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

Abstract：

BACKGROUND:In vivo administration of norepinephrine fails to cause beta-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 beta-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. beta1-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 beta-adrenergic receptor signaling after exposure to norepinephrine in the denervated heart. Defects in neuronal uptake may play a pivotal role in beta-adrenergic receptor desensitization in vivo.

journal_name

J Card Fail

journal_title

Journal of cardiac failure

authors

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

doi

10.1054/jcaf.2000.19223

keywords:

subject

Has Abstract

pub_date

2000-12-01 00:00:00

pages

350-8

issue

4

eissn

1071-9164

issn

1532-8414

pii

S1071-9164(00)04953-8

journal_volume

6

pub_type

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