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Anti‐Proliferative and Anti‐Inflammatory Actions of Imidazoline Agents: Are Imidazoline Receptors Involved?
Author(s) -
REGUNATHAN S.,
FEINSTEIN D. L.,
REIS D. J.
Publication year - 1999
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1999.tb09389.x
Subject(s) - agmatine , idazoxan , imidazoline receptor , nitric oxide synthase , glial fibrillary acidic protein , astrocyte , receptor , chemistry , vascular smooth muscle , endocrinology , medicine , microbiology and biotechnology , biology , biochemistry , arginine , antagonist , enzyme , central nervous system , immunohistochemistry , amino acid , prazosin , smooth muscle
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 (IC 50 , 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 (IC 50 , 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 [ 3 H]‐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 I 2 type, the anti‐inflammatory response is probably not mediated by I‐receptors but possibly by direct actions on signal transduction enzymes.