Anti-Proliferative and Anti-Inflammatory Actions of Imidazoline Agents: Are Imidazoline Receptors Involved?

Authors

  • S. REGUNATHAN,

    Corresponding author
    1. Division of Neurobiology, Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10021, USA
    Search for more papers by this author
  • D. L. FEINSTEIN,

    1. Division of Neurobiology, Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10021, USA
    Search for more papers by this author
  • D. J. REIS

    1. Division of Neurobiology, Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York 10021, USA
    Search for more papers by this author

Address for correspondence: Dr. S. Regunathan, Division of Neurobiology, Cornell University Medical College, 411 East 69th Street, New York, NY 10021. Phone, 212 570–2900; fax, 212 988–3672; e-mail, sregun@mail.med.cornell.edu

Abstract

ABSTRACT: We have shown that cultured vascular smooth muscle cells (VSMC) and brain astroglial cells express I-receptors of the I;i2 subtype. While imidazoline agents are anti-proliferative in smooth muscle cells, they increase the expression of glial fibrillary acidic protein (GFAP) in astrocytes. Because increases in GFAP suppress the induction of calcium-independent, inducible nitric oxide synthase (NOS-2), we measured whether idazoxan and related imidazolines and agmatine would also suppress the expression of NOS-2. Cultured astrocytes and macrophages, RAW 264.7 cell line, were incubated with lipopolysaccharide (LPS, 1 μg/ml) or cytokine mixture in the presence of 1–100 μM of idazoxan, agmatine, or other imidazoline agents. Idazoxan potently (IC50, 10 μM) decreased the activity of NOS-2 in astrocytes, but was less potent in RAW 264.7 cells. By contrast, agmatine was most potent in RAW 264.7 cells (IC50, 10 μM) but less potent in glial cells and VSMC. Both idazoxan and agmatine decreased the activity of NOS-2 by reducing the levels of enzyme protein as measured by immunoblot and immunocytochemistry. No specific binding of [3H]-idazoxan was observed in RAW 264.7 cell membranes. We conclude that idazoxan, agmatine, and selected imidazoline agents inhibit the expression of NOS-2 and proliferation in primary glial cells and VSMC. While the antiproliferative actions appear mediated by I-receptors of the I2 type, the anti-inflammatory response is probably not mediated by I-receptors but possibly by direct actions on signal transduction enzymes.

Ancillary