title: Irregular electrical activation of intrinsic cardiac adrenergic cells increases catecholamine-synthesizing enzymes.
abstract: BACKGROUND
  Recently, increased cardiac norepinephrine levels were observed in patients who were exposed to irregular stimulation during electrophysiological testing. The molecular mechanisms remain unclear. Intrinsic cardiac adrenergic (ICA) cells are present in mammalian hearts and contain catecholamine-synthesizing enzymes sufficient to produce biologically active norepinephrine levels. Thus, we aimed to investigate the expression of catecholamine-synthesizing enzymes by ICA cells exposed to irregular pacing.
  
  
  METHODS
  Co-cultures of cardiomyocytes and ICA cells were exposed to irregular pacing for 48h (standard deviation (SD)=5%, 25% and 50% of mean cycle length) at a constant rate of 5Hz. The expression of catecholamine-synthesizing enzymes including tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DBH) were analyzed on mRNA and protein levels.
  
  
  RESULTS
  First, immunolabeling identified ICA cells presenting TH and DBH staining around the cell nucleus. Irregular pacing with 25% SD at a constant rate of 5Hz significantly increased the expression of TH and DBH enzyme synthesis. Pharmacological approaches have shown that both metoprolol and losartan reversed the irregular pacing induced DBH increase, whereas the expression of TH was only blocked by metoprolol in a significant manner. Blockade of the endothelin-A receptor by BQ123 or the calcineurin-NFAT pathway by cyclosporine-A, 11R-VIVIT or FK506 revealed a potential role of both cascades in irregular pacing induced catecholamine-synthesizing enzyme expression.
  
  
  CONCLUSIONS
  ICA cells respond to irregular electrical activation with an increase in catecholamine-synthesizing enzymes. Drugs commonly used in clinical routine significantly influence the expression of TH and DBH by ICA cells via different signaling routes.
authors: Department of Cardiology, RWTH Aachen University, Aachen, Germany. esaygili@ukaachen.de
authors: Erol
authors: E
authors: Saygili
authors: Claudia
authors: C
authors: Günzel
authors: Esra
authors: E
authors: Saygili
authors: Fawad
authors: F
authors: Noor-Ebad
authors: Robert H G
authors: RH
authors: Schwinger
authors: Karl
authors: K
authors: Mischke
authors: Nikolaus
authors: N
authors: Marx
authors: Patrick
authors: P
authors: Schauerte
authors: Obaida R
authors: OR
authors: Rana
mesh_terms: D000818:Animals; D065095:Calcineurin Inhibitors; D002395:Catecholamines / Q000096:biosynthesis; D018920:Coculture Techniques; D016572:Cyclosporine / Q000494:pharmacology; D004299:Dopamine beta-Hydroxylase / Q000096:biosynthesis* / Q000235:genetics; D004558:Electric Stimulation; D065130:Endothelin A Receptor Antagonists; D004837:Epinephrine / Q000502:physiology*; D019808:Losartan / Q000494:pharmacology; D008790:Metoprolol / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology* / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D016559:Tacrolimus / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D065095:Calcineurin Inhibitors; D002395:Catecholamines; D065130:Endothelin A Receptor Antagonists; D050778:NFATC Transcription Factors; D010456:Peptides, Cyclic; D016572:Cyclosporine; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D008790:Metoprolol; D019808:Losartan; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D016559:Tacrolimus; D004837:Epinephrine