Presynaptic modulation of the norepinephrine-induced β-adrenergic receptor desensitization phenomenon in vivo

I. Nakamura, T. Yoshikawa, T. Anzai, A. Baba, M. Iwata, Y. Wainai, M. Suzuki, S. Ogawa

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background: In vivo administration of norepinephrine fails to cause β-adrenergic receptor desensitization. However, short-term exposure of cultured cells to norepinephrine induces the phenomenon in vitro. We sought to identify the local regulatory mechanisms responsible for in vivo β-adrenergic receptor desensitization in congestive heart failure. Methods and Results: Control rabbits received norepinephrine (n = 7) or saline (n = 7) for 1 week, and rabbits with chemical denervation induced by 6-hydroxydopamine also received norepinephrine (n = 7) or saline (n = 7). Myocardial norepinephrine content decreased 80% in both groups of denervated rabbits. β1-Adrenergic receptor density in denervated rabbits receiving norepinephrine was lower than in those receiving saline but not in control rabbits receiving norepinephrine. Isoproterenol-competition assay revealed that there was a lower number of high-affinity binding sites with loss of guanosine triphosphate shift in denervated rabbits receiving norepinephrine. Isoproterenol-stimulated adenylyl cyclase activity in control rabbits receiving norepinephrine was lower than in those receiving saline. In denervated rabbits receiving norepinephrine, forskolin-stimulated adenylyl cyclase activity was also reduced. Immunoreactive G-protein coupled receptor kinase-2 level was increased in denervated rabbits receiving norepinephrine. Conclusion: There are profound alterations in β-adrenergic receptor signaling after exposure to norepinephrine in the denervated heart. Defects in neuronal uptake may play a pivotal role in β-adrenergic receptor desensitization in vivo.

Original languageEnglish
Pages (from-to)350-358
Number of pages9
JournalJournal of Cardiac Failure
Volume6
Issue number4
DOIs
Publication statusPublished - 2000 Jan 1

Keywords

  • Adenylyl cyclase
  • Denervation
  • G-protein coupled receptor kinase
  • Heart failure

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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