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.
Highlights
Natriuretic peptides (NPs) comprise a family of structurally related, but genetically distinct peptide hormones, including atrial NP (ANP), brain/B-type NP (BNP), and C-type NP (CNP).[1]
C-type NP plasma concentrations are comparatively low compared with ANP/BNP, but they increase during heart failure,[8,9] and CNP may play an important role in the pathophysiology of this condition
To investigate the influence of neural NPR-B signalling on cardiovascular autonomic control, spectral analysis of blood pressure and heart rate variability (HRV) was performed
Summary
Natriuretic peptides (NPs) comprise a family of structurally related, but genetically distinct peptide hormones, including atrial NP (ANP), brain/B-type NP (BNP), and C-type NP (CNP).[1]. The NPs mediate their actions through cell surface receptors.[14] ANP and BNP bind to natriuretic peptide receptor A (NPR-A), whereas CNP activates NPR-B. Both receptors have intrinsic guanylyl cyclase activity, resulting in an increase in cGMP15 and protein kinase G signalling.[16,17,18] the cardiac phenotypes of NPR-A signalling have been well studied within transgenic and disease models, little is known about the cardiac signalling of NPR-B. We hypothesized that this TGR would display elevated sympathetic nerve activity compared with its SD control in vivo, and investigated the cellular mechanisms by which CNP influences cardiac sympathetic neurotransmission in the SD rat in vitro
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