Natriuretic peptide receptor B maintains heart rate and sinoatrial node function via cyclic GMP-mediated signalling

Abstract

Aims Heart rate (HR) is a critical indicator of cardiac performance that is determined by sinoatrial node (SAN) function and regulation. Natriuretic peptides, including C-type NP (CNP) have been shown to modulate ion channel function in the SAN when applied exogenously. CNP is the only NP that acts as a ligand for natriuretic peptide receptor-B (NPR-B). Despite these properties, the ability of CNP and NPR-B to regulate HR and intrinsic SAN automaticity in vivo, and the mechanisms by which it does so, are incompletely understood. Thus, the objective of this study was to determine the role of NPR-B signaling in regulating HR and SAN function. Methods and Results We have used NPR-B deficient mice (NPR-B+/-) to study HR regulation and SAN function using telemetry in conscious mice, intracardiac electrophysiology in anesthetized mice, high resolution optical mapping in isolated SAN preparations, patch-clamping in isolated SAN myocytes, and molecular biology in isolated SAN tissue. These studies demonstrate that NPR-B+/- mice exhibit slow HR, increased corrected SAN recovery time, and slowed SAN conduction. Spontaneous AP firing frequency in isolated SAN myocytes was impaired in NPR-B+/- mice due to reductions in the hyperpolarization activated current (If) and L-type Ca2+ current (ICa,L). If and ICa,L were reduced due to lower cGMP levels and increased hydrolysis of cAMP by phosphodiesterase 3 (PDE3) in the SAN. Inhibiting PDE3 or restoring cGMP signaling via application of 8-Br-cGMP abolished the reductions in cAMP, AP firing, If, and ICa,L, and normalized SAN conduction, in the SAN in NPR-B+/- mice. NPR-B+/- mice did not exhibit changes in SAN fibrosis and showed no evidence of cardiac hypertrophy or changes in ventricular function. Conclusions NPR-B plays an essential physiological role in maintaining normal HR and SAN function by modulating ion channel function in SAN myocytes via a cGMP/PDE3/cAMP signaling mechanism.

Evaluation of non-linear heart rate variability using multi-scale multi-fractal detrended fluctuation analysis in mice: Roles of the autonomic nervous system and sinoatrial node

“…Furthermore, we sought to assess the contributions of changes in ANS activity as well as intrinsic SAN function to the fractal structure of the HRV. Initially, we used time and frequency domain analysis to demonstrate changes in HRV during ANS blockade in vivo as well as in isolated atrial preparations and Frontiers in Physiology frontiersin.org isolated SAN myocytes, that are typical of those shown in previous studies (Moghtadaei et al, 2017;Dorey et al, 2020;Dorey et al, 2021;Dorey et al, 2022). However, nonlinear HRV analysis using MSMFDFA provided additional insight not possible with traditional approaches.…”

Physiological and Pathophysiological Effects of C-Type Natriuretic Peptide on the Heart

“…Subsequently, natriuretic peptides (including CNP) and their cognate receptors were shown to modulate ion channel function in the SAN [ 138 , 139 , 140 ]. Recently, to investigate the physiological roles of NPR-B signaling in regulating heart rate and SAN function, NPR-B-deficient mice were used, and it was revealed that NPR-B plays an essential physiological role in maintaining normal heart rate and SAN function by modulating ion channel function in SAN myocytes via a cGMP/PDE3/cAMP signaling mechanism [ 141 ].…”

CNP, the Third Natriuretic Peptide: Its Biology and Significance to the Cardiovascular System

“…Therefore, maintaining an optimal heart rate is very important. Recently, Dorey et al evaluated HR regulation and sinoatrial node (SAN) function in heterozygous GC-B KO mice, which exhibit a slow HR, increased corrected SAN recovery time, and slowed SAN conduction, without evidence of cardiac hypertrophy or a change in cardiac function [ 40 ]. Hyperpolarization activated currents ( I f ) and L-type Ca 2+ currents ( I CaL ) were reduced due to lower levels of cGMP and the increased hydrolysis of cAMP by phosphodiesterase III (PDE III) in the SAN.…”

“…The application of 8-Br-cGMP, an analog of cGMP, restored the I f and I CaL as well as SAN conduction. These data suggest that GC-B signaling is involved in the maintaining of normal HR and SAN function via the cGMP/PDE III/cAMP signaling mechanism [ 40 ].…”