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Presynaptic α2-autoreceptors in mouse heart atria: evidence for the α2D subtype

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Abstract

Presynaptic α2-autoreceptors in mouse atria were characterized in terms of the α2A, α2B, α2C and α2D subtypes. Segments of the atria were preincubated with 3H-noradrenaline and then superfused and stimulated electrically. The affinity of up to 16 antagonists for the autoreceptors was assessed as (1) pEC30% values, i.e. concentrations that increased previously autoinhibited release of 3H-noradrenaline (120 pulses, 3 Hz) by 30%, and (2) pKd values against the release-inhibiting effect of 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) under conditions of no or little autoinhibition (2 trains of 20 pulses, 50 Hz, train interval 120 s).

The pKd values correlated well with the pEC30% values (r = 0.98; P<0.001; slope of regression line 0.93), indicating that UK 14,304 and released noradrenaline modulated the release of noradrenaline through pharmacologically identical receptors. Comparison with antagonist affinities for (1) prototypic native α2 radioligand binding sites, (2) radioligand binding sites in COS cells transfected with α2 subtype genes, and (3) previously classified presynaptic α2-autoreceptors — all taken from the literature — indicated that the mouse atrial autoreceptors corresponded to the α2D subtype. For example, the pKd values at mouse atrial autoreceptors correlated closely with pKd values at native α2D binding sites in the bovine pineal gland (r = 0.96; P<0.001); with pKd values at α2D binding sites in COS cells transfected with the rat α2D gene (r= 0.85; P<0.01); and with pKd values at guinea-pig cerebral and atrial and mouse cerebral α2D-autoreceptors (r=0.96–0.98; P<0.001). The antagonist pKd values at mouse atrial autoreceptors correlated less with pKd values at α2A, α2B, and α2C sites.

It is concluded that the presynaptic α2-autoreceptors in mouse atria are α2D This identification supports the hypothesis that at least the majority of α2-autoreceptors belong to the α2A/D pair of orthologous α2-adrenoceptors.

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References

  • Blaxall HS, Murphy TJ, Baker JC, Ray C, Bylund DB (1991) Characterization of the alpha-2C adrenergic receptor subtype in the opossum kidney and in the OK cell line. J Pharmacol Exp Ther 259:323–329

    Google Scholar 

  • Bohmann C, Schollmeyer P, Rump LC (1993) α2-Autoreceptor subclassification in rat isolated kidney by use of short trains of electrical stimulation. Br J Pharmacol 108:262–268

    Google Scholar 

  • Bylund DB, Ray-Prenger C, Murphy TJ (1988) Alpha-2A and alpha-2B adrenergic receptor subtypes: Antagonist binding in tissues and cell lines containing only one subtype. J Pharmacol Exp Ther 245:600–607

    Google Scholar 

  • Bylund DB, Blaxall HS, Iversen LJ, Caron MG, Lefkowitz RJ, Lomasney JW (1992) Pharmacological characteristics of α2-adrenergic receptors: comparison of pharmacologically defined subtypes with subtypes identified by molecular cloning. Mol Pharmacol 42:1–5

    Google Scholar 

  • Bylund DB, Eikenberg DC, Hieble JP, Langer SZ, Lefkowitz RJ, Minneman KP, Molinoff PB, Ruffolo RR, Trendelenburg U (1994) International Union of Pharmacology nomenclature of adrenoceptors. Pharmacol Rev 46:121–136

    Google Scholar 

  • Cambridge D (1981) UK-14,304, a potent and selective α2-agonist for the characterisation of α2-adrenoceptor subtypes. Eur J Pharmacol 72:413–415

    Google Scholar 

  • Connaughton S, Docherty JR (1990) Functional evidence for heterogeneity of peripheral prejunctional α2-adrenoceptors. Br J Pharmacol 101:285–290

    Google Scholar 

  • Devedjian JC, Esclapez F, Denis-Pouxviel C, Paris H (1994) Further characterization of human α2-adrenoceptor subtypes: [3H]RX821002 binding and definition of additional selective drugs. Eur J Pharmacol 252:43–49

    Google Scholar 

  • Funk L, Trendelenburg AU, Limberger N, Starke K (1995) Subclassification of presynaptic α2-adrenoceptors: α2D-autoreceptors and α2D-adrenoceptors modulating release of acetylcholine in guinea-pig ileum. Naunyn-Schmiedeberg's Arch Pharmacol 352:58–66

    Google Scholar 

  • Gleason MM, Hieble JP (1991) Ability of SK&F 104078 and SK&F 104856 to identify alpha-2 adrenoceptor subtypes in NCB20 cells and guinea pig lung. J Pharmacol Exp Ther 259:1124–1132

    Google Scholar 

  • Gleason MM, Hieble JP (1992) The α2-adrenoceptors of the human retinoblastoma cell line (Y79) may represent an additional example of the α2C-adrenoceptor. Br J Pharmacol 107:222–225

    Google Scholar 

  • Harrison JK, D'Angelo DD, Zeng D, Lynch KR (1991) Pharmacological characterization of rat α2-adrenergic receptors. Mol Pharmacol 40:407–412

    Google Scholar 

  • Langer SZ (1974) Presynaptic regulation of catecholamine release. Biochem Pharmacol 23:1793–1800

    Google Scholar 

  • Lanier SM, Downing S, Duzic E, Homcy CJ (1991) Isolation of rat genomic clones encoding subtypes of the α2-adrenergic receptor. J Biol Chem 266:10470–10478

    Google Scholar 

  • Limberger N, Trendelenburg AU, Starke K (1992) Pharmacological characterization of presynaptic α2-autoreceptors in rat submaxillary gland and heart atrium. Br J Pharmacol 107:246–255

    Google Scholar 

  • Limberger N, Funk L, Trendelenburg AU, Starke K (1995a) Subclassification of presynaptic α2-adrenoceptors: α2A-autoreceptors in rabbit atria and kidney. Naunyn-Schmiedeberg's Arch Pharmacol 352:31–42

    Google Scholar 

  • Limberger N, Trendelenburg AU, Starke K (1995b) Subclassification of presynaptic α2-adrenoceptors: α2D-autoreceptors in mouse brain. Naunyn-Schmiedeberg's Arch Pharmacol 352:43–48

    Google Scholar 

  • Link R, Daunt D, Barsh G, Chruscinski A, Kobilka B (1992) Cloning of two mouse genes encoding α2-adrenergic receptor subtypes and identification of a single amino acid in the mouse α2-C10 homolog responsible for an interspecies variation in antagonist binding. Mol Pharmacol 42:16–27

    Google Scholar 

  • MacKinnon AC, Kilpatrick AT, Kenny BA, Spedding M, Brown CM (1992) [3H]-RS-15385–197, a selective and high affinity radioligand for α2-adrenoceptors: implications for receptor classification. Br J Pharmacol 106:1011–1018

    Google Scholar 

  • Michel AD, Loury DN, Whiting RL (1989) Differences between the α2-adrenoceptor in rat submaxillary gland and the α2A- and α2B-adrenoceptor subtypes. Br J Pharmacol 98:890–897

    Google Scholar 

  • Molderings GJ, Göthett M (1995) Subtype determination of presynaptic α2-autoreceptors in the rabbit pulmonary artery and human saphenous vein. Naunyn-Schmiedeberg's Arch Pharmacol 352:483–490

    Google Scholar 

  • Motulsky HJ, Ransnas LA (1987) Fitting curves to data using nonlinear regression: a practical and nonmathematical review. FASEB J 1:365–374

    Google Scholar 

  • Paris H, Voisin T, Remaury A, Rouyer-Fessard C, Daviaud D, Langin D, Laburthe M (1990) Alpha-2 adrenoceptor in rat jejunum epithelial cells: Characterization with [3H]RX821002 and distribution along the villus-crypt axis. J Pharmacol Exp Ther 254:888–893

    Google Scholar 

  • Renouard A, Widdowson PS, Millan MJ (1994) Multiple alpha2 adrenergic receptor subtypes. I. Comparison of [3H]RX821002-labeled rat Ralpha-2A adrenergic receptors in cerebral cortex to human Halpha2A adrenergic receptor and other populations of alpha-2 adrenergic subtypes. J Pharmacol Exp Ther 270:946–957

    Google Scholar 

  • Richelson E, Nelson A (1984) Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro. J Pharmacol Exp Ther 230:94–102

    Google Scholar 

  • Rump CL, Bohmann C, Schaible U, Schöllhom J, Limberger N (1995) α2C-Adrenoceptor-modulated release of noradrenaline in human right atrium. Br J Pharmacol 116:2617–2624

    Google Scholar 

  • Simonneaux V, Ebadi M, Bylund DB (1991) Identification and characterization of α2D-adrenergic receptors in bovine pineal gland. Mol Pharmacol 40:235–241

    Google Scholar 

  • Smith K, Connaughton S, Docherty JR (1992) Investigations of prejunctional α2-adrenoceptors in rat atrium, vas deferens and submandibular gland. Eur J Pharmacol 211:251–256

    Google Scholar 

  • Smith K, Gavin K, Docherty JR (1995) Investigation of the subtype of α2-adrenoceptor mediating prejunctional inhibition of cardio-acceleration in the pithed rat heart. Br J Pharmacol 115:316–320

    Google Scholar 

  • Starke K, Montel H, Gayk W, Merker R (1974) Comparison of the effects of clonidine on pre- and postsynaptic adrenoceptors in the rabbit pulmonary artery. Naunyn-Schmiedeberg's Arch Pharmacol 285:133–150

    Google Scholar 

  • Starke K, Endo T, Taube HD (1975) Relative pre- and postsynaptic potencies of α-adrenoceptor agonists in the rabbit pulmonary artery. Naunyn-Schmiedeberg's Arch Pharmacol 291:55–78

    Google Scholar 

  • Starke K, Göthert M, Kilbinger H (1989) Modulation of neurotransmitter release by presynaptic autoreceptors. Physiol Rev 69:864–989

    Google Scholar 

  • Starke K, Trendelenburg AU, Limberger N (1995) Presynaptic α2-adrenoceptors: subtype determination. Pharmacol Commun 6:99–108

    Google Scholar 

  • Trendelenburg AU, Limberger N, Starke K (1993) Presynaptic α2-autoreceptors in brain cortex: α2D in the rat and α2A, in the rabbit. Naunyn-Schmiedeberg's Arch Pharmacol 348:35–45

    Google Scholar 

  • Trendelenburg AU, Limberger N, Rump LC (1994) α2-Adrenergic receptors of the α2C subtype mediate inhibition of norepinephrine release in human kidney cortex. Mol Pharmacol 45:1168–1176

    Google Scholar 

  • Trendelenburg AU, Limberger N, Starke K (1995) Subclassification of presynaptic α2-adrenoceptors: α2D-autoreceptors in guinea-pig atria and brain. Naunyn-Schmiedeberg's Arch Pharmacol 352:49–57

    Google Scholar 

  • Trendelenburg AU, Wahl CA, Starke K (1996) Antagonists that differentiate between α2A, and α2D-adrenoceptors. Naunyn-Schmiedeberg's Arch Pharmacol 353:245–249

    Google Scholar 

  • Uhlén S, Wikberg JES (1991a) Delineation of rat kidney α2A- and α2B-adrenoceptors with [3H]RX821002 radioligand binding: computer modelling reveals that guanfacine is an α2A-selective compound. Eur J Pharmacol 202:235–243

    Google Scholar 

  • Uhlén S, Wikberg JES (1991b) Rat spinal cord α2-adrenoceptors are of the α2A-subtype: Comparison with α2A-and α2B-adrenoceptors in rat spleen, cerebral cortex and kidney using 3H-RX821002 ligand binding. Pharmacol Toxicol 69:341–350

    Google Scholar 

  • Uhlén S, Wikberg JES (1991c) Delineation of three pharmacological subtypes of α2-adrenoceptor in the rat kidney. Br J Pharmacol 104:657–664

    Google Scholar 

  • Uhlén S, Xia Y, Chhajlani V, Felder CC, Wikberg JES (1992) [3H]-MK 912 binding delineates two α2-adrenoceptor subtypes in rat CNS one of which is identical with the cloned pA2d α2-adrenoceptor. Br J Pharmacol 106:986–995

    Google Scholar 

  • Uhlén S, Xia Y, Chhajlani V, Lien EJ, Wikberg JES (1993) Evidence for the existence of two forms of α2A-adrenoceptors in the rat. Naunyn-Schmiedeberg's Arch Pharmacol 347:280–288

    Google Scholar 

  • Uhlén S, Porter AC, Neubig RR (1994) The novel alpha-2 adrenergic radioligand [3H]-MK912 is alpha-2C selective among human alpha-2A, alpha-2B and alpha-2C adrenoceptors. J Pharmacol Exp Ther 271:1558–1565

    Google Scholar 

  • Waud DR (1976) Analysis of dose-response relationships. In: Narahashi T, Bianchi CP (eds) Advances in general and cellular pharmacology, vol 1. Plenum, New York London, pp 145–178

    Google Scholar 

  • Xia Y, Uhlén S, Chhajlani V, Lien EJ, Wikberg JES (1993) Further evidence for the existence of two forms of α2B-adrenoceptors in rat. Pharmacol Toxicol 72:40–49

    Google Scholar 

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  1. Pharmakologisches Institut, Hermann-Herder-Strasse 5, D-79104, Freiburg i.Br., Germany

    Christian Andreas Wahl, Anne-Ulrike Trendelenburg & Klaus Starke

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  1. Christian Andreas Wahl
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  2. Anne-Ulrike Trendelenburg
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  3. Klaus Starke
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Wahl, C.A., Trendelenburg, AU. & Starke, K. Presynaptic α2-autoreceptors in mouse heart atria: evidence for the α2D subtype. Naunyn-Schmiedeberg's Arch Pharmacol 354, 253–261 (1996). https://doi.org/10.1007/BF00171055

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