FTY720 is considered a potent nonselective S1P receptor agonist. Upon binding to the S1P receptor, FTY720 induces internalization of the receptors and induces their degradation, leading to a downregulation in the number of S1P receptors. By reducing the number of receptors, FTY720 can be considered as a functional antagonist. SEW2871 is a highly selective S1P1 receptor agonist that in contrast to FTY720 does not induce degradation of its receptor after internalization and is thereby not able to Thiamet G downregulate S1P1 receptors. We found that FTY720 induced a profound decrease in the amount of circulating lymphocytes, but not in neutrophils or monocytes. FTY720-induced lymphopenia was present at the onset of extracorporeal circulation and lasted for 24 hours thereafter. In contrast, the number of circulating lymphocytes was not affected by SEW2871. Further, CPB induced a marked systemic inflammatory response as evidenced with the increase in plasma IL-6, which was unaffected by the pre-operative treatment with the single dose of FTY-720. Collectively, the above data UNC1215 strongly indicate that the reported vascular effects of FTY720 and SEW2871 are independent of its effect on immune cells. Both FTY720 and SEW2871 decreased the MAP significantly during the operative period, which most likely involves their action on S1P1 receptors. Indeed, activation of S1P1 receptors on endothelium enhances the production of nitric oxide and has vasodilatory effects. Alternatively, the reduction in MAP by FTY720 might involve signaling through S1P3 receptors, as described previously or it might be result from S1P3 receptors induced bradycardia. We did not record heart rate and therefore we cannot report whether the pretreatment with the experimental compound also caused bradycardia in our experimental settings. Further, FTY720 may inhibit the secretion of prostanoids, including contractile prostaglandins such as thromboxane A2, via a receptor-independent inhibition of phospolipase A2, a key enzyme of arachidonic acid-derived eicosanoid formation.