title: Depletion of cardiac catecholamine stores impairs cardiac norepinephrine re-uptake by downregulation of the norepinephrine transporter.
abstract: In heart failure (HF), a disturbed cardiac norepinephrine (NE) homeostasis is characterized by depleted cardiac NE stores, impairment of the cardiac NE re-uptake by the neuronal norepinephrine transporter (NET) and enhanced cardiac NE net release. Reduced cardiac NE content appears to be caused by enhanced cardiac NE net release from sympathetic neurons in HF, triggered by neurohumoral activation. However, it remains unclear whether reduced NE itself has an impact on cardiac NE re-uptake, independent of neurohumoral activation. Here, we evaluated whether depletion of cardiac NE stores alone can regulate cardiac NE re-uptake. Treatment of Wistar rats with reserpine (5 mg/kg/d) for one (1d) or five days (5d) resulted in markedly reduced cardiac NE content, comparable to NE stores in experimental HF due to pressure overload. In order to assess cardiac NE re-uptake, the specific cardiac [3H]-NE uptake via the NET in a Langendorff preparation was measured. Reserpine treatment led to decreased NE re-uptake at 1d and 5d compared to saline treatment. Expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of the NE synthesis, was elevated in left stellate ganglia after reserpine. Mechanistically, measurement of NET mRNA expression in left stellate ganglia and myocardial NET density revealed a post-transcriptional downregulation of the NET by reserpine. In summary, present data demonstrate that depletion of cardiac NE stores alone is sufficient to impair cardiac NE re-uptake via downregulation of the NET, independent of systemic neurohumoral activation. Knowledge about the regulation of the cardiac NE homeostasis may offer novel therapeutic strategies in HF.
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.|DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Kreusser
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.|DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany.
authors.forename: Lorenz H
authors.initials: LH
authors.lastname: Lehmann
authors.affiliation: Department of Cardiology, Theresienkrankenhaus, Mannheim, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Haass
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.|DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany.
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Buss
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.|DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany.|Department of Cardiology, University Hospital Mannheim, Mannheim, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Lossnitzer
mesh_terms: D000818:Animals; D002395:Catecholamines / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004452:Echocardiography; D006321:Heart / Q000000981:diagnostic imaging; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D006339:Heart Rate; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012110:Reserpine / Q000494:pharmacology; D013233:Stellate Ganglion / Q000378:metabolism / Q000473:pathology; D014316:Tritium / Q000737:chemistry; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
chemical_list: D002395:Catecholamines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012333:RNA, Messenger; D014316:Tritium; D012110:Reserpine; D014446:Tyrosine 3-Monooxygenase