Inhibitory effect of sphingosine‐1‐phosphate (S1P) on microvessel acute permeability response is rapidly reversible

We showed that S1P inhibits the acute bradykinin (Bk) induced permeability response ( Cardiovasc Res 88:344–351) as determined by paired measurements of hydraulic conductivity (L p ; cm/s/cmH 2 O × 10 −7 ) of individually perfused venular mesenteric microvessels of anesthetized rat. The Bk response was measured first with no S1P, then after a 30 min S1P (1 μM) pre‐treatment period followed by concurrent treatment with S1P and Bk (10 nM). With S1P the second Bk response was 26% of the first (0.26 ± 0.06, n=11). We then tested if S1P pretreatment alone was sufficient for inhibition. By omitting S1P from the second Bk test (pretreatment‐only group) we found the very different result that there was no inhibition of the Bk response after 30 min of S1P pretreatment (1.07 ± 0.11, n=8), similar to control experiments where Bk was tested twice in the absence of S1P. Lastly, in vessels not pretreated with S1P during the 30 min washout period and then tested with Bk in the presence of S1P (concurrent‐only treatment group) inhibition was as strong (0.14 ± 0.05, n=5) as that with both pretreatment and concurrent treatment together. There was no inhibition in vessels tested with 5 μM S1P, indicating that the lack of response in the 1 μM S1P pretreatment‐only group is not due to a low concentration effect. We conclude that there is very rapid onset of S1P inhibition, but there is also a very rapid loss of inhibition on removal of the S1P. Supp. NIH HL28607