Biological significance of agmatine, an endogenous ligand at imidazoline binding sites

Many publications have shown that imidazoline derivatives such as clonidine, moxonidine or rilmenidine reduce sympathetic tone via a central mechanism and that as a result they reduce plasma catecholamines and blood pressure (Reid et al., 1995). This reduction in blood pressure appears not to be regulated via peripheral, presynaptically localized receptors, since neither catecholamine depletion by reserpine, or destruction of the nerve endings with 6‐hydroxydopamine produces a notable weakening of the clonidine‐induced blood pressure reduction (Haeusler, 1974a,1974b; Kobinger & Pichler, 1976; Finch et al., 1975). In contrast, selective α2‐adrenoceptor antagonists such as rauwolscine dose‐dependently block hypotension induced by intravertebral application of clonidine. While some classical α2‐adrenoceptor antagonists such as SKF86466 (in contrast to the imidazoline derivatives efaroxan and idazoxan) did not inhibit the clonidine‐induced hypotension in the CNS (Ernsberger et al., 1988b; 1994; Haxhiu et al., 1994), this was discussed to due to underdosage of the antagonist (Bock et al., 1999). Hence the effects of clonidine are due to a central α2‐adrenoceptor‐mediated mechanism. The first signs that imidazoline derivatives might also work via non‐adrenergic binding sites stem from Ruffolo (1977); the imadazoline derivative tetrahydrozoline was able to antagonize oxymetazoline‐induced contraction, but not the contractile response induced by phenylethylamine derivatives such as noradrenaline, methoxamine or phenylephrine. Clear indications for a novel receptor type came from Bousquet et al. (1984), who reported hypotension after microinjection of clonidine into the rostroventrolateral medulla (RVLM). α‐methylnoradrenaline showed no blood pressure reducing effect in the same model. The authors therefore assumed that binding sites must be present in the RVLM which preferentially bind imidazolines. Radioligand binding studies on RVLM membranes showed selective binding sites for imidazolines (Ernsberger et al., 1987). These data confirmed the assumptions of Ernsberger et al. (1988a; 1992); Buccafusco et al. (1995) and Bousquet et al. (1984) that the C1 region of the RVLM appeared to be the decisive area involved (Reis et al., 1989).