Comparison of the properties of agmatine and endogenous clonidine-displacing substance at imidazoline and alpha-2 adrenergic receptors.

Nonadrenergic imidazoline receptors (I receptors) mediate the central antihypertensive effects of clonidine. Agmatine, an arginine metabolite that is synthesized within bovine brain and exhibits clonidine-displacing substance (CDS) activity, might be the endogenous I receptor neurotransmitter. The authors compared the affinity of agmatine versus the potency of endogenous bovine hypothalamic CDS, at bovine adrenomedullary I1 receptors and at human clonidine-binding sites: human alpha-2A, alpha-2B and alpha-2C expressed on transfected cell lines, I1 sites on human platelet plasma membranes and I2b (amiloride-insensitive) sites on human platelet intracellular membranes. The alpha-2 and I1 sites were labeled with [125I]p-iodoclonidine and the I2b sites were labeled with [3H]-idazoxan. Agmatine displayed preferential affinity for I1 receptors, with both high (H) and low (L) affinity components; the rank order was I1(human)(H) > I1(bovine)(H) > I2b = I1(human)(L) = I1(bovine) (L) = alpha-2A = alpha-2B = alpha-2C. By comparison, hypothalamic CDS competition curves modeled to a single site for all receptors, i.e., I1(bovine) > I2b = alpha-2C > I1(human) = alpha-2A = alpha-2B. Thus, agmatine alone cannot explain the rank order of potency of hypothalamic CDS. Moreover, I1 sites on human platelets differ from I1 sites on bovine adrenomedullary cells with respect to CDS potency but not agmatine affinity. These results do not rule out agmatine as an I1 transmitter but suggest that other I-receptor ligands might exist within endogenous CDS.