title: Imidazoline receptors and agmatine in blood vessels: a novel system inhibiting vascular smooth muscle proliferation.
abstract: We investigated whether vascular smooth muscle and endothelial cells express imidazoline (I-) receptors, their endogenous ligand agmatine and/or its biosynthetic enzyme arginine decarboxylase (ADC), and if I-receptors regulate smooth muscle proliferation. Membranes of cultured rat aortic smooth muscle or bovine pulmonary artery endothelial cells bind 3H-idazoxan. Binding was inhibited by: idazoxan > cirazoline > UK 14,304 > naphazoline > tolazoline > guanabenz > amiloride > clonidine = phentolamine > > epinephrine. Agmatine competitively inhibited binding of 3H-idazoxan (Ki of 240 +/- 25 nM). Smooth muscle and endothelial cells were immunostained in vitro and in situ by antibodies to an I-receptor binding protein and by antibodies to agmatine. Rat aorta also contained substantial amounts of agmatine measured by HPLC (8.69 +/- 1.1 ng/g). Membranes of rat aorta and cultured endothelial but not smooth muscle cells expressed substantial amounts of ADC. The incorporation of 3H-thymidine and numbers of smooth muscle cells stimulated by fetal calf serum was inhibited > 90% by: idazoxan > UK 14,304 > naphazoline > cirazoline > agmatine highly correlating (r= .996; P < .01) with affinities for 3H-idazoxan binding site. Tolazoline, but not rauwolscine, blocked the antiproliferative action of idazoxan. We conclude that (1) vascular smooth muscle and endothelium contain imidazoline receptors of the I2 subclass; (2) stimulation of the receptors inhibits vascular smooth muscle proliferation; (3) agmatine, synthesized in endothelium by ADC may be an endogenous agonist of I2 receptors to inhibit vascular growth and (4) I2 receptors may be functionally active.
authors.affiliation: Department of Neurology and Neuroscience, Cornell University Medical College, New York, New York, USA.
authors.forename: S
authors.initials: S
authors.lastname: Regunathan
authors.forename: C
authors.initials: C
authors.lastname: Youngson
authors.forename: W
authors.initials: W
authors.lastname: Raasch
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: D J
authors.initials: DJ
authors.lastname: Reis
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D004146:Dioxanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019329:Idazoxan; D007093:Imidazoles / Q000494:pharmacology; D054755:Imidazoline Receptors; D007150:Immunohistochemistry; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011869:Radioligand Assay; D051381:Rats; D011955:Receptors, Drug / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D007093:Imidazoles; D054755:Imidazoline Receptors; D011955:Receptors, Drug; D019329:Idazoxan