Relationship between Desensitization and Downregulation of B-Adrenoceptors in Cardiac Tissues after Prolonged In Vivo Infusion of T-0509,aB1-Adrenoceptor Agonist

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To examine the contribution of β-adrenoceptor (βAR) downregulation to desensitization of βARs by chronic administration of a βAR agonist, we compared the adenylyl cyclase (AC) activities in two kinds of cardiac ventricular membranes with decreased available βARs: one was derived from rats infused with a selective β<SUB>1</SUB>AR agonist, T-0509 [(−)-(<I>R</I>)-1-(3, 4-dihydroxyphenyl)-2-[(3, 4-dimethoxyphenethyl)amino]ethanol hydrochloride], in vivo (40 μg/kg/hr, s.c. for 6 days); and the other was obtained from treatment of control membranes with an irreversible βAR antagonist, bromoacetyl alprenolol methane (BAAM). T-0509 infusion decreased the densities of β<SUB>1</SUB>ARs and, β<SUB>2</SUB>ARs by 26% and 32%, respectively, and reduced the maximal isoproterenol-stimulated AC activity by 53%. The amount of G<SUB>sα</SUB> and G</SUB>iα</SUB> proteins in the membranes was not significantly changed by T-0509 infusion. To make preparations that mimic the T0509-induced downregulation, we treated the control membranes with 100 nM BAAM in vitro. The BAAM treatment decreased the B<SUB>max</SUB>, value of [<SUP>125</SUP>I] iodocyanopindolol for β1ARs and β2ARs by 29070 and 36070, respectively, whereas it reduced the maximal effect of isoproterenol on AC activity only by 37%. These results suggest that downregulation of βARs cannot fully account for the desensitization by chronic treatment of T-0509 and that other mechanism(s) can play a significant role in the loss of responsiveness.

収録刊行物

  • The Japanese journal of pharmacology

    The Japanese journal of pharmacology 73(4), 325-332, 1997-04-01

    The Japanese Pharmacological Society

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各種コード

  • NII論文ID(NAID)
    10008677828
  • NII書誌ID(NCID)
    AA00691188
  • 本文言語コード
    ENG
  • 資料種別
    ART
  • ISSN
    00215198
  • NDL 記事登録ID
    4196929
  • NDL 雑誌分類
    ZS51(科学技術--薬学)
  • NDL 請求記号
    Z53-D199
  • データ提供元
    CJP書誌  NDL  J-STAGE 
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