Influence of Imidazolines on Catecholamine Release in Pithed Spontaneously Hypertensive Rats

Abstract

The actions of the imidazoline derivatives clonidine, moxonidine, and rilmenidine and of the recently discovered clonidine-displacing substance agmatine on stimulation-induced norepinephrine overflow and epinephrine release were studied in pithed spontaneously hypertensive rats. All three imidazolines dose-dependently decreased norepinephrine overflow and led to an increase in epinephrine release when the highest dose of each compound was injected. The alpha 2-adrenoceptor antagonist rauwolscine shifted the dose-response curves of plasma norepinephrine concentrations to higher levels. Agmatine did not change norepinephrine overflow but increased epinephrine release into plasma after the highest dose administered. It is concluded that the investigated imidazolines decrease norepinephrine overflow via presynaptic alpha 2-adrenoceptors, whereas epinephrine release is mediated through putative imidazoline receptors on the adrenal medulla.

Agmatine, an endogenous ligand at imidazoline binding sites, does not antagonize the clonidine‐mediated blood pressure reaction

“…For this reason we studied the effects of agmatine: (1) by injecting agmatine intravenously or directly into the central nervous system of pithed or anaesthetized spontaneously hypertensive rats (SHR); (2) by determining the cardiovascular interaction between agmatine and clonidine; and (3) by identifying a mechanism which might be responsible for the agmatine‐induced regulation of blood pressure and heart rate. The use of SHR in our study was based on experience gained with this model from earlier studies; clonidine and agmatine were both shown to influence blood pressure and/or catecholamine overflow in pithed SHR (Häuser & Dominiak, 1995; Häuser et al ., 1995). Furthermore, CDS was shown to be increased in plasma of hypertensive patients and was positively correlated with blood pressure (Dontenwill et al ., 1993).…”

Modification of Noradrenaline Release in Pithed Spontaneously Hypertensive Rats by I1-Binding Sites in Addition to α2-Adrenoceptors

“…Studies in conscious and pithed rabbits have supported the view that central sympathetic inhibition is mediated only via ␣ 2 -adrenoceptors (Urban et al, 1995;Bock et al, 1999;Szabo et al, 1999). In pithed, spontaneously hypertensive rats (SHR) and rabbits, rilmenidine and moxonidine decreased the stimulated overflow of noradrenaline (Hä user et al, 1995;Urban et al, 1995;Szabo et al, 1999). Because imidazoline derivatives were still able to reduce noradrenaline overflow dose dependently after rauwolscine pretreatment, an ␣ 2 -adrenoceptor-independent mechanism was suggested (Hä user et al, 1995).…”

“…4) increased noradrenaline overflow dose dependently during ␣ 2 -adrenoceptor blockade, strengthening the idea of antagonism between efaroxan and moxonidine at I 1 -binding sites regarding noradrenaline release. Such a picture regarding noradrenaline release is paralleled when focusing on presynaptic ␣ 2 -adrenoceptors: a stimulation for example by the agonist moxonidine causes a decrease, whereas an inhibition by rauwolscine or phenoxybenzamine increases noradrenaline release (Hä user et al, 1995). However, our findings differ from in vitro findings in that the electrically evoked [ 3 H]noradrenaline overflow in the presence of phenoxybenzamine or rauwolscine was either diminished Molderings et al, 1997) or remained unchanged (Molderings and Göthert, 1998), a fact suggesting different modes/sites of action in in vivo and in vitro situations (see above for discussion).…”

“…In pithed, spontaneously hypertensive rats (SHR) and rabbits, rilmenidine and moxonidine decreased the stimulated overflow of noradrenaline (Hä user et al, 1995;Urban et al, 1995;Szabo et al, 1999). Because imidazoline derivatives were still able to reduce noradrenaline overflow dose dependently after rauwolscine pretreatment, an ␣ 2 -adrenoceptor-independent mechanism was suggested (Hä user et al, 1995). However, it seems not unlikely that clonidine, moxonidine, or rilmenidine induces sympathetic inhibitory effects via ␣ 2 -adrenoceptors even in the presence of rauwolscine, because this ␣ 2 -blocker was characterized to be a competitive antagonist , which would strengthen the idea of an imidazoline binding site-independent regulation of noradrenaline release.…”

Norepinephrine Release Is Reduced by I1‐Receptors in Addition to a2‐Adrenoceptors

“…The best way to demonstrate in vivo whether imidazoline binding sites would have some regulatory impact on noradrenaline release is to employ α 2A/C ‐double knockout (KO) mice. Since this animal model was not available to us, we decided to overcome the limitation of a competitive blockade of α 2 ‐adrenoceptors with rauwolscine (this α 2 ‐AR antagonist was used in previous studies3) by performing experiments in pithed rats under irreversible α 2 ‐AR blockade (by using phenoxybenzamine) or blockade of I 1 ‐receptors (by using AGN192403). Thus, the aim of this study was to determine whether imidazoline binding sites contribute to the moxonidine‐induced modification of noradrenaline release in vivo, and if so, to specify the subtype of imidazoline binding sites involved in mediating this effect.…”