INCREASE IN MYOCARDIAL Gi-PROTEINS IN HEART FAILURE

Neumann, Joachim; Scholz, Hasso; Döring, Volker; Schmitz, Wilhelm; Meyerinck, L. von; Kalmár, P.

doi:10.1016/s0140-6736(88)92601-3

Cited by 297 publications

(97 citation statements)

References 8 publications

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“…In fact, receptorindependent stimulation of adenylate cyclase by GTP (acting directly on G proteins) was greater in the fl-blocker-treated patients than in the control subjects. (Feldman et al, 1988;Neumann et al, 1988). Secondly, long-term in vitro treatment of rat cardiomyocytes with noradrenaline causes a shift in the GdGi-ratio towards elevated Gi-protein (Reithmann et al, 1989).…”

Section: Resultsmentioning

confidence: 99%

Chronic β₁‐adrenoceptor antagonist treatment sensitizes β₂‐adrenoceptors, but desensitizes M₂‐muscarinic receptors in the human right atrium

Motomura¹,

Deighton²,

Zerkowski

et al. 1990

British J Pharmacology

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1 In 64 patients undergoing coronary artery bypass grafting the effects of chronic fl1-adrenoceptor antagonist (metoprolol, atenolol, bisoprolol) treatment on right atrial fi-adrenoceptor and muscarinic M2-receptor number and functional responsiveness were investigated.2 The fil-adrenoceptor antagonists increased right atrial fl,-adrenoceptor number, did not affect fl2-adrenoceptor number, and decreased muscarinic M2-receptor number. 3 Concomitantly, activation of right atrial adenylate cyclase by 1OuM GTP, 10pM isoprenaline and 1 UM forskolin was enhanced and inhibition by 100pM carbachol was diminished. 4 On isolated, electrically driven right atria the 6,1-adrenoceptor-mediated positive inotropic effect of noradrenaline was -even with fil-adrenoceptor number increased -not altered, while the fi2-adrenoceptor-mediated effect of procaterol was markedly enhanced. However, the carbachol-induced negative inotropic effect was decreased.5 It is concluded that chronic fl1-adrenoceptor antagonist treatment increases fil-adrenoceptor number and concomitantly sensitizes f2-adrenoceptor function, but desensitizes muscarinic M2-receptor function in the human heart.

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Section: Resultsmentioning

confidence: 99%

Chronic β₁‐adrenoceptor antagonist treatment sensitizes β₂‐adrenoceptors, but desensitizes M₂‐muscarinic receptors in the human right atrium

Motomura¹,

Deighton²,

Zerkowski

et al. 1990

British J Pharmacology

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“…Human congestive heart failure (CHF) has been associated with increased levels of Gi in the LV (15)(16)(17). It has been postulated that increased Gi may contribute to the inability of the heart to respond to adrenergic stimulation, and therefore may be of pathophysiological importance in CHF.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of cardiac guanosine 5'-triphosphate-binding proteins in right atrium and left ventricle in pacing-induced congestive heart failure.

Urasawa¹,

Helmer²,

Hammond³

1993

J. Clin. Invest.

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The extent to which congestive heart failure (CHF) is dependent upon increased levels of the cardiac inhibitory GTP-binding protein (Gi), and the impact of CHF on the cardiac stimulatory GTP-binding protein (Gs) and mechanisms by which Gs may change remain unexplored. We have addressed these unsettled issues using pacing-induced CHF in pigs to examine physiological, biochemical, and molecular features of the right atrium (RA) and left ventricle (LV). CHF was associated with an 85±20% decrease in LV segment shortening (P < 0.001) and a 3.5-fold increase (P = 0.006) in the ED5, for isoproterenol-stimulated heart rate responsiveness. Myocardialfg-adrenergic receptor number was decreased 54% in RA (P = 0.004) and 57% in LV (P < 0.001), and multiple measures of adenylyl cyclase activity were depressed 49±8% in RA (P < 0.005), and 44±9% in LV (P < 0.001). Quantitative immunoblotting established that Gi and Gs were decreased in RA (Gi: 59% reduction; P < 0.0001; Gs: 28% reduction; P < 0.007) and LV (Gi: 35% reduction; P < 0.008; Gs: 28% reduction; P < 0.01 ) after onset of CHF. Reduced levels of Gi and Gs were confirmed by ADP ribosylation studies, and diminished function of Gs was established in reconstitution studies. Steady state levels for Gsa mRNA were increased in RA and unchanged in LV, and significantly more GSa was found in the supernatant (presumably cytosolic) fraction in RA and LV membrane homogenates after CHF, suggesting that increased Gs degradation, rather than decreased Gs synthesis, is the mechanism by which Gs is downregulated. We conclude that cardiac Gi content poorly predicts adrenergic responsiveness or contractile function, that decreased Gs is caused by increased degradation rather than decreased synthesis, and that alterations in fI-adrenergic receptors, adenylyl cyclase, and GTP-binding proteins are uniform in RA and LV in this model of congestive heart failure. (J. Clin. Invest. 1993. 91:939-949.)

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“…These data, therefore, support the above-outlined role of NDPK B/Gβγ complex as modulator of basal G protein activity. Interestingly, the net effect of the NDPK B-mediated regulation of adenylyl cyclase activity in failing hearts was an inhibition, which obviously correlates to the relative prevalence of Gα i in CHF (Neumann et al 1988). In contrast, in sarcolemmal membranes of canine hearts, NDPK stimulates adenylyl cyclase via Gα s (Niroomand et al 1997).…”

Section: Ndpk-g Protein Interaction: Are There Alterations In Disease?mentioning

confidence: 99%

Interaction of nucleoside diphosphate kinase B with heterotrimeric G protein βγ dimers: consequences on G protein activation and stability

Wieland

2007

Naunyn-Schmied Arch Pharmacol

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INCREASE IN MYOCARDIAL Gi-PROTEINS IN HEART FAILURE

Cited by 297 publications

References 8 publications

Chronic β₁‐adrenoceptor antagonist treatment sensitizes β₂‐adrenoceptors, but desensitizes M₂‐muscarinic receptors in the human right atrium

Chronic β₁‐adrenoceptor antagonist treatment sensitizes β₂‐adrenoceptors, but desensitizes M₂‐muscarinic receptors in the human right atrium

Downregulation of cardiac guanosine 5'-triphosphate-binding proteins in right atrium and left ventricle in pacing-induced congestive heart failure.

Interaction of nucleoside diphosphate kinase B with heterotrimeric G protein βγ dimers: consequences on G protein activation and stability

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INCREASE IN MYOCARDIAL Gi-PROTEINS IN HEART FAILURE

Cited by 297 publications

References 8 publications

Chronic β1‐adrenoceptor antagonist treatment sensitizes β2‐adrenoceptors, but desensitizes M2‐muscarinic receptors in the human right atrium

Chronic β1‐adrenoceptor antagonist treatment sensitizes β2‐adrenoceptors, but desensitizes M2‐muscarinic receptors in the human right atrium

Downregulation of cardiac guanosine 5'-triphosphate-binding proteins in right atrium and left ventricle in pacing-induced congestive heart failure.

Interaction of nucleoside diphosphate kinase B with heterotrimeric G protein βγ dimers: consequences on G protein activation and stability

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Chronic β₁‐adrenoceptor antagonist treatment sensitizes β₂‐adrenoceptors, but desensitizes M₂‐muscarinic receptors in the human right atrium

Chronic β₁‐adrenoceptor antagonist treatment sensitizes β₂‐adrenoceptors, but desensitizes M₂‐muscarinic receptors in the human right atrium