Abstract :
Clonidine and related antihypertensive agents, rilmenidine and moxonidine, lower blood pressure (BP) by centrally inhibiting sympathetic nerve activity. Although initially considered as agonists at central α2-adrenergic receptors, these agents also bind to a newly recognized binding site, imidazoline (1-) receptors expressed in several subclasses, I1 and I2. I-receptors are widely distributed in various organs including kidney, adrenal medulla, pancreatic β-cells, vascular smooth muscle and brain. Interaction of clonidine-like drugs with central I1 receptors lowers BP and interactions with α2-adrenergic receptors generates central side effects such as somnolence. Hence, increasing efficacy at I-receptors predicts greater therapeutic efficacy. Several endogenous ligands for I-receptors have been identified including agmatine and clonidine displacing substance (CDS). Agmatine, an amine, is decarboxylated arginine and in bacteria a precursor of polyamines. Agmatine and its biosynthetic enzyme arginine decarboxylase are expressed in various mammalian tissues and may be a novel neurotransmitter/hormone. Agmatine is a natural ligand at I-receptors of all classes, binds to adrenergic receptors of only the α2-adrenergic subclass, and blocks cholinergic nicotinic receptor function. It is present in endothelium and may represent a new endothelially-derived vascular regulator particularly of vascular muscle regeneration. CDS has not been defined structurally but is not a peptide nor catecholamine. It has a MW 580, is differentially distributed in organs, is bioactive, and interacts with antibodies to clonidine and allied drugs. Abnormalities in concentrations of CDS in serum of subjects with hypertension and in the CSF of patients with stroke have been reported. The development of selective ligands for I-receptors may represent a novel approach to hypertensive therapy.
