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Regulation and possible functional implications of G-protein mRNA expression in nonfailing and failing ventricular myocardium

  • T. Eschenhagen
  • U. Mende
  • M. Nose
  • W. Schmitz
  • H. Scholz
  • J. Schulte am Esch
  • R. Sempell
  • A. Warnholtz
  • J.-M. Wüstel

Summary

In human end-stage heart failure an increased amount of inhibitory G-protein α-subunits (G) is assumed to play a role in desensitization of the adenylyl cyclase signaling pathway. In the present study, northern blot experiments with 32P-labeled cDNA probes in ventricular tissue samples from explanted human hearts revealed that G2- and G3- mRNA are the predominant G-mRNA subtypes in human ventricles, whereas G1-mRNA was not detectable. The mRNA for the stimulatory G-protein α-subunit (G) consisted of two mRNA sizes. Quantification of mRNA levels revealed a 103 ± 38% increase in Giα–2-mRNA levels in hearts with idiopathic dilative cardiomyopathy (IDC; n = 8), and a 77 ± 25% increase in hearts with ischemic cardiomyopathy (ICM; n = 6) as compared to nonfailing controls (NF, n = 8). In contrast, Giα–3- and G-mRNA levels were similar in failing and nonfailing hearts. To investigate whether or not the increased expression of Giα–2-mRNA might be due to chronically elevated catecholamine levels, we determined the influence of a 4-day infusion of isoprenaline (Iso; 2.4 mg/kg d), propranolol (Prop; 9.9 mg/kg d), Iso + Prop or 0.9% NaCl as control (Ctr) on myocardial G-mRNA and G-protein levels in rats. In Iso-treated rats, hybridization experiments revealed a 49 ± 18% (n = 7) and 27 ± 7% (n = 8) increase in G–2 and Giα–3-mRNA, respectively. Pertussis toxin-catalyzed ADP-ribosylation revealed a 22 ± 7% (n = 8) increase in Giprotein as compared to Ctr (n = 8). These alterations were accompanied by an increased potency for the negative inotropic effect (NIE) of carbachol (mean EC50: 0.04 µM vs. 0.28 µM) in the presence of Iso in isolated electrically driven (1 Hz) papillary muscles. Prop itself had no effect, but it antagonized all Iso-induced effects. We conclude that, in human heart failure due to IDC or ICM, increased G2-, but not Giα–3-mRNA levels accompany the increased amount of G-protein, suggesting that this increase is at least in part due to increased de novo synthesis. The experiments in rats demonstrated that chronic β-adrenergic stimulation leads to an increased expression of G-mRNA and -protein, and to an enhanced potency of the negative inotropic effect of muscarinic agonists. These results support the hypothesis that increased expression of G might play a pathophysiological role in human end-stage heart failure as a process of adaptation to an increased adrenergic drive.

Key words

G-proteins mRNA expression pertussis toxin substrates force of contraction 

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Copyright information

© Dr. Dietrich Steinkopff Verlag GmbH & Co.KG, Darmstadt 1992

Authors and Affiliations

  • T. Eschenhagen
    • 1
    • 2
  • U. Mende
    • 1
  • M. Nose
    • 1
  • W. Schmitz
    • 1
  • H. Scholz
    • 1
  • J. Schulte am Esch
    • 1
  • R. Sempell
    • 1
  • A. Warnholtz
    • 1
  • J.-M. Wüstel
    • 1
  1. 1.Abteilung Allgemeine PharmakologieUniversitäts-Krankenhaus EppendorfGermany
  2. 2.Abteilung Allgemeine PharmakologieUniversitäts-Krankenhaus EppendorfGermany

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