasoconstriction to U46619 (a thromboxane analogue) or to endothelin‐1 did not differ between WT, S1P2 and S1P3 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 S1P2 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 S1P3 receptors. The purported S1P2 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 S1P1 receptors and NO generation. British Journal of Pharmacology (2008) 153, 140–147; doi:10.1038/sj.bjp.0707581; published online 19 November 2007

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