Analysis of sphingosine 1-phosphate receptors involved in constriction of isolated cerebral arteries with receptor null mice and pharmacological tools
Analysis of sphingosine 1-phosphate receptors involved in constriction of isolated cerebral arteries with receptor null mice and pharmacological tools
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DOI：
10.1038/sj.bjp.0707581
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发表时间：
2008-01-01
影响因子：
7.3
通讯作者：
Waeber, C.
中科院分区：
文献类型：
--
作者：
Salomone, S.;Potts, E. M.;Waeber, C.
背景和目的：1-磷酸鞘氨醇（S1 P）选择性地和有效地收缩离体脑动脉，但这种反应尚未被明确表征。实验方法：使用遗传学（S1 P（2）和S1 P（3）受体缺失小鼠）和药理学工具表征参与S1 P诱导的脑血管收缩的受体亚型（磷酸-FTY 720，S1 P（1/3/4/5）受体激动剂; SEW 2871，S1 P（1）受体激动剂; JTE-013，S1 P（2）受体拮抗剂; VPC 23019，S1 P（1/3）受体拮抗剂）。在钢丝肌描记器中研究大鼠或小鼠的离体基底动脉或外周动脉（股动脉、肠系膜阻力）。关键结果：S1 P浓度依赖性地收缩大鼠、野生型（WT）和S1 P（2）缺失小鼠的基底动脉，但几乎不影响S1 P（3）缺失小鼠的血管张力。WT、S1 P（2）和S1 P（3）缺失小鼠对U46619（血栓素类似物）或内皮素-1的血管收缩没有差异。JTE-013不仅能抑制S1 P引起的血管收缩，而且能抑制KCl、U46619和ET-1引起的血管收缩。在WT和S1 P（2）缺失小鼠中观察到这种效应。VPC 23019可增加内皮完整的大鼠和小鼠基底动脉对S1 P的浓度依赖性血管收缩，但对无内皮的大鼠基底动脉无此作用。Phospho-FTY 720浓度依赖性地收缩大鼠基底动脉，但不是股动脉或肠系膜阻力动脉，而SEW 2871没有引起任何反应，在相同的arteries.Conclusions和影响：S1 P通过S1 P（3）受体收缩脑动脉。据称的S1 P（2）受体拮抗剂JTE-013似乎没有选择性，至少在啮齿动物中是这样。VPC 23019增强S1 P（1）诱导的收缩可能与阻断S1 P（1）受体和NO生成有关。
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.