Indomethacin differentiates the renal effects of sphingosine-1-phosphate and sphingosylphosphorylcholine

The sphingomyelin breakdown products sphingosine-1-phosphate (S1P) and sphingosylphosphorylcholine (SPC) constrict intrarenal microvessels in vitro in a pertussis toxin (PTX) sensitive manner, and S1P also reduces renal blood flow in vivo. Nevertheless, both S1P and SPC have been reported to enhance diuresis and natriuresis. This pattern is similar to that of neuropeptide Y, which also reduces renal blood flow and enhances diuresis and natriuresis. The latter effects are inhibited by the cyclooxygenase inhibitor indomethacin, and various S1P and SPC responses have also been linked to the cyclooxygenase pathway. Therefore, we have investigated whether indomethacin can alter the renal effects of S1P and SPC in anaesthetised rats in vivo. In line with earlier experiments S1P bolus injections dose-dependently reduced renal blood flow (by up to 4.8 +/- 0.5 ml min(-1)), and this was not significantly affected by indomethacin treatment (5 mg kg(-1) i.p.). Infusion of S1P but not of SPC (30 microg kg(-1) min(-1) each) for 60 min reduced renal blood flow by up to 0.8 +/- 0.2 ml min(-1), and this was not markedly altered by indomethacin. Despite the differential renovascular effect, both S1P and SPC enhanced diuresis by up to 215 +/- 65 and 201 +/- 58 microl 15 min(-1) respectively, and natriuresis by up to 25 +/- 9 and 29 +/- 11 micromol 15 min(-1) respectively. While indomethacin abolished the SPC-induced diuresis and natriuresis, it, if anything, slightly enhanced the diuretic and natriuretic effect of S1P. To determine whether tubular SPC effects are receptor-mediated, PTX experiments were performed. SPC-induced enhancements of diuresis and natriuresis were abolished by PTX. We conclude that S1P, SPC and neuropeptide Y exhibit distinct patterns of modulation of renal function and that indomethacin allows such effects to be differentiated.