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

Abstract

Since agmatine has been identified as a clonidine displacing substance (CDS), the aim of this study was to investigate whether agmatine can mimic CDS-induced cardiovascular reactions in organ bath experiments, pithed spontaneously hypertensive rats (SHR) and anaesthetized SHR. Intravenously-administered agmatine significantly reduced the blood pressure and heart rate of anaesthetized SHR at doses higher than 1 and 3 mg kg(-1), respectively. These effects are probably mediated via central mechanisms, since there was an approximate 8 fold rightward shift of the dose-response curve in the pithed SHR (indicating a weakened cardiovascular effect). Moreover, in organ bath experiments, agmatine failed to alter the contractility of intact or endothelium-denuded aortal rings. When agmatine was administered i.c.v. to anaesthetized SHR, blood pressure was increased without any alteration of heart rate, whereas blood pressure was unchanged and heart rate was increased after injection into the 4th brain ventricle. This suggests that haemodynamic reaction patterns after central application are related to distinct influences on central cardiovascular mechanisms. Agmatine reduces noradrenaline release in pithed SHR while alpha(2)-adrenoceptors are irreversibly blocked with phenoxybenzamine, but not while I(1)-binding sites are selectively blocked with AGN192403. This suggests that agmatine may modulate noradrenaline release in the same way that clonidine does, i.e. via imidazoline binding sites; this involves a reduction in sympathetic tone which in turn reduces blood pressure and heart rate. Finally, CDS-like cardiovascular activity appears not to be due to agmatine, since (i) blood pressure in anaesthetized SHR is decreased by agmatine and clonidine, and (ii) agmatine did not antagonize the blood pressure reaction to clonidine in pithed or anaesthetized SHR.

Figure 1

Effects of various drugs on the KCl (20 mM)-induced contraction of isolated thoracic aortal rings. (A) Influence of agmatine (AGM) on the contractility of aortal rings in the presence or absence of endothelium compared to controls. (B) Influence of clonidine (CLO) on vascular tone in intact aortal rings in the absence or presence of agmatine (1 mM). (C) Influence of phenylephrine (PHE) on contractility in intact aortal rings in the absence or presence of agmatine (1 mM). Values are expressed as means±s.e.mean of 5 – 6 experiments.

Figure 2

The influence of agmatine and clonidine on diastolic blood pressure (DBP) and heart rate of anaesthetized (A,B) or pithed (C,D) SHR. Agmatine decreased DPB and heart rate significantly (P<0.05) in anaesthetized and pithed SHR, respectively at doses >> and >33 mg kg⁻¹ respectively. Values are expressed as means±s.e.mean of 8 – 9 experiments.

Figure 3

The influence of agmatine on diastolic blood pressure (DBP, A) and heart rate (B) in anaesthetized SHR after microinjection into the central lateral (i.c.v.) or 4th ventricle. Each agmatine dose was applied within a volume of 5 μl. Values are expressed as means±s.e.mean of 7 – 8 experiments. ^*P<0.05, versus control injection.

Figure 4

The influence of agmatine (10 mg kg⁻¹) on the clonidine-induced increase of diastolic blood pressure (DBP) and heart rate reduction in pithed SHR. Values are expressed as means±s.e.mean of 7 experiments. ^*P<0.05, versus clonidine/NaCl.

Figure 5

The influence of agmatine on the clonidine-induced decrease of diastolic blood pressure (DBP) and heart rate reduction in anaesthetized SHR. Values are expressed as means±s.e.mean of 7 experiments. ^*P<0.05 versus clonidine/NaCl.