Libin Cardiovascular Institute, Department of Cardiac Sciences, Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6, Canada.
Cardiovasc Res. 2023 Dec 30;119(17):2697-2711. doi: 10.1093/cvr/cvad138.
The sympathetic nervous system increases HR by activating β-adrenergic receptors (β-ARs) and increasing cAMP in sinoatrial node (SAN) myocytes while phosphodiesterases (PDEs) degrade cAMP. Chronotropic incompetence, the inability to regulate heart rate (HR) in response to sympathetic nervous system activation, is common in hypertensive heart disease; however, the basis for this is poorly understood. The objective of this study was to determine the mechanisms leading to chronotropic incompetence in mice with angiotensin II (AngII)-induced hypertensive heart disease.
C57BL/6 mice were infused with saline or AngII (2.5 mg/kg/day for 3 weeks) to induce hypertensive heart disease. HR and SAN function in response to the β-AR agonist isoproterenol (ISO) were studied in vivo using telemetry and electrocardiography, in isolated atrial preparations using optical mapping, in isolated SAN myocytes using patch-clamping, and using molecular biology. AngII-infused mice had smaller increases in HR in response to physical activity and during acute ISO injection. Optical mapping of the SAN in AngII-infused mice demonstrated impaired increases in conduction velocity and altered conduction patterns in response to ISO. Spontaneous AP firing responses to ISO in isolated SAN myocytes from AngII-infused mice were impaired due to smaller increases in diastolic depolarization (DD) slope, hyperpolarization-activated current (If), and L-type Ca2+ current (ICa,L). These changes were due to increased localization of PDE4D surrounding β1- and β2-ARs in the SAN, increased SAN PDE4 activity, and reduced cAMP generation in response to ISO. Knockdown of PDE4D using a virus-delivered shRNA or inhibition of PDE4 with rolipram normalized SAN sensitivity to β-AR stimulation in AngII-infused mice.
AngII-induced hypertensive heart disease results in impaired HR responses to β-AR stimulation due to up-regulation of PDE4D and reduced effects of cAMP on spontaneous AP firing in SAN myocytes.
交感神经系统通过激活β肾上腺素能受体（β-ARs）并增加窦房结（SAN）心肌细胞中的 cAMP 来增加心率（HR），而磷酸二酯酶（PDEs）则降解 cAMP。在高血压性心脏病中，自主神经系统激活时调节心率（HR）的能力下降（即变时性功能不全）很常见；然而，其基础机制尚不清楚。本研究的目的是确定血管紧张素 II（AngII）诱导的高血压性心脏病小鼠变时性功能不全的发生机制。
C57BL/6 小鼠接受盐水或 AngII（2.5mg/kg/天，持续 3 周）输注以诱导高血压性心脏病。通过遥测和心电图在体内研究β-AR 激动剂异丙肾上腺素（ISO）对 HR 和 SAN 功能的影响，在分离的心房制剂中使用光学映射，在分离的 SAN 心肌细胞中使用膜片钳技术，以及使用分子生物学方法。AngII 输注小鼠在体力活动和急性 ISO 注射时 HR 增加幅度较小。AngII 输注小鼠 SAN 的光学映射显示，在 ISO 刺激下，传导速度增加和传导模式改变。来自 AngII 输注小鼠的分离 SAN 心肌细胞中 ISO 引起的自发性 AP 放电反应受损，原因是舒张期去极化（DD）斜率、超极化激活电流（If）和 L 型 Ca2+电流（ICa,L）增加较小。这些变化是由于 SAN 中β1-和β2-AR 周围 PDE4D 的定位增加、SAN PDE4 活性增加以及 ISO 反应中 cAMP 生成减少所致。使用病毒递送的 shRNA 敲低 PDE4D 或用 rolipram 抑制 PDE4 可使 AngII 输注小鼠的 SAN 对β-AR 刺激的敏感性正常化。
AngII 诱导的高血压性心脏病导致 HR 对β-AR 刺激的反应受损，原因是 PDE4D 的上调以及 cAMP 对 SAN 心肌细胞自发性 AP 放电的影响降低。
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