title: Presynaptic imidazoline receptors and alpha 2-adrenoceptors in the human heart: discrimination by clonidine and moxonidine.
abstract: The involvement of presynaptic alpha 2-autoreceptors and imidazoline receptors in the modulation of noradrenaline release was investigated in strips from human atrial appendages preincubated with [3H]noradrenaline and superfused with medium containing desipramine and corticosterone. Electrical impulses were applied transmurally at 2 Hz. The imidazoline derivatives moxonidine and clonidine reduced to evoked tritium overflow in a concentration-dependent manner. Moxonidine was 18-fold more potent than clonidine. The concentration-response curve for moxonidine, but not for clonidine was shifted to the right by the alpha 2-adrenoceptor antagonist rauwolscine. The apparent pA2 value of rauwolscine against moxonidine was 8.41. An inhibitory effect was also observed for the imidazoline derivative BDF 6143 (4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline), a mixed alpha 2-adrenoceptor antagonist/imidazoline receptor agonist; BDF 6143 was about 2-fold more potent than clonidine. Rauwolscine (1 microM) did not substantially shift the concentration-response curve of BDF 6143. It is concluded that noradrenaline release in the human atrium is inhibited not only via presynaptic alpha 2-autoreceptors but also via presynaptic non-I1, non-I2 imidazoline receptors. The failure of rauwolscine to antagonize the inhibitory effect of clonidine suggests that clonidine preferentially stimulates the presynaptic imidazoline receptors; the alpha 2-adrenoceptor component of its action is probably suppressed by an inhibitory interaction between the two receptors. In contrast, moxonidine acts via presynaptic alpha 2-autoreceptors, leaving the presynaptic imidazoline receptor unaffected.
authors.affiliation: Klinik für Herz- und Gefässchirurgie, Bonn, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Likungu
authors.forename: G J
authors.initials: GJ
authors.lastname: Molderings
authors.forename: M
authors.initials: M
authors.lastname: Göthert
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003000:Clonidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D054833:Isoindoles; D008297:Male; D008875:Middle Aged; D018341:Receptors, Adrenergic, alpha-2 / Q000145:classification; D011955:Receptors, Drug / Q000187:drug effects*; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D007093:Imidazoles; D054833:Isoindoles; D018341:Receptors, Adrenergic, alpha-2; D011955:Receptors, Drug; D015016:Yohimbine; C036966:4-chloro-2-(2-imidazolin-2-ylamino)isoindoline; C043482:moxonidine; D003000:Clonidine