title: Presynaptic effects of moxonidine in isolated buffer perfused rat hearts: role of imidazoline-1 receptors and alpha2-adrenoceptors.
abstract: Numerous studies support the concept that centrally acting antihypertensive drugs, such as imidazolines, mediate sympathoinhibition not only via activation of central nervous alpha2-adrenoceptors (alpha2-AR) but also via imidazoline-1 receptors (I1-R). An additional presynaptic involvement in sympathetic neurotransmission of imidazolines, via I1-R independent of alpha2-AR, is still controversial and remains to be clarified in the heart. Concentration response curves on endogenous norepinephrine (NE) overflow evoked by stimulation of epicardial postganglionic sympathetic nerves in isolated buffer-perfused rat hearts were performed for brimonidine, moxonidine, rauwolscine, 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane (AGN192403), and efaroxan. To unmask an I1-R-mediated effect of moxonidine, hearts were pre-exposed in additional experiments with brimonidine or rauwolscine with or without AGN192403 or efaroxan, respectively. Moxonidine reduced stimulated NE overflow (log EC50: -6.15 +/- 0.14). AGN192403, a selective ligand at I1-R, had no influence on the dose-response curve of moxonidine (log EC50: -6.01 +/- 0.25). After pre-exposure to brimonidine [ stimulation 1 (S1) + stimulation 2 (S2); 10(-5) M], the inhibitory action of moxonidine was potentiated compared with control (32.0 +/- 2.8 versus 73.13 +/- 3.0%) and completely abolished with AGN192403 or efaroxan. This effect was also totally inhibited by pre-exposure with indomethacin (10(-7) M) and tricyclodecan-9-yl-xanthogenate (D-609), an inhibitor of phosphatidylcholine-selective phospholipase C (PC-PLC; 10(-7) M). Conversely, moxonidine was without modulating efficacy under alpha2-AR-blockade by rauwolscine. In summary, we demonstrate that moxonidine reduces NE release independently of I1-R, demonstrating the prominent effect of alpha2-AR in cardiac tissue under basal conditions. We also demonstrate that I1-R are involved in NE release under conditions of alpha2-AR-stimulation involving both a pathway of prostaglandins and PC-PLC.
authors.affiliation: Medizinische Klinik II, Medizinische Universität zu Lübeck, Lübeck, Germany. urschaefer@hotmail.com
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schäfer
authors.forename: Christof
authors.initials: C
authors.lastname: Burgdorf
authors.forename: Astrid
authors.initials: A
authors.lastname: Engelhardt
authors.forename: Thomas
authors.initials: T
authors.lastname: Kurz
authors.forename: Gert
authors.initials: G
authors.lastname: Richardt
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists; D000818:Animals; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D000068438:Brimonidine Tartrate; D002021:Buffers; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology*; D054755:Imidazoline Receptors; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009636:Norbornanes; D009638:Norepinephrine / Q000378:metabolism; D010477:Perfusion; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D011955:Receptors, Drug / Q000819:agonists / Q000502:physiology*; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D001952:Bridged-Ring Compounds; D002021:Buffers; D007093:Imidazoles; D054755:Imidazoline Receptors; D009636:Norbornanes; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D011955:Receptors, Drug; D013859:Thiocarbamates; D013871:Thiones; C410887:imidazoline I1 receptors; D015016:Yohimbine; D000068438:Brimonidine Tartrate; C046498:tricyclodecane-9-yl-xanthogenate; C043482:moxonidine; D009638:Norepinephrine; D007213:Indomethacin