Huang Bing S, White Roselyn A, Leenen Frans H H
Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
Am J Physiol Regul Integr Comp Physiol. 2012 Jul 15;303(2):R236-45. doi: 10.1152/ajpregu.00381.2011. Epub 2012 May 30.
In Dahl salt-sensitive (S) rats, Na(+) entry into the cerebrospinal fluid (CSF) and sympathoexcitatory and pressor responses to CSF Na(+) are enhanced. Salt-inducible kinase 1 (SIK1) increases Na(+)/K(+)-ATPase activity in kidney cells. We tested the possible role of SIK1 in regulation of CSF [Na(+)] and responses to Na(+) in the brain. SIK1 protein and activity were lower in hypothalamic tissue of Dahl S (SS/Mcw) compared with salt-resistant SS.BN13 rats. Intracerebroventricular infusion of the protein kinase inhibitor staurosporine at 25 ng/day, to inhibit SIK1 further increased mean arterial pressure (MAP) and HR but did not affect the increase in CSF [Na(+)] or hypothalamic aldosterone in Dahl S on a high-salt diet. Intracerebroventricular infusion of Na(+)-rich artificial CSF caused significantly larger increases in renal sympathetic nerve activity, MAP, and HR in Dahl S vs. SS.BN13 or Wistar rats on a normal-salt diet. Intracerebroventricular injection of 5 ng staurosporine enhanced these responses, but the enhancement in Dahl S rats was only one-third that in SS.BN13 and Wistar rats. Staurosporine had no effect on MAP and HR responses to intracerebroventricular ANG II or carbachol, whereas the specific protein kinase C inhibitor GF109203X inhibited pressor responses to intracerebroventricular Na(+)-rich artificial CSF or ANG II. These results suggest that the SIK1-Na(+)/K(+)-ATPase network in neurons acts to attenuate sympathoexcitatory and pressor responses to increases in brain [Na(+)]. The lower hypothalamic SIK1 activity and smaller effect of staurosporine in Dahl S rats suggest that impaired activation of neuronal SIK1 by Na(+) may contribute to their enhanced central responses to sodium.
在 Dahl 盐敏感（S）大鼠中，钠离子进入脑脊液（CSF）以及对脑脊液钠离子的交感神经兴奋和升压反应增强。盐诱导激酶 1（SIK1）可增加肾细胞中的钠钾 ATP 酶活性。我们测试了 SIK1 在调节脑脊液[Na⁺]以及大脑对钠离子反应中的可能作用。与盐抵抗的 SS.BN13 大鼠相比，Dahl S（SS/Mcw）大鼠下丘脑组织中的 SIK1 蛋白和活性较低。每天脑室内注入 25 ng 蛋白激酶抑制剂星形孢菌素以进一步抑制 SIK1，可使高盐饮食的 Dahl S 大鼠的平均动脉压（MAP）和心率进一步升高，但不影响脑脊液[Na⁺]的升高或下丘脑醛固酮水平。在正常盐饮食条件下，脑室内注入富含钠离子的人工脑脊液会使 Dahl S 大鼠的肾交感神经活动、MAP 和心率的升高幅度明显大于 SS.BN13 或 Wistar 大鼠。脑室内注射 5 ng 星形孢菌素可增强这些反应，但 Dahl S 大鼠的增强幅度仅为 SS.BN13 和 Wistar 大鼠的三分之一。星形孢菌素对脑室内注射血管紧张素 II 或卡巴胆碱引起的 MAP 和心率反应无影响，而特异性蛋白激酶 C 抑制剂 GF109203X 可抑制对脑室内富含钠离子的人工脑脊液或血管紧张素 II 的升压反应。这些结果表明，神经元中的 SIK1 - 钠钾 ATP 酶网络可减弱对脑内[Na⁺]升高的交感神经兴奋和升压反应。Dahl S 大鼠下丘脑 SIK1 活性较低以及星形孢菌素的作用较小，提示钠离子对神经元 SIK1 的激活受损可能导致它们对钠的中枢反应增强。
