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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Author(s)

Abstract

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.

Journal

  • The Japanese Journal of Pharmacology

    The Japanese Journal of Pharmacology 73(4), 325-332, 1997-04-01

    The Japanese Pharmacological Society

References:  22

Codes

  • NII Article ID (NAID)
    10008677828
  • NII NACSIS-CAT ID (NCID)
    AA00691188
  • Text Lang
    ENG
  • Article Type
    ART
  • ISSN
    00215198
  • NDL Article ID
    4196929
  • NDL Source Classification
    ZS51(科学技術--薬学)
  • NDL Call No.
    Z53-D199
  • Data Source
    CJP  NDL  J-STAGE 
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