Abstract 15759: B-type And C-type Natriuretic Peptides Regulate Heart Rate And Sinoatrial Node Function By Activating Multiple Natriuretic Peptide Receptor Subtypes
The natriuretic peptides (NPs) BNP and CNP elicit their effects by binding to specific receptors denoted NPR-A, NPR-B and NPR-C. NPR-A and NPR-B stimulate guanylyl cyclase (GC) and cGMP signaling, while NPR-C is coupled to the activation of inhibitory G proteins. The effects of NPs in the sinoatrial node (SAN), which determines heart rate (HR) in vivo, are poorly understood; thus we have investigated the roles of NPRs in HR regulation and SAN function using BNP (binds NPR-A and NPR-C) and CNP (binds NPR-B and NPR-C) as agonists. ECG recordings in Langendorff-perfused mouse hearts show that BNP (500 nM) increased HR from 348 ± 15 to 437 ± 23 beats/min (n=5; P<0.01). Patch-clamp recordings in isolated mouse SAN myocytes show that BNP (100 nM) increased spontaneous AP frequency from 148.5 ± 5.5 to 183 ± 6.3 APs/min (n=8; P<0.05) in association with increases in the diastolic depolarization slope, L-type Ca2+ current (ICa,L) and the hyperpolarization-activated current If. CNP elicited very similar effects to BNP. The effects of BNP on spontaneous AP firing were completely blocked by the NPR-A antagonist A71915 (n=5). Furthermore, BNP and CNP increased spontaneous AP firing in NPR-C knockout (NPR-C-/-) mice to the same extent as in wildtype mice (n=7). The NPR-C agonist cANF had no effect on HR or spontaneous AP firing in basal conditions; however, following stimulation with the β-adrenergic receptor (β-AR) agonist isoproterenol (ISO; 1 µM) cANF decreased HR from 468 ± 21 to 405 ± 14 (n=5; P<0.001) and spontaneous AP frequency from 185.3 ± 10 to 164 ± 8.7 APs/min (n=9; P<0.05). The effects of cANF in the presence of ISO were completely absent in NPR-C-/- mice. Unlike in basal conditions BNP and CNP (500 nM) decreased HR in the presence of ISO (n=5 per group; P<0.05); however, the magnitude of the reductions (BNP: 382 ± 3 to 352 ± 5 beats/min; CNP: 464 ± 9 to 432 ± 10 beats/min) were smaller (~30 beats/min) compared to cANF (~60 beats/min). Expression of all three NPRs in the SAN was confirmed by quantitative PCR and immunocytochemistry. These data show that BNP and CNP regulate HR and SAN function in the presence of β-AR activation by activating the GC-linked NPR-A and NPR-B receptors as well as NPR-C whereas in basal conditions NP effects are only attributable to the activation of NPR-A and NPR-B.
- © 2011 by American Heart Association, Inc.