Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan; and
Department of Advanced Cardiovascular Regulation and Therapeutics, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
Am J Physiol Heart Circ Physiol. 2015 Mar 1;308(5):H530-9. doi: 10.1152/ajpheart.00586.2014. Epub 2014 Dec 19.
The cardiac sympathetic afferent (CSA), which plays an important role in heart-brain communication for sympathoexcitation, is stimulated in heart failure. Additionally, high salt intake leads to further sympathoexcitation due to activation of hypothalamic epithelial Na(+) channels (ENaCs) in heart failure. In the present study, we stimulated the CSA in adult male mice by epicardial application of capsaicin and using ethanol as a control to determine whether CSA stimulation led to activation of hypothalamic ENaCs, resulting in salt-induced sympathoexcitation. Three days after capsaicin treatment, an upregulation of hypothalamic α-ENaCs, without activation of mineralocorticoid receptors, was observed. We also examined expression levels of the known ENaC activator TNF-α. Hypothalamic TNF-α increased in capsaicin-treated mice, whereas intracerebroventricular infusion of the TNF-α blocker etanercept prevented capsaicin-induced upregulation of α-ENaCs. To examine brain arterial pressure (AP) sensitivity toward Na(+), we performed an intracerebroventricular infusion of high Na(+)-containing (0.2 M) artificial cerebrospinal fluid. AP and heart rate were significantly increased in capsaicin-treated mice compared with control mice. CSA stimulation also caused excitatory responses with high salt intake. Compared with a regular salt diet, the high-salt diet augmented AP, heart rate, and 24-h urinary norepinephrine excretion, which is an indirect marker of sympathetic activity with mineralocorticoid receptor activation, in capsaicin-treated mice but not in ethanol-treated mice. Treatment with etanercept or the ENaC blocker benzamil prevented these salt-induced excitatory responses. In summary, we show that CSA stimulation leads to an upregulation of hypothalamic α-ENaCs mediated via an increase in TNF-α and results in increased salt sensitivity.
心脏交感传入神经（CSA）在心脏-大脑通讯中起重要作用，可引起交感兴奋。心力衰竭时 CSA 被刺激。此外，由于心力衰竭时下丘脑上皮钠通道（ENaC）的激活，高盐摄入导致进一步的交感兴奋。在本研究中，我们通过心外膜应用辣椒素来刺激成年雄性小鼠的 CSA，并使用乙醇作为对照，以确定 CSA 刺激是否导致下丘脑 ENaC 激活，从而导致盐诱导的交感兴奋。在辣椒素处理 3 天后，观察到下丘脑 α-ENaC 的上调，而没有激活盐皮质激素受体。我们还检查了已知的 ENaC 激活剂 TNF-α的表达水平。下丘脑 TNF-α在辣椒素处理的小鼠中增加，而脑室内输注 TNF-α阻断剂依那西普可防止辣椒素诱导的 α-ENaC 上调。为了检查对 Na+的脑动脉压（AP）敏感性，我们进行了含有高 Na+（0.2 M）的人工脑脊液的脑室内输注。与对照小鼠相比，辣椒素处理的小鼠的 AP 和心率显着增加。CSA 刺激也会引起高盐摄入的兴奋性反应。与常规盐饮食相比，高盐饮食增加了 CAP 处理的小鼠的 AP、心率和 24 小时尿去甲肾上腺素排泄，这是一种间接标记物，可反映交感神经活动和盐皮质激素受体的激活，而在乙醇处理的小鼠中则没有。依那西普或 ENaC 阻滞剂苯唑胺的治疗可防止这些盐诱导的兴奋反应。总之，我们表明 CSA 刺激导致下丘脑 α-ENaC 的上调，这是通过 TNF-α的增加介导的，导致盐敏感性增加。
