C-type natriuretic peptide and NPR-B signalling inhibits cardiac sympathetic neurotransmission and autonomic function

Autor/innen

  • J. Buttgereit
  • J. Shanks
  • D. Li
  • G. Hao
  • A. Athwal
  • T.H. Langenickel
  • H. Wright
  • A.C. da Costa Goncalves
  • J. Monti
  • R. Plehm
  • E. Popova
  • F. Qadri
  • I. Lapidus
  • B. Ryan
  • C. Özcelik
  • D.J. Paterson
  • M. Bader
  • N. Herring

Journal

  • Cardiovascular Research

Quellenangabe

  • Cardiovasc Res 112 (3): 637-644

Zusammenfassung

  • AIMS: B-type natriuretic peptide (BNP)-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 hypothesised that CNP acts similarly to BNP, and that transgenic rats (TGR) with neuron specific overexpression of a dominant negative NPR-B receptor would develop heightened sympathetic drive. METHODS AND RESULTS: Mean arterial pressure (MAP) and heart rate (HR) were significantly (p<0.05) elevated in freely moving TGRs (n=9) compared to Sprague Dawley (SD) controls (n=10). TGR had impaired left ventricular systolic function (LVSF) 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 (250nM, n=8) significantly reduced the tachycardia during right stellate ganglion stimulation (1-7Hz) in-vitro whilst the response to bath applied norepinephrine (NE, 1{mu}M, n=6) remained intact. CNP (250nM, n=8) significantly reduced the release of (3)H-NE in isolated atria and this was prevented by the NPR-B antagonist P19 (250nM, n=6). The neuronal Ca(2+) current (n=6) and intracellular Ca(2+) 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 {mu}g/kg per day) significantly reduced MAP and HR to levels observed in the SD (n=9). CONCLUSIONS: CNP 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 LVSF secondary to sympatho-excitation.


DOI

doi:10.1093/cvr/cvw184