Chronic norepinephrine elicits desensitization by uncoupling the beta-receptor.

Vatner, Dorothy E.; Vatner, Stephen F.; Nejima, Jun; Uemura, Nobuhisa; Susanni, E. E. T.; Hintze, Thomas H.; Homcy, Charles J.

doi:10.1172/jci114357

Cited by 85 publications

(41 citation statements)

References 41 publications

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“…Since in PPH subjects systemic plasma norepinephrine levels were increased but ,3-adrenergic receptors and neurotransmitter levels were not altered in nonfailing left ventricles, elevated circulating norepinephrine could not have caused the abnormalities present in PPH right ventricles. Additionally, Vatner et al (58) have recently shown that normally functioning canine heart exposed to elevated circulating norepinephrine levels develops up-regulation of uncoupled myocardial #3-adrenergic receptors and a decrease in G5, along with a shift of the agonist binding state from high to low affinity. None of these changes were present in nonfailing left or failing right ventricles ofPPH hearts.…”

Section: Discussionmentioning

confidence: 99%

Beta-adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms.

Bristow¹,

Minobe²,

Rasmussen³

et al. 1992

J. Clin. Invest.

289

156

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These data indicate that: (a) Adrenergic neuroeffector abnormalities present in the failing human heart are due to local mechanisms; systemic processes do not produce j-adrenergic neuroeffector abnormalities. (b) Pressure-overloaded failing right ventricles of PPH subjects exhibit decreased activity of the catalytic subunit of adenylate cyclase, an abnormality not previously described in the failing human heart. (J.

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Section: Discussionmentioning

confidence: 99%

Beta-adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms.

Bristow¹,

Minobe²,

Rasmussen³

et al. 1992

J. Clin. Invest.

289

156

View full text Add to dashboard Cite

show abstract

“…Previous in vivo studies have detected BAR desensitization and downregulation in different tissues after long-term infusion with fi agonists or chronic pathological increases in circulating catecholamines, such as in heart failure, hypertension, or pheochromocytoma (43)(44)(45) (2,18).…”

Section: Discussionmentioning

confidence: 99%

Rapid desensitization of neonatal rat liver beta-adrenergic receptors. A role for beta-adrenergic receptor kinase.

García-Higuera

Mayor²

1994

J. Clin. Invest.

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Exposure of fl-adrenergic receptors (BAR) to agonists often leads to a rapid loss of receptor responsiveness. The proposed mechanisms of such rapid receptor desensitization include receptor phosphorylation by either cAMP-dependent protein kinase or the specific 8-adrenergic receptor kinase (BARK), leading to functional uncoupling from adenylyl cyclase and sequestration of the receptors away from the cell surface. To evaluate the physiological role of such mechanisms, we have investigated whether rapid regulation of BAR occurs in the neonatal rat liver immediately after birth, a physiological situation characterized by a dramatic but transient increase in plasma catecholamines. We have detected a rapid, transient uncoupling of liver plasma membrane BARs from adenylyl cyclase (corresponding to a desensitization of -45%) within the first minutes of extrauterine life, followed by a transient sequestration of -40% of the BARs away from the plasma membrane. In agreement with such pattern of desensitization, we have detected (by enzymatic and immunological assays) rapid changes in BARK specific activity in different neonatal rat liver subcellular fractions that take place within the same time frame of BAR uncoupling and sequestration. Our results provide new evidence on the potential role of BAR desensitization mechanisms in vivo and suggest that they are involved in modulating catecholamines actions at the moment of birth. Furthermore, our data indicate that in addition to its suggested role as a rapid modulator of adrenergic receptor function at synapse, rapid BARK-mediated receptor regulation may have functional relevance in other tissues in response to high circulating or local levels of agonists. (J. Clin. Invest. 1994. 93:937-943.)

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“…The means by which 13 blockade has been effective in restoring contractile performance in those patients is unclear. Three potential mechanisms include (a) 13 blockade-enhanced responsiveness of a depressed : receptor adenyl cyclase complex allowing enhanced response to endogenous catecholamines (22)(23)(24), (b) protection of the myocardium from the potential toxic effects of prolonged exposure to high levels of circulating catecholamines (25,26) thereby improving innate contractile function, and (c) enhanced myocardial performance secondary to the bradycardia induced by 13 blockade.…”

Section: Introductionmentioning

confidence: 99%

Effects of chronic beta-adrenergic blockade on the left ventricular and cardiocyte abnormalities of chronic canine mitral regurgitation.

Tsutsui¹,

et al. 1994

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The mechanism by which ft blockade improves left ventricular dysfunction in various cardiomyopathies has been ascribed to improved contractile function of the myocardium or to improved ,8-adrenergic responsiveness. In this study we tested two hypotheses: (a) that chronic 13 blockade would improve the left ventricular dysfunction which develops in mitral regurgitation, and (b) that an important mechanism of this effect would be improved innate contractile function of the myocardium.Two groups of six dogs with chronic severe mitral regurgitation were studied. After 3 mo both groups had developed similar and significant left ventricular dysfunction. One group was then graduallyfl-blocked while the second group continued to be observed without further intervention. In the group that remained unblocked, contractile function remained depressed.However, in the group that received chronic ,f blockade, contractile function improved substantially.The contractility of cardiocytes isolated from the unblocked hearts and then studied in the absence of1f receptor stimulation was extremely depressed. However, contractility of cardiocytes isolated from the ,8-blocked ventricles was virtually normal. Consistent with these data, myofibrillar density was much higher, 55±4% in the f-blocked group vs. 39±2% (P < 0.01) in the unblocked group; thus, there were more contractile elements to generate force in the f-blocked group.We conclude that chronic ft blockade improves left ventricular function in chronic experimental mitral regurgitation. This improvement was associated with an improvement in the innate contractile function of isolated cardiocytes, which in turn is associated with an increase in the number of contractile elements. (J. Clin. Invest. 1994. 93:2639-2648.) Key words: mitral valve insufficiency * adrenergic fi receptor blockaders * ventricular function * left heart failure * congestive hypertrophy

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Chronic norepinephrine elicits desensitization by uncoupling the beta-receptor.

Cited by 85 publications

References 41 publications

Beta-adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms.

Beta-adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms.

Rapid desensitization of neonatal rat liver beta-adrenergic receptors. A role for beta-adrenergic receptor kinase.

Effects of chronic beta-adrenergic blockade on the left ventricular and cardiocyte abnormalities of chronic canine mitral regurgitation.

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