title: C-type natriuretic peptide and natriuretic peptide receptor B signalling inhibits cardiac sympathetic neurotransmission and autonomic function.
abstract: B-type natriuretic peptide (BNP)-natriuretic peptide receptor A (NPR-A) receptor signalling inhibits cardiac sympathetic neurotransmission, although C-type natriuretic peptide (CNP) is the predominant neuropeptide of the nervous system with expression in the heart and vasculature. We hypothesized that CNP acts similarly to BNP, and that transgenic rats (TGRs) with neuron-specific overexpression of a dominant negative NPR-B receptor would develop heightened sympathetic drive.
  
  
  
  Mean arterial pressure and heart rate (HR) were significantly (P < 0.05) elevated in freely moving TGRs (n = 9) compared with Sprague Dawley (SD) controls (n = 10). TGR had impaired left ventricular systolic function and spectral analysis of HR variability suggested a shift towards sympathoexcitation. Immunohistochemistry demonstrated co-staining of NPR-B with tyrosine hydroxylase in stellate ganglia neurons. In SD rats, CNP (250 nM, n = 8) significantly reduced the tachycardia during right stellate ganglion stimulation (1-7 Hz) in vitro whereas the response to bath-applied norepinephrine (NE, 1 μM, n = 6) remained intact. CNP (250 nM, n = 8) significantly reduced the release of3H-NE in isolated atria and this was prevented by the NPR-B antagonist P19 (250 nM, n = 6). The neuronal Ca2+current (n = 6) and intracellular Ca2+transient (n = 9, using fura-2AM) were also reduced by CNP in isolated stellate neurons. Treatment of the TGR (n = 9) with the sympatholytic clonidine (125 µg/kg per day) significantly reduced mean arterial pressure and HR to levels observed in the SD (n = 9).
  
  
  
  C-type natriuretic peptide reduces cardiac sympathetic neurotransmission via a reduction in neuronal calcium signalling and NE release through the NPR-B receptor. Situations impairing CNP-NPR-B signalling lead to hypertension, tachycardia, and impaired left ventricular systolic function secondary to sympatho-excitation.
authors: Experimental and Clinical Research Center (ECRC), a joint institution of the Max Delbrück Center for Molecular Medicine (MDC) and the Charité Medical Faculty, Berlin, Germany.|Max Delbrück Center for Molecular Medicine (MDC), Campus Berlin-Buch, Robert-Rössle-Strasse 10, 13092 Berlin, Germany.
authors: Jens
authors: J
authors: Buttgereit
authors: Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX13PT, UK.
authors: Julia
authors: J
authors: Shanks
authors: Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX13PT, UK.
authors: Dan
authors: D
authors: Li
authors: Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX13PT, UK.
authors: Guoliang
authors: G
authors: Hao
authors: Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX13PT, UK.
authors: Arvinder
authors: A
authors: Athwal
authors: Translational Medicine, Clinical Pharmacology and Profiling, Novartis Pharma AG, Basel, Switzerland.
authors: Thomas H
authors: TH
authors: Langenickel
authors: Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX13PT, UK.
authors: Hannah
authors: H
authors: Wright
authors: Leibniz Institute for Molecular Pharmacology (FMP), Campus Berlin-Buch, Berlin, Germany.
authors: Andrey C
authors: AC
authors: da Costa Goncalves
authors: Helios Clinic Bad Saarow, Pieskower Strasse 33, Bad Saarow, Germany.
authors: Jan
authors: J
authors: Monti
authors: Max Delbrück Center for Molecular Medicine (MDC), Campus Berlin-Buch, Robert-Rössle-Strasse 10, 13092 Berlin, Germany.
authors: Ralph
authors: R
authors: Plehm
authors: Max Delbrück Center for Molecular Medicine (MDC), Campus Berlin-Buch, Robert-Rössle-Strasse 10, 13092 Berlin, Germany.
authors: Elena
authors: E
authors: Popova
authors: Experimental and Clinical Research Center (ECRC), a joint institution of the Max Delbrück Center for Molecular Medicine (MDC) and the Charité Medical Faculty, Berlin, Germany.|Max Delbrück Center for Molecular Medicine (MDC), Campus Berlin-Buch, Robert-Rössle-Strasse 10, 13092 Berlin, Germany.
authors: Fatimunnisa
authors: F
authors: Qadri
authors: Max Delbrück Center for Molecular Medicine (MDC), Campus Berlin-Buch, Robert-Rössle-Strasse 10, 13092 Berlin, Germany.
authors: Irina
authors: I
authors: Lapidus
authors: Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX13PT, UK.
authors: Brent
authors: B
authors: Ryan
authors: Experimental and Clinical Research Center (ECRC), a joint institution of the Max Delbrück Center for Molecular Medicine (MDC) and the Charité Medical Faculty, Berlin, Germany.|Max Delbrück Center for Molecular Medicine (MDC), Campus Berlin-Buch, Robert-Rössle-Strasse 10, 13092 Berlin, Germany.
authors: Cemil
authors: C
authors: Özcelik
authors: Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX13PT, UK.
authors: David J
authors: DJ
authors: Paterson
authors: Max Delbrück Center for Molecular Medicine (MDC), Campus Berlin-Buch, Robert-Rössle-Strasse 10, 13092 Berlin, Germany neilherring@doctors.org.uk mbader@mdc-berlin.de.
authors: Michael
authors: M
authors: Bader
authors: Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX13PT, UK neilherring@doctors.org.uk mbader@mdc-berlin.de.
authors: Neil
authors: N
authors: Herring
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D020013:Calcium Signaling; D020022:Genetic Predisposition to Disease; D006321:Heart / Q000294:innervation*; D006339:Heart Rate; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D020098:Natriuretic Peptide, C-Type / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D010641:Phenotype; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*; D013233:Stellate Ganglion / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000378:metabolism* / Q000503:physiopathology; D009435:Synaptic Transmission; D013599:Systole; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016277:Ventricular Function, Left; D000099242:Atrial Natriuretic Factor Receptor B
chemical_list: D020098:Natriuretic Peptide, C-Type; D009638:Norepinephrine; D017461:Receptors, Atrial Natriuretic Factor; D014446:Tyrosine 3-Monooxygenase; D000099242:Atrial Natriuretic Factor Receptor B
keywords: Calcium; Hypertension; Natriuretic peptides; Norepinephrine; Sympathetic