Search Results - (Author, Cooperation:T. Eschenhagen)

2014-04-22

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Angioplasty, Balloon/adverse effects ; Animals ; Aorta/drug effects/*injuries/pathology ; Apoptosis/drug effects ; Arteries/drug effects/*injuries/pathology ; Cell Proliferation/drug effects ; Constriction, Pathologic/pathology/*prevention & control ; Coronary Vessels/drug effects/injuries/pathology ; Dichloroacetic Acid/*pharmacology/*therapeutic use ; Disease Models, Animal ; Enzyme Activation/drug effects ; Gene Knockdown Techniques ; Humans ; Hyperplasia/drug therapy/pathology ; Iliac Artery/drug effects/injuries/pathology ; Mammary Arteries/drug effects/injuries/pathology ; Membrane Potential, Mitochondrial/drug effects ; Mitochondria, Heart/drug effects/metabolism ; Myocytes, Smooth Muscle/drug effects/pathology ; Protein-Serine-Threonine Kinases/antagonists & inhibitors/deficiency/genetics ; Rabbits ; Rats ; Secondary Prevention ; Stents/adverse effects ; Swine ; Tunica Intima/*drug effects/injuries/*pathology

1065-6995

Elsevier Journal Backfiles on ScienceDirect 1907 - 2002

Biology

Electronic Resource

0022-2828

G-Protein α-subunit ; Gene expression ; In vitro transcription assay ; Rat heart ; β-adrenergic stimulation

Elsevier Journal Backfiles on ScienceDirect 1907 - 2002

Medicine

Electronic Resource

0022-2828

Dilated cardiomyopathy ; G-proteins ; Heart failure ; Ischaemic cardiomyopathy ; Pertussis toxin substrates ; Radioimmunoassay

Elsevier Journal Backfiles on ScienceDirect 1907 - 2002

Medicine

Electronic Resource

1432-1076

Albright hereditary osteodystrophy ; Pseudohypoparathyroidism type Ia ; Pseudopseudohypoparathyroidism ; G protein expression

Springer Online Journal Archives 1860-2000

Medicine

Abstract We examined a German family with five members affected by Albright hereditary osteodystrophy (AHO). The only patient with pseudohypoparathyroidism type Ia (PHP-Ia) presented clinically with latent tetany, mental retardation, round face, short stature, brachymetacarpia and calcifications of subcutaneous tissue, heart and brain, whereas all other four members with pseudopseudohypoparathyroidism (pseudo-PHP) showed only subcutaneous calcifications and brachymetaphalangia. The PHP-Ia patient exhibited hypocalcaemia, hyperphosphataemia, elevated immunoreactive parathyroid hormone (PTH), and a blunted response of cyclic adenosine monophosphate (cAMP) in plasma and urine to synthetic 1-38 hPTH. In addition, latent primary hypothyroidism was found. In contrast, all tested healthy family members as well as the patients with pseudo-PHP exhibited normal calcium metabolism including cAMP response to exogenous PTH. In Northern blot experiments all patients with AHO, regardless whether affected by PHP-Ia or pseudo-PHP, revealed significantly reduced mRNA levels coding for the α subunit of the G protein that stimulates adenylyl cyclase (Gsα), when compared with healthy family members. In contrast, there was no significant difference between healthy and affected subjects with regard to the levels of the mRNA coding for the α subunit of Giα-2, the main inhibitory G protein of adenylyl cyclase. The results indicate that reduced expression of Gsα is a useful genetic marker in some families with AHO, regardless whether patients are affected by PHP-Ia or by pseudo-PHP.

Electronic Resource

1432-1041

Key words Metoprolol ; Cardiomyopathy ; G-proteins; β-adrenoceptor density

Springer Online Journal Archives 1860-2000

Chemistry and Pharmacology

Medicine

Abstract Objective: In human heart failure downregulation of β-adrenoceptors and upregulation of Gi-protein α-subunits (Giα) results desensitization of the myocardial β-adrenergic signal transduction pathway and reduced positive inotropic effects of catecholamines. Metoprolol treatment has been shown to restore the reduced β-adrenoceptor density in dilated cardiomyopathy. The main objective of the present study was to investigate whether metoprolol also decreases the elevated inhibitory Giα levels in patients suffering from congestive heart failure. Methods: Total Giα was determined by pertussis toxin-catalysed ADP ribosylation and β1- and β2-adrenoceptor densities by radioligand binding in right ventricular myocardial biopsies of 18 patients with dilated or ischaemic cardiomyopathy (NYHA II–IV) before and after 3 months of therapy. Nine controls were treated with conventional therapy only [diuretics, digitalis, nitrates, angiotensin-converting enzyme (ACE) inhibitors], and nine received the β1-selective blocker metoprolol in addition (mean 98 ± 12 mg daily). Results: In biopsies from patients treated with metoprolol, Giα significantly decreased to 74% of predrug value and total β-adrenoceptor increased by a selective increase in β1- adrenoceptors (44.7 vs 34.0 fmol ⋅ mg−1 protein). These effects were accompanied by significantly increased oxygen uptake at the anaerobic threshold (8.65 vs 6.95 ml ⋅ kg−1⋅ min−1). In the control group no significant changes in biochemical and clinical parameters occurred. Conclusion: Metoprolol partly reverses Giα-upregulation and β-adrenoceptor downregulation in heart failure, which might contribute to the clinical improvement of patients treated with β-blockers.

Electronic Resource

1432-1041

Captopril ; Dilated cardiomyopathy ; ACE-inhibitors ; G-proteins ; β-adrenoceptor density

Springer Online Journal Archives 1860-2000

Chemistry and Pharmacology

Medicine

Abstract In end-stage heart failure due to idiopathic dilated cardiomyopathy β1-adrenoceptors are downregulated and G1α-proteins are upregulated. The aim of the present study was to investigate the influence of the angiotensin-converting enzyme inhibitor captopril on β-adrenoceptor density and Giα-proteins in sequential endomyocardial biopsies. Nineteen patients with mild to moderate congestive heart failure due to idiopathic dilated cardiomyopathy (NYHA Class II–III) were studied before and after 8–11 weeks of therapy. Patients were randomised into a captopril and a control group; 9 patients received captopril 12.5–50 mg per day, (divided in 2–3 doses) p.o. in addition to “conventional” therapy with digoxin and diuretics, and 10 controls received “conventional” therapy only. Echocardiography, spiroergometry, right heart catheterisation and endomyocardial biopsies were performed before (baseline) and after treatment. Compared to baseline, captopril increased total β-adrenoceptor density by selectively increasing β1-adrenoceptors (31.6 vs 41.2 fmol·mg−1; p〈0.05) but had no significant effect on Giα-proteins. The results indicate that treatment with angiotensin-converting enzyme inhibitors partly restores myocardial β1-adrenoceptor density, and this action effect may contribute to the clinical improvement of patients with idiopathic dilated cardiomyopathy treated in this way.

Electronic Resource

1435-1803

Gene expression ; reporter gene assay

Springer Online Journal Archives 1860-2000

Medicine

Abstract Increased expression of the inhibitory G protein Giα-2 is assumed to contributed to desensitization of adenylyl cyclase in human heart failure. The mechanisms of upregulation involve increases in myocardial Giα-2 protein, mRNA and gene transcriptional activity. To elucidate these mechanisms in more detail, the 5′ flanking region of the human Giα-2 gene (−1214/+115 bp) was cloned upstream of the bacterial chloramphenicol acetyltransferase (CAT) gene and transfected in embryonic chick cardiomyocytes. CAT activity was measured 48 h after transfection. Unstimulated activity of the −1214/+115 bp construct was about 10fold higher than activity of the basal CAT-construct (pGEMCAT). 5′ deletion from −1214/+115 to −85/+115 bp upstream of the transcriptional start site increased, further stepwise deletions to 46/+115 gradually decreased promotor activity. Deletion from −46/+115 to −33/+115 bp completely abolished promotor activity. Stimulation of cardiomyocytes that had been transfected with the −1214/+115 CAT-construct with isoprenaline (10 μM), forskolin (10 μM), forskolin (10 μM) plus IBMX (10 μM) or dibutyryl-cAMP (1 mM) for 24 h induced an increase in CAT activity to 139±12% (n=9), 211±18% (n=12), 256±20% (n=5) and 198±28% (n=7) of unstimulated values, respectively. We conclude: 1) In chicken cardiomyocytes a sequence element of 52 bp between −85 and −33 bp is necessary to provide basal Giα-2 promotor activity. 2) Elevation of cAMP has a stimulatory effect on the human Giα-2 promotor, thereby offering a mechanism for β-adrenoceptor-mediated increases in Giα-2 in the heart.

Electronic Resource