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

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 signalling in regulating HR and SAN function. We have used NPR-B deficient mice (NPR-B+/-) to study HR regulation and SAN function using telemetry in conscious mice, intracardiac electrophysiology in anaesthetized 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 signalling 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. 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 signalling mechanism.

Dorey TW ，Mackasey M ，Jansen HJ ，McRae MD ，Bohne LJ ，Liu Y ，Belke DD ，Atkinson L ，Rose RA ... -  《-》

The natriuretic peptides BNP and CNP increase heart rate and electrical conduction by stimulating ionic currents in the sinoatrial node and atrial myocardium following activation of guanylyl cyclase-linked natriuretic peptide receptors.

Natriuretic peptides (NPs) are best known for their ability to regulate blood vessel tone and kidney function whereas their electrophysiological effects on the heart are less clear. Here, we measured the effects of BNP and CNP on sinoatrial node (SAN) and atrial electrophysiology in isolated hearts as well as isolated SAN and right atrial myocytes from mice. BNP and CNP dose-dependently increased heart rate and conduction through the heart as indicated by reductions in R-R interval, P wave duration and P-R interval on ECGs. In conjunction with these ECG changes BNP and CNP (100 nM) increased spontaneous action potential frequency in isolated SAN myocytes by increasing L-type Ca(2+) current (I(Ca,L)) and the hyperpolarization-activated current (I(f)). BNP had no effect on right atrial myocyte APs in basal conditions; however, in the presence of isoproterenol (10nM), BNP increased atrial AP duration and I(Ca,L). Quantitative gene expression and immunocytochemistry data show that all three NP receptors (NPR-A, NPR-B and NPR-C) are expressed in the SAN and atrium. The effects of BNP and CNP on SAN and right atrial myocytes were maintained in mutant mice lacking functional NPR-C receptors and blocked by the NPR-A antagonist A71915 indicating that BNP and CNP function through their guanylyl cyclase-linked receptors. Our data also show that the effects of BNP and CNP are completely absent in the presence of the phosphodiesterase 3 inhibitor milrinone. Based on these data we conclude that NPs can increase heart rate and electrical conduction by activating the guanylyl cyclase-linked NPR-A and NPR-B receptors and inhibiting PDE3 activity.

Springer J ，Azer J ，Hua R ，Robbins C ，Adamczyk A ，McBoyle S ，Bissell MB ，Rose RA ... -  《-》

Natriuretic peptides regulate heart rate and sinoatrial node function by activating multiple natriuretic peptide receptors.

Natriuretic peptides, including BNP and CNP, elicit their effects via two guanylyl cyclase-linked receptors denoted NPR-A and NPR-B as well as a third receptor, NPR-C. The relative contributions of these receptors to the overall effects of NPs on heart rate (HR) and sinoatrial node (SAN) function are very poorly understood. The effects of BNP and CNP (10-500 nM) on HR and SAN myocyte spontaneous action potential (AP) firing were studied using wildtype mice and mice lacking functional NPR-C receptors (NPR-C(-/-)). In basal conditions and 10 nM doses of the β-adrenergic receptor (β-AR) agonist isoproterenol (ISO) BNP and CNP increased HR and AP firing in SAN myocytes. The NPR-C selective agonist cANF (10-500 nM) had no effects in basal conditions, but decreased HR and SAN AP frequency in the presence of ISO. These effects of cANF were completely absent in NPR-C(-/-) mice. Strikingly, in the presence of 1 μM doses of ISO, BNP and CNP switched to causing decreases in HR and SAN AP frequency. These decreases were not as large as those elicited by cANF and were absent in NPR-C(-/-) hearts, where BNP instead elicited a further increase in HR. Inhibition of NPR-A with A71915, in the presence of 1 μM ISO, enabled BNP to signal exclusively through NPR-C and to decrease HR as effectively as cANF. Together these data demonstrate that BNP and CNP affect HR and SAN function by activating multiple receptor subtypes. NPR-A/B mediate increases in HR and SAN function, but these effects are opposed by NPR-C, which plays an increasingly important signaling role in the presence of β-AR stimulation.

Azer J ，Hua R ，Vella K ，Rose RA ... -  《-》

Effects of C-type natriuretic peptide on ionic currents in mouse sinoatrial node: a role for the NPR-C receptor.

Rose RA ，Lomax AE ，Kondo CS ，Anand-Srivastava MB ，Giles WR ... -  《AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY》

Effects of natriuretic peptides on electrical conduction in the sinoatrial node and atrial myocardium of the heart.

Azer J ，Hua R ，Krishnaswamy PS ，Rose RA ... -  《-》