Abstract
Natriuretic peptides (NPs) play essential roles in the regulation of cardiovascular function. NP effects are mediated by receptors known as NPR-A, NPR-B or NPR-C. NPs have potent effects on regulation of heart rate (HR) by the autonomic nervous system (ANS), but the role of NPR-C in these effects has not been investigated. Accordingly, we have used telemetric ECG recordings in awake, freely moving wildtype and NPR-C knockout (NPR-C−/−) mice and performed heart rate variability (HRV) analysis to assess alterations in sympatho-vagal balance on the heart following loss of NPR-C. Our novel data demonstrate that NPR-C−/− mice are characterized by elevations in HR, reductions in circadian changes in HR and enhanced occurrence of sinus pauses, indicating increased arrhythmogenesis and a loss of HRV. Time domain and frequency domain analyses further demonstrate that HRV is reduced in NPR-C−/− mice in association with a reduction in parasympathetic activity. Importantly, the low frequency to high frequency ratio was increased in NPR-C−/− mice indicating that sympathetic activity is also enhanced. These changes in autonomic regulation were confirmed using atropine and propranolol to antagonize the ANS. These findings illustrate that loss of NPR-C reduces HRV due to perturbations in the regulation of the heart by the ANS.
Highlights
Natriuretic peptides (NPs), including atrial (ANP), B-type (BNP) and C-type (CNP) NPs, are a well-known group of peptide hormones that play essential and critical roles in the regulation of cardiovascular function in normal and disease conditions[1,2,3]
Our data demonstrate that NP receptors (NPRs)-C−/− mice are characterized by increased incidences of sinus pauses, elevated Heart rate (HR) and an impaired capacity to modulate HR according to activity level in different physiological conditions such as at night vs. during the day
In healthy mammals, including humans, HR is adjusted by the dynamic interactions between the sympathetic and parasympathetic nervous systems[24], which is known as heart rate variability (HRV)
Summary
Natriuretic peptides (NPs), including atrial (ANP), B-type (BNP) and C-type (CNP) NPs, are a well-known group of peptide hormones that play essential and critical roles in the regulation of cardiovascular function in normal and disease conditions[1,2,3]. NPR-C, on the other hand, is functionally coupled to inhibitory G-proteins (Gi), which inhibit adenylyl cyclases and activate phospholipid signaling upon NP binding[2,3,11]. Heart rate (HR), a critical indicator of cardiac performance, is determined by the intrinsic rate of spontaneous activity in the sinoatrial node (SAN) and is importantly modulated by the autonomic nervous system (ANS)[12,13]. We have shown that in the presence of acute β-adrenergic receptor (β-AR) activation, NPs reduce HR and slow electrical conduction in the SAN by inhibiting spontaneous action potential firing in SAN myocytes[16,17,18]. We have shown that loss of NPR-C results in SAN dysfunction, as well as atrial arrhythmias, due to structural remodeling and fibrosis in the SAN and atria of NPR-C−/− mice[18]
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