title: Stimulation of imidazoline receptors inhibits proliferation of human coronary artery vascular smooth muscle cells.
abstract: Vascular smooth muscle cells of rat aorta express imidazoline receptors whose stimulation, by drugs or an endogenous ligand, agmatine, inhibits serum-stimulated proliferation. We investigated whether imidazoline receptors are expressed in human vascular smooth muscle cells if their stimulation is antiproliferative. Cultured human coronary artery vascular smooth muscle cells express a nonadrenergic binding site for 3H-idazoxan and an imidazoline receptor-binding protein as revealed by immunocytochemical and immunoblot analyses with a specific antibody. Idazoxan and agmatine dose-dependently inhibited serum-stimulated proliferation of these cells as measured by the incorporation of 3H-thymidine (IC50: 5 and 70 micromol/L, respectively) and serum-stimulated expression of proliferating cell nuclear antigen and cell numbers. The agents inhibited proliferation of human and rat (aorta) smooth muscle cells stimulated by either norepinephrine (6560+/-440 disintegrations per minute norepinephrine versus 3345+/-220 norepinephrine and idazoxan), angiotensin II (7680+/-335 disintegrations per minute angiotensin II versus 3769+/-450 angiotensin II and idazoxan), or platelet-derived growth factor (IC50: 3 micromol/L for idazoxan and 40 micromol/L for agmatine), indicating inhibition of mitosis mediated by G-protein or receptor tyrosine kinase pathways. We conclude that human vascular smooth muscle cells express imidazoline-receptors whose activation inhibits proliferation by interacting at a distal step in an intracellular signal cascade common to G-protein and receptor tyrosine kinase mitogenic pathways. Agmatine, synthesized in endothelium, may act as a paracrine regulator of vascular smooth muscle cell proliferation through imidazoline receptors, and agents acting at this site may be useful in treating vascular hyperplasia.
authors.affiliation: Department of Neurology & Neuroscience, Cornell University Medical College, New York City, NY 10021, USA.
authors.forename: S
authors.initials: S
authors.lastname: Regunathan
authors.forename: D J
authors.initials: DJ
authors.lastname: Reis
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000376:Agmatine / Q000494:pharmacology*; D000818:Animals; D001158:Arteries; D002352:Carrier Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D019329:Idazoxan / Q000378:metabolism / Q000494:pharmacology*; D054755:Imidazoline Receptors; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D011955:Receptors, Drug / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*
chemical_list: D000317:Adrenergic alpha-Antagonists; D002352:Carrier Proteins; D054755:Imidazoline Receptors; D011955:Receptors, Drug; D000376:Agmatine; D019204:GTP-Binding Proteins; D019329:Idazoxan