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


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.


CONCLUSIONS
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.
Nakamura
I
I
Department of Medicine, Keio University School of Medicine, Tokyo, Japan.
Yoshikawa
T
T
Anzai
T
T
Baba
A
A
Iwata
M
M
Wainai
Y
Y
Suzuki
M
M
Ogawa
S
S
D000818:Animals; D003714:Denervation; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology*; D006333:Heart Failure / Q000209:etiology* / Q000378:metabolism* / Q000503:physiopathology; D006439:Hemodynamics / Q000502:physiology; D009638:Norepinephrine / Q000097:blood / Q000494:pharmacology* / Q000502:physiology*; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D017661:Receptors, Presynaptic / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
D011943:Receptors, Adrenergic, beta; D017661:Receptors, Presynaptic; D009638:Norepinephrine