Natriuretic peptide receptor B maintains heart rate and sinoatrial node function via cyclic GMP-mediated signalling
Natriuretic peptide receptor B maintains heart rate and sinoatrial node function via cyclic GMP-mediated signalling
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DOI：
10.1093/cvr/cvab245
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发表时间：
2021-07-17
影响因子：
10.8
通讯作者：
Rose, Robert A.
中科院分区：
文献类型：
--
作者：
Dorey, Tristan W.;Mackasey, Martin;Rose, Robert A.
心率（HR）是心脏性能的关键指标，由窦房结（SAN）功能和调节决定。已证明，当外源性应用时，利钠肽（包括C型NP（CNP））可调节SAN中的离子通道功能。CNP是唯一作为利钠肽受体-B（NPR-B）配体的NP。尽管有这些特性，CNP和NPR-B在体内调节HR和内在SAN自律性的能力及其机制尚不完全清楚。因此，本研究的目的是确定NPR-B信号在调节HR和SAN功能中的作用。方法和结果我们已经使用NPR-B缺陷小鼠（NPR-B+/-）研究HR调节和SAN功能，使用遥测清醒小鼠，麻醉小鼠心内电生理学，高分辨率光学测绘分离SAN制剂，膜片钳分离SAN心肌细胞，和分离SAN组织的分子生物学。这些研究表明，NPR-B+/-小鼠表现出缓慢的HR、增加的校正SAN恢复时间和减慢的SAN传导。在NPR-B+/-小鼠中，由于超极化激活电流（I-f）和L型Ca 2+电流（I-Ca，I-L）的减少，分离的SAN肌细胞的自发AP放电频率受损。I-f和I-Ca、I-L降低是由于SAN中cGMP水平降低和磷酸二酯酶3（PDE 3）对cAMP的水解增加。通过应用8-Br-cGMP抑制PDE 3或恢复cGMP信号传导，可消除NPR-B+/-小鼠SAN中cAMP、AP放电、I-f和I-Ca、I-L的降低，并使SAN传导正常化。NPR-B+/-小鼠未表现出SAN纤维化的变化，也未表现出心脏肥大或心室功能变化的证据。结论NPR-B通过cGMP/PDE 3/cAMP信号通路调节窦房结细胞离子通道功能，在维持正常心率和窦房结功能中起重要作用。
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 signalling 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 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 (I-f) and L-type Ca2+ current (I-Ca,I-L). I-f and I-Ca,I-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, I-f, and I-Ca,I-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 signalling mechanism.