Nishihara Masaaki, Takesue Ko, Hirooka Yoshitaka
Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Department of Advanced Cardiovascular Regulation and Therapeutics for Cardiovascular Diseases, Kyushu University Center for Disruptive Cardiovascular Medicine, Fukuoka, Japan.
Auton Neurosci. 2017 May;204:88-97. doi: 10.1016/j.autneu.2016.09.018. Epub 2016 Oct 4.
Sympathoexcitation plays an important role in the pathogenesis of hypertension in patients with chronic kidney disease (CKD). The paraventricular nucleus of the hypothalamus (PVN) in the brain controls sympathetic outflow through γ-amino butyric acid (GABA)-ergic mechanisms. Renal denervation (RDN) exerts a long-term antihypertensive effect in hypertension with CKD; however, the effects of RDN on sympathetic nerve activity and GABA-ergic modulation in the PVN are not clear. We aimed to elucidate whether RDN modulates sympathetic outflow through GABA-ergic mechanisms in the PVN in hypertensive mice with CKD.
In 5/6-nephrectomized male Institute of Cancer Research mice (Nx) at 4 weeks after nephrectomy, systolic blood pressure (SBP) was significantly increased, accompanied by sympathoexcitation. The Nx-mice underwent RDN or sham operation, and the mice were divided into three groups (Control, Nx-Sham, and Nx-RDN). At 2 weeks after RDN, SBP was significantly decreased and urinary sodium excretion was increased in Nx-RDN compared with Nx-Sham. Urinary norepinephrine excretion (uNE) levels did not differ significantly between Nx-RDN and Nx-Sham. At 6 weeks after RDN, SBP continued to decrease and uNE levels also decreased in Nx-RDN compared with Nx-Sham. Bicuculline microinjection into the PVN increased mean arterial pressure and lumbar sympathetic nerve activity in all groups. The pressor responses and change in lumbar sympathetic nerve activity were significantly attenuated in Nx-Sham, but were enhanced in Nx-RDN at 6 weeks after RDN.
The findings from the present study indicate that RDN has a prolonged antihypertensive effect and, at least in the late phase, decreases sympathetic nerve activity in association with enhanced GABA-ergic input into the PVN in mice with CKD.
交感神经兴奋在慢性肾脏病（CKD）患者高血压发病机制中起重要作用。大脑下丘脑室旁核（PVN）通过γ-氨基丁酸（GABA）能机制控制交感神经输出。肾去神经支配（RDN）对CKD高血压患者有长期降压作用；然而，RDN对PVN交感神经活动和GABA能调节的影响尚不清楚。我们旨在阐明RDN是否通过CKD高血压小鼠PVN中的GABA能机制调节交感神经输出。
在5/6肾切除的雄性癌症研究所小鼠（Nx）肾切除术后4周，收缩压（SBP）显著升高，伴有交感神经兴奋。对Nx小鼠进行RDN或假手术，并将小鼠分为三组（对照组、Nx-假手术组和Nx-RDN组）。RDN术后2周，与Nx-假手术组相比，Nx-RDN组SBP显著降低，尿钠排泄增加。Nx-RDN组与Nx-假手术组尿去甲肾上腺素排泄（uNE）水平无显著差异。RDN术后6周，与Nx-假手术组相比，Nx-RDN组SBP持续降低，uNE水平也降低。向PVN微量注射荷包牡丹碱可使所有组的平均动脉压和腰交感神经活动增加。在RDN术后6周，Nx-假手术组的升压反应和腰交感神经活动变化显著减弱，但Nx-RDN组增强。
本研究结果表明，RDN具有持久的降压作用，至少在晚期，可降低CKD小鼠的交感神经活动，同时增强PVN的GABA能输入。
