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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 |
