title: Regulation of cyclic adenosine monophosphate release by selective β2-adrenergic receptor stimulation in human terminal failing myocardium before and after ventricular assist device support.
abstract: 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 β1-adrenergic receptors (β1-ARs). Little is known about the regulation of AC and β2-AR coupling after VAD; moreover β2-AR stimulation during VAD was claimed to induce myocardial recovery.
  
  
  METHODS
  We analyzed in VAD-supported human myocardium the regulation of AC activity upon β1-AR and selective β2-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 β2-AR using clenbuterol (β2-AR agonist) and bisoprolol (β1-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 β2-AR did not reveal influence of VAD support on β2-AR-AC coupling. Stimulation of ventricular trabeculae by > 100 μmole/liter clenbuterol revealed negative inotropic responses.
  
  
  CONCLUSIONS
  VAD does not influence β2-AR coupling to AC stimulation. Elevated response to catecholamines after VAD support is influenced by β1-AR upregulation and modulation of AC activity. Restoration of β-adrenergic responsiveness was restricted to acutely failing hearts.
authors.affiliation: Herz- und Diabeteszentrum NRW, Klinik f. Thorax- und Kardiovaskularchirurgie, E. & H. Klessmann-Institut f. Kardiovaskuläre Forschung und Entwicklung, Bad Oeynhausen, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Kassner
authors.forename: Karl
authors.initials: K
authors.lastname: Toischer
authors.forename: Birte
authors.initials: B
authors.lastname: Bohms
authors.forename: Peter
authors.initials: P
authors.lastname: Kolkhof
authors.forename: Getu
authors.initials: G
authors.lastname: Abraham
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuβ
authors.forename: Michiel
authors.initials: M
authors.lastname: Morshuis
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schulte Eistrup
authors.forename: Aly
authors.initials: A
authors.lastname: El-Banayosy
authors.forename: Jan
authors.initials: J
authors.lastname: Gummert
authors.forename: Hendrik
authors.initials: H
authors.lastname: Milting
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000328:Adult; D000368:Aged; D017298:Bisoprolol / Q000494:pharmacology; D002395:Catecholamines / Q000494:pharmacology; D002648:Child; D002976:Clenbuterol / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D005260:Female; D006333:Heart Failure / Q000378:metabolism* / Q000628:therapy*; D006353:Heart-Assist Devices; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D005576:Colforsin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D002976:Clenbuterol; D017298:Bisoprolol