Center for Precision Medicine, Department of Medicine, School of Medicine University of Missouri, One Hospital Drive, Columbia, MO 65212, USA.
Department of Pharmacology, The University of Arkansas for Medical Sciences, 4301 West Markham Street, Little Rock, AR 72205, USA.
Cardiovasc Res. 2023 Jul 6;119(8):1751-1762. doi: 10.1093/cvr/cvad056.
Chronic stress is a well-known risk factor for the development of hypertension. However, the underlying mechanisms remain unclear. Corticotropin-releasing hormone (CRH) neurons in the central nucleus of the amygdala (CeA) are involved in the autonomic responses to chronic stress. Here, we determined the role of CeA-CRH neurons in chronic stress-induced hypertension.
Borderline hypertensive rats (BHRs) and Wistar-Kyoto (WKY) rats were subjected to chronic unpredictable stress (CUS). Firing activity and M-currents of CeA-CRH neurons were assessed, and a CRH-Cre-directed chemogenetic approach was used to suppress CeA-CRH neurons. CUS induced a sustained elevation of arterial blood pressure (ABP) and heart rate (HR) in BHRs, while in WKY rats, CUS-induced increases in ABP and HR quickly returned to baseline levels after CUS ended. CeA-CRH neurons displayed significantly higher firing activities in CUS-treated BHRs than unstressed BHRs. Selectively suppressing CeA-CRH neurons by chemogenetic approach attenuated CUS-induced hypertension and decreased elevated sympathetic outflow in CUS-treated BHRs. Also, CUS significantly decreased protein and mRNA levels of Kv7.2 and Kv7.3 channels in the CeA of BHRs. M-currents in CeA-CRH neurons were significantly decreased in CUS-treated BHRs compared with unstressed BHRs. Blocking Kv7 channel with its blocker XE-991 increased the excitability of CeA-CRH neurons in unstressed BHRs but not in CUS-treated BHRs. Microinjection of XE-991 into the CeA increased sympathetic outflow and ABP in unstressed BHRs but not in CUS-treated BHRs.
CeA-CRH neurons are required for chronic stress-induced sustained hypertension. The hyperactivity of CeA-CRH neurons may be due to impaired Kv7 channel activity, which represents a new mechanism involved in chronic stress-induced hypertension.
慢性应激是高血压发展的一个众所周知的危险因素。然而，其潜在机制尚不清楚。杏仁中央核（CeA）中的促肾上腺皮质释放激素（CRH）神经元参与慢性应激的自主反应。在这里，我们确定了 CeA-CRH 神经元在慢性应激诱导的高血压中的作用。
边缘性高血压大鼠（BHRs）和 Wistar-Kyoto（WKY）大鼠接受慢性不可预测应激（CUS）。评估 CeA-CRH 神经元的放电活动和 M 电流，并使用 CRH-Cre 定向化学遗传方法抑制 CeA-CRH 神经元。CUS 引起 BHRs 的动脉血压（ABP）和心率（HR）持续升高，而在 WKY 大鼠中，CUS 引起的 ABP 和 HR 升高在 CUS 结束后很快恢复到基线水平。与未应激的 BHRs 相比，CUS 处理的 BHRs 中的 CeA-CRH 神经元表现出明显更高的放电活动。通过化学遗传方法选择性抑制 CeA-CRH 神经元可减轻 CUS 诱导的高血压，并降低 CUS 处理的 BHRs 中升高的交感神经输出。此外，CUS 显著降低了 BHRs CeA 中 Kv7.2 和 Kv7.3 通道的蛋白和 mRNA 水平。与未应激的 BHRs 相比，CUS 处理的 BHRs 中的 CeA-CRH 神经元中的 M 电流明显降低。用其阻断剂 XE-991 阻断 Kv7 通道增加了未应激的 BHRs 中 CeA-CRH 神经元的兴奋性，但在 CUS 处理的 BHRs 中则没有。XE-991 微注射到 CeA 中会增加未应激的 BHRs 中的交感神经输出和 ABP，但不会增加 CUS 处理的 BHRs 中的交感神经输出和 ABP。
CeA-CRH 神经元是慢性应激诱导的持续性高血压所必需的。CeA-CRH 神经元的过度活跃可能是由于 Kv7 通道活性受损所致，这代表了慢性应激诱导的高血压涉及的新机制。
