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Research ArticleCARDIOVASCULAR

Immune Cell Regulation and Cardiovascular Effects of Sphingosine 1-Phosphate Receptor Agonists in Rodents Are Mediated via Distinct Receptor Subtypes

M. Forrest, S.-Y. Sun, R. Hajdu, J. Bergstrom, D. Card, G. Doherty, J. Hale, C. Keohane, C. Meyers, J. Milligan, S. Mills, N. Nomura, H. Rosen, M. Rosenbach, G.-J. Shei, I. I. Singer, M. Tian, S. West, V. White, J. Xie, R. L. Proia and S. Mandala
Journal of Pharmacology and Experimental Therapeutics May 2004, 309 (2) 758-768; DOI: https://doi.org/10.1124/jpet.103.062828
M. Forrest
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S.-Y. Sun
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R. Hajdu
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J. Bergstrom
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D. Card
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G. Doherty
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J. Hale
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C. Keohane
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C. Meyers
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J. Milligan
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S. Mills
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N. Nomura
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H. Rosen
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M. Rosenbach
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G.-J. Shei
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I. I. Singer
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M. Tian
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S. West
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V. White
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J. Xie
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R. L. Proia
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S. Mandala
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Abstract

Sphingosine 1-phosphate (S1P) is a bioactive lysolipid with pleiotropic functions mediated through a family of G proteincoupled receptors, S1P1,2,3,4,5. 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 (2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol) 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: compound potency on S1P3 correlated with toxicity and bradycardia; the shift in potency of phosphorylated-FTY720 for inducing lymphopenia versus bradycardia and hypertension was consistent with affinity for S1P1 relative to S1P3; and 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.

Footnotes

  • ↵1 Present address: Array BioPharma, Boulder, CO.

  • ↵2 Present address: The Scripps Research Institute, La Jolla, CA.

  • DOI: 10.1124/jpet.103.062828.

  • ABBREVIATIONS: S1P, sphingosine 1-phosphate; IK.Ach, inwardly rectifying K+ currents; CHO, Chinese hamster ovary; MAP, mean arterial pressure; DAPI, 4,6-diamidino-2-phenylindole; [35S]GTPγS, guanosine 5′-O-(3-[35S]thio)triphosphate; FTY720, 2-amino-2-(2-[4-octylphenyl] ethyl)-1,3-propanediol; PECAM, platelet-endothelial cell adhesion molecule.

    • Received November 11, 2003.
    • Accepted January 26, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 309 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 309, Issue 2
1 May 2004
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Research ArticleCARDIOVASCULAR

Immune Cell Regulation and Cardiovascular Effects of Sphingosine 1-Phosphate Receptor Agonists in Rodents Are Mediated via Distinct Receptor Subtypes

M. Forrest, S.-Y. Sun, R. Hajdu, J. Bergstrom, D. Card, G. Doherty, J. Hale, C. Keohane, C. Meyers, J. Milligan, S. Mills, N. Nomura, H. Rosen, M. Rosenbach, G.-J. Shei, I. I. Singer, M. Tian, S. West, V. White, J. Xie, R. L. Proia and S. Mandala
Journal of Pharmacology and Experimental Therapeutics May 1, 2004, 309 (2) 758-768; DOI: https://doi.org/10.1124/jpet.103.062828

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Research ArticleCARDIOVASCULAR

Immune Cell Regulation and Cardiovascular Effects of Sphingosine 1-Phosphate Receptor Agonists in Rodents Are Mediated via Distinct Receptor Subtypes

M. Forrest, S.-Y. Sun, R. Hajdu, J. Bergstrom, D. Card, G. Doherty, J. Hale, C. Keohane, C. Meyers, J. Milligan, S. Mills, N. Nomura, H. Rosen, M. Rosenbach, G.-J. Shei, I. I. Singer, M. Tian, S. West, V. White, J. Xie, R. L. Proia and S. Mandala
Journal of Pharmacology and Experimental Therapeutics May 1, 2004, 309 (2) 758-768; DOI: https://doi.org/10.1124/jpet.103.062828
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