Elsevier

Medical Hypotheses

Volume 62, Issue 1, January 2004, Pages 82-85
Medical Hypotheses

Hyperdynamic circulation in liver cirrhosis: desensitization of vasoconstrictive receptors by G protein-coupled receptor kinases

https://doi.org/10.1016/S0306-9877(03)00311-6Get rights and content

Abstract

Liver cirrhosis is complicated by a hyperdynamic circulation characterized by a generalized arterial vasodilatation. This vasodilatation occurs despite high plasma concentration of several potent vasoconstrictive substances like angiotensin, vasopressin, endothelin and norepinephrine. The experimental evidence available shows that compensatory adrenergic and vasoconstrictive signals are not normally transmitted intracellularly. G protein-coupled receptor kinases phosporylate plasma membrane receptors and block the transmission of the signal intracellularly. We hypothesize that these kinases are responsible for the desensitization to vasoconstrictors observed in patients with liver cirrhosis. Pharmacological intervention at this level might be beneficial to treat complications like ascites and variceal bleeding.

References (44)

  • M. Schepke et al.

    Contractile hyporesponsiveness of hepatic arteries in humans with cirrhosis: evidence for a receptor-specific mechanism

    Hepatology

    (2001)
  • Z. Ma et al.

    Cirrhotic cardiomyopathy: getting to the heart of the matter

    Hepatology

    (1996)
  • Z. Ma et al.

    Role of altered beta-adrenoceptor signal transduction in the pathogenesis of cirrhotic cardiomyopathy in rats

    Gastroenterology

    (1996)
  • J. Wess

    Molecular basis of receptor/G-protein-coupling selectivity

    Pharmacol. Ther.

    (1998)
  • R.J. Lefkowitz

    G Protein-coupled receptor kinases

    Cell

    (1993)
  • S.S. Ferguson et al.

    Molecular mechanisms of G protein-coupled receptor desensitization and resensitization

    Life Sci.

    (1998)
  • C.V. Carman et al.

    G-protein-coupled receptors: turn-ons and turn-offs

    Curr. Opin. Neurobiol.

    (1998)
  • C. Fehr et al.

    Molecular cloning of rat G-protein-coupled receptor kinase 6 (GRK6) from brain tissue, and its mRNA expression in different brain regions and peripheral tissues

    Brain Res. Mol. Brain Res.

    (1997)
  • N.J. Freedman et al.

    Phosphorylation and desensitization of the human beta 1-adrenergic receptor. Involvement of G protein-coupled receptor kinases and cAMP-dependent protein kinase

    J. Biol. Chem.

    (1995)
  • S. Pippig et al.

    Overexpression of beta-arrestin and beta-adrenergic receptor kinase augment desensitization of beta 2-adrenergic receptors

    J. Biol. Chem.

    (1993)
  • D. Diviani et al.

    Effect of different G protein-coupled receptor kinases on phosphorylation and desensitization of the alpha1B-adrenergic receptor

    J. Biol. Chem.

    (1996)
  • N.J. Freedman et al.

    Phosphorylation and desensitization of human endothelin A and B receptors. Evidence for G protein-coupled receptor kinase specificity

    J. Biol. Chem.

    (1997)
  • Cited by (0)

    Grant Support: This work was supported by grants of Swiss National Foundation # 3100A0-100513 to J.-F. Dufour.

    View full text