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

Abstract

AimsB-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.Methods and resultsMean 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 of 3H-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).ConclusionC-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.

Natriuretic peptide system expression in murine and human submandibular salivary glands: a study of the spatial localisation of ANB, BNP, CNP and their receptors

“…Upon stretch of the cardiac wall, ANP and BNP are released into the circulation, inducing increased renal excretion of sodium and water, increased vascular permeability and vasodilation, leading to a reduction in systemic blood pressure (Curry 2005;Houben et al 2005), while CNP induces vasodilation (Wei et al 1993). Recent research has also shown BNP and CNP regulate cardiovascular function by direct inhibition of cardiac sympathetic neurotransmission (Buttgereit et al 2016;Li et al 2015). Identification of NP production and NPR expression in a broad range of tissues suggests this system has biological effects beyond the regulation of kidney and cardiovascular functions.…”

Natriuretic peptides and peripheral autonomic neurotransmission: back to the A, B, and C’s.

“…The slow pace of developing novel HF therapies available to patients highlights the need for novel pathways that have therapeutic potential, which may extend beyond HF to other cardiovascular diseases. The present study by Buttgereit et al 4 and that of Li et al 3 suggest a back to the 'A B C's' is needed on NP signalling in physiologic and pathophysiologic conditions, and highlights the need for further research in this area.…”

“…At doses in the pathophysiologic range, CNP does not have diuretic or natriuretic effects in normal patients 8,9 , while other studies also suggest that vasodepressor and natriuretic activity of CNP is weaker than ANP. 10 These studies did not assess biomarkers of sympathetic neurotransmission to determine whether CNP-modulated sympathetic signalling, however, they emphasize that the primary action of CNP may be geared towards preventing sympathetic neuron hyperactivity as suggested by this study and others, 4,11 and to facilitate vagal neurotransmission as previously shown. 12 Although elucidating key mechanisms for CNP-mediated modulation of sympathetic neurotransmission furthers our understanding of NPs as a family, some important considerations are raised regarding what occurs in pathology.…”

“…CNP, which is present in endothelial cells and ventricular myocardium, is also abundant in the nervous system. CNP levels increase in HF, similar to ANP and BNP, but its physiological relevance has not been well understood.In this issue of the journal Buttgereit et al 4 extend our understanding of the physiological roles played by CNP, using a rat model overexpressing a neuron-specific dominant negative form of NPR-B. The authors show that inhibition of NPR-B signalling results in sympathoexcitation, analogous to the physiological effect of blocking NPR-A signalling.…”

“…In this issue of the journal Buttgereit et al 4 extend our understanding of the physiological roles played by CNP, using a rat model overexpressing a neuron-specific dominant negative form of NPR-B. The authors show that inhibition of NPR-B signalling results in sympathoexcitation, analogous to the physiological effect of blocking NPR-A signalling.…”