Ma Hongyu, Cui Ziye, Guo Xinqi, Zhao Qiyue, Zhang Ying, Guan Yue, Yang Peiyun, Zhu Huaibing, Wang Sheng, Zhang Xiangjian, Zhang Yi, Pan Hui-Lin, Ma Huijie
Department of Physiology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China.
Department of Physiology, Hebei Medical University, Shijiazhuang, 050017, Hebei, China; Key Laboratory of Neurophysiology of Hebei Province, Shijiazhuang, 050017, Hebei, China.
Neuropharmacology. 2023 Jun 1;230:109506. doi: 10.1016/j.neuropharm.2023.109506. Epub 2023 Mar 15.
Hyperactivity of presympathetic neurons in the hypothalamic paraventricular nucleus (PVN) plays a key role in generating excess sympathetic output in hypertension. However, the mechanisms driving hyperactivity of PVN presympathetic neurons in hypertension are unclear. In this study, we determined the role of corticotropin-releasing factor (CRF) in the PVN in augmented glutamatergic input, neuronal excitability and sympathetic outflow in hypertension. The number of CRF or c-Fos immunoreactive neurons and CRF/c-Fos double-labeled neurons in the PVN was significantly greater in spontaneously hypertensive rats (SHRs) than in normotensive Wistar-Kyoto (WKY) rats. Blocking glutamatergic input reduced the CRF-potentiated excitability of spinally projecting PVN neurons. Furthermore, CRF knockdown via Crispr/Cas9 in the PVN decreased the frequencies of spontaneous firing and miniature excitatory postsynaptic currents (mEPSCs) in spinally projecting PVN neurons in SHRs. In addition, the mRNA and protein levels of CRFR1, but not CRFR2, in the PVN were significantly higher in SHRs than in WKY rats. Blocking CRFR1 with NBI-35965, but not blocking CRFR2 with Antisauvagine-30, reduced the frequencies of spontaneous firing and mEPSCs of spinally projecting PVN neurons in SHRs. Also, microinjection of NBI-35965 into the PVN significantly reduced arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA) in anesthetized SHRs, but not in WKY rats. However, microinjection of Antisauvagine-30 into the PVN had no effect on ABP or RSNA in WKY rats and SHRs. Our findings suggest that endogenous CRF in the PVN potentiates glutamatergic input and firing activity of PVN presympathetic neurons via CRFR1, resulting in augmented sympathetic outflow in hypertension.
下丘脑室旁核（PVN）中交感神经节前神经元的过度活跃在高血压时产生过多交感神经输出中起关键作用。然而，高血压时驱动PVN交感神经节前神经元过度活跃的机制尚不清楚。在本研究中，我们确定了促肾上腺皮质激素释放因子（CRF）在PVN中对高血压时增强的谷氨酸能输入、神经元兴奋性和交感神经输出的作用。自发性高血压大鼠（SHR）PVN中CRF或c-Fos免疫反应性神经元以及CRF/c-Fos双标神经元的数量显著多于正常血压的Wistar-Kyoto（WKY）大鼠。阻断谷氨酸能输入可降低CRF增强的脊髓投射PVN神经元的兴奋性。此外，通过Crispr/Cas9在PVN中敲低CRF可降低SHR脊髓投射PVN神经元的自发放电频率和微小兴奋性突触后电流（mEPSC）。此外，SHR的PVN中CRFR1而非CRFR2的mRNA和蛋白水平显著高于WKY大鼠。用NBI-３５９６５阻断CRFR1，但不用抗 sauvagine-30阻断CRFR2，可降低SHR脊髓投射PVN神经元的自发放电频率和mEPSC。同样，向PVN微量注射NBI-３５９６５可显著降低麻醉SHR的动脉血压（ABP）和肾交感神经活动（RSNA），但对WKY大鼠无此作用。然而，向PVN微量注射抗sauvagine-30对WKY大鼠和SHR的ABP或RSNA均无影响。我们的研究结果表明，PVN中的内源性CRF通过CRFR1增强PVN交感神经节前神经元的谷氨酸能输入和放电活动，导致高血压时交感神经输出增加。
