Irregular electrical activation of intrinsic cardiac adrenergic cells increases catecholamine-synthesizing enzymes

BackgroundRecently, 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.MethodsCo-cultures of cardiomyocytes and ICA cells were exposed to irregular pacing for 48 h (standard deviation (SD) = 5%, 25% and 50% of mean cycle length) at a constant rate of 5 Hz. The expression of catecholamine-synthesizing enzymes including tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DBH) were analyzed on mRNA and protein levels.ResultsFirst, immunolabeling identified ICA cells presenting TH and DBH staining around the cell nucleus. Irregular pacing with 25% SD at a constant rate of 5 Hz 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.ConclusionsICA 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.

► Cardiac norepinephrine levels are increased in patients during irregular heartbeat.
► ICA cells in mammalian hearts express catecholamine-synthesizing enzymes.
► ICA cells respond to irregular electrical activation with an increase in TH and DBH.
► Endothelin-1 and Cn–NFAT signaling are promising targets to modify enzyme synthesis by ICA cells.