title: 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.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology Medical University of Lübeck, Germany. raasch@medinf.mu-luebeck.de
authors.forename: Walter
authors.initials: W
authors.lastname: Raasch
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schäfer
authors.forename: Fatimunnisa
authors.initials: F
authors.lastname: Qadri
authors.forename: Peter
authors.initials: P
authors.lastname: Dominiak
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000376:Agmatine / Q000378:metabolism* / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001665:Binding Sites / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology*; D003000:Clonidine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D054755:Imidazoline Receptors; D008024:Ligands; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011918:Rats, Inbred SHR; D011955:Receptors, Drug / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
chemical_list: D000316:Adrenergic alpha-Agonists; D054755:Imidazoline Receptors; D008024:Ligands; D011955:Receptors, Drug; D000376:Agmatine; D003000:Clonidine