Received for publication November 17, 2003.
Revised January 14, 2004.
Accepted for publication January 26, 2004.

Immune Cell Regulation and Cardiovascular Effects of Sphingosine 1-Phosphate Receptor Agonists in Rodents are Mediated via Distinct Receptor Sub-Types

Abstract

Sphingosine 1-phosphate is a bioactive lysolipid with pleiotropic functions mediated through a family of G protein coupled receptors, S1P_1,2,3,4,5. Physiological effects of S1P receptor agonists include regulation of cardiovascular function and immunosuppression via redistribution of lymphocytes from blood to secondary lymphoid organs. The phosphorylated metabolite of the immunosuppressant agent FTY720, and other phosphonate analogs with differential receptor selectivity were investigated. No significant species differences in compound potency or rank order of activity on receptors cloned from human, murine, and rat sources were observed. All synthetic analogs were high affinity agonists on S1P₁, with IC₅₀ values for ligand binding between 0.3 and 14 nM. The correlation between S1P₁ receptor activation and the ED₅₀ for lymphocyte reduction was highly significant (p < 0.001), and lower for the other receptors. In contrast to S1P₁ mediated effects on lymphocyte recirculation, three lines of evidence link S1P₃ receptor activity with acute toxicity and cardiovascular regulation: 1) compound potency on S1P₃ correlated with toxicity and bradycardia; 2) the shift in potency of phosphorylated-FTY720 for inducing lymphopenia vs. bradycardia and hypertension was consistent with affinity for S1P₁ relative to S1P₃; 3) toxicity, bradycardia, and hypertension were absent in S1P₃^-/- mice. Blood pressure effects of agonists in anesthetized rats were complex whereas hypertension was the predominant effect in conscious rats and mice. Immunolocalization of S1P₃ in rodent heart revealed abundant expression on myocytes and perivascular smooth muscle cells consistent with regulation of bradycardia and hypertension, whereas S1P₁ expression was restricted to the vascular endothelium.

Key words: FTY720, S1P receptors, heart rate, hypertension, lymphocyte trafficking, sphingosine 1-phosphate

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