Imidazoline receptors and agmatine in blood vessels: a novel system inhibiting vascular smooth muscle proliferation.

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.