IMIDAZOLINE RECEPTORS AND AGMATINE IN BLOOD-VESSELS - A NOVEL SYSTEM INHIBITING VASCULAR SMOOTH-MUSCLE PROLIFERATION

We investigated whether vascular smooth muscle and endothelial cells e xpress imidazoline (I-) receptors, their endogenous ligand agmatine an d/or its biosynthetic enzyme arginine decarboxylase (ADC), and if I-re ceptors regulate smooth muscle proliferation. Membranes of cultured ra t aortic smooth muscle or bovine pulmonary artery endothelial cells bi nd H-3-idazoxan. Binding was inhibited by: idazoxan > cirazoline > UK 14,304 > naphazoline > tolazoline > guanabenz > amiloride > clonidine = phentolamine much greater than epinephrine. Agmatine competitively i nhibited binding of H-3-idazoxan (K-i of 240 +/- 25 nM). Smooth muscle and endothelial cells were immunostained in vitro and in situ by anti bodies 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 endothel ial but not smooth muscle cells expressed substantial amounts of ADC. The incorporation of H-3-thymidine and numbers of smooth muscle cells stimulated by fetal calf serum was inhibited > 90% by: idazoxan > UK 1 4,304 > naphazoline > cirazoline > agmatine highly correlating (r = .9 96; P < .01) with affinities for H-3-idazoxan binding site. Tolazoline , but not rauwolscine, blocked the antiproliferative action of idazoxa n. We conclude that (1) vascular smooth muscle and endothelium contain imidazoline receptors of the I-2 subclass; (2) stimulation of the rec eptors inhibits vascular smooth muscle proliferation; (3) agmatine, sy nthesized in endothelium by ADC may be an endogenous agonist of I-2 re ceptors to inhibit vascular growth and (4) I-2 receptors may be functi onally active.