Document Detail

Regulation of cyclic adenosine monophosphate release by selective β(2)-adrenergic receptor stimulation in human terminal failing myocardium before and after ventricular assist device support.
MedLine Citation:
PMID:  22975104     Owner:  NLM     Status:  In-Data-Review    
BACKGROUND: Response to catecholamines is blunted in terminal heart failure due to β-receptor downregulation and uncoupling from adenylyl cyclase (AC). Improved myocardial responsiveness to catecholamines after ventricular assist device (VAD) support is associated with upregulation of β(1)-adrenergic receptors (β(1)-ARs). Little is known about the regulation of AC and β(2)-AR coupling after VAD; moreover β(2)-AR stimulation during VAD was claimed to induce myocardial recovery.
METHODS: We analyzed in VAD-supported human myocardium the regulation of AC activity upon β(1)-AR and selective β(2)-AR stimulation in 8 non-failing hearts (NF) and 17 paired samples of VAD patients. AC messenger RNA was measured by TaqMan. AC was stimulated via β(2)-AR using clenbuterol (β(2)-AR agonist) and bisoprolol (β(1)-AR blocker). Organ bath experiments were done with trabeculae from both ventricles. Samples were stratified according to chronic or acute heart failure history.
RESULTS: Isoprenaline-induced AC activity was downregulated (p < 0.001) pre-VAD and increased significantly (p < 0.05) after unloading (mean ± standard deviation pmole/mg/min) in NF (47.9 ± 14.9), pre-VAD (24.35 ± 13.3), and post-VAD (50.04 ± 50.25). Forskolin stimulation revealed significant (p < 0.05) upregulation of AC activity during VAD, especially in acutely failing hearts (NF, 192.1 ± 68.7; pre-VAD, 191.1 ± 60.4; post-VAD, 281.5 ± 133). However, forskolin stimulation relative to isoprenaline-induced inotropy remained reduced before and after VAD compared with NF. The selective stimulation of β(2)-AR did not reveal influence of VAD support on β(2)-AR-AC coupling. Stimulation of ventricular trabeculae by > 100 μmole/liter clenbuterol revealed negative inotropic responses.
CONCLUSIONS: VAD does not influence β(2)-AR coupling to AC stimulation. Elevated response to catecholamines after VAD support is influenced by β(1)-AR upregulation and modulation of AC activity. Restoration of β-adrenergic responsiveness was restricted to acutely failing hearts.
Astrid Kassner; Karl Toischer; Birte Bohms; Peter Kolkhof; Getu Abraham; Gerd Hasenfuβ; Michiel Morshuis; Sebastian Schulte Eistrup; Aly El-Banayosy; Jan Gummert; Hendrik Milting
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation     Volume:  31     ISSN:  1557-3117     ISO Abbreviation:  J. Heart Lung Transplant.     Publication Date:  2012 Oct 
Date Detail:
Created Date:  2012-09-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9102703     Medline TA:  J Heart Lung Transplant     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1127-35     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.
Herz- und Diabeteszentrum NRW, Klinik f. Thorax- und Kardiovaskularchirurgie, E. & H. Klessmann-Institut f. Kardiovaskuläre Forschung und Entwicklung, Bad Oeynhausen, Germany.
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