Exercise Science, Health and Physical Education Department, Michigan Technological University, Houghton, Michigan; USA.
J Neurophysiol. 2010 Nov;104(5):2329-37. doi: 10.1152/jn.01013.2009. Epub 2010 Aug 18.
Although evidence indicates that activation of presympathetic paraventricular nucleus (PVN) neurons contributes to the pathogenesis of salt-sensitive hypertension, the underlying cellular mechanisms are not fully understood. Recent evidence indicates that small conductance Ca(2+)-activated K(+) (SK) channels play a significant role in regulating the excitability of a key group of sympathetic regulatory PVN neurons, those with axonal projections to the rostral ventrolateral medulla (RVLM; i.e., PVN-RVLM neurons). In the present study, rats consuming a high salt (2% NaCl) diet were made hypertensive by systemic infusion of angiotensin II (AngII), and whole cell patch-clamp recordings were made in brain slice from retrogradely labeled PVN-RVLM neurons. To determine if the amplitude of SK current was altered in neurons from hypertensive rats, voltage-clamp recordings were performed to isolate SK current. Results indicate that SK current amplitude (P < 0.05) and density (P < 0.01) were significantly smaller in the hypertensive group. To investigate the impact of this on intrinsic excitability, current-clamp recordings were performed in separate groups of PVN-RVLM neurons. Results indicate that the frequency of spikes evoked by current injection was significantly higher in the hypertensive group (P < 0.05-0.01). Whereas bath application of the SK channel blocker apamin significantly increased discharge of neurons from normotensive rats (P < 0.05-0.01), no effect was observed in the hypertensive group. In response to ramp current injections, subthreshold depolarizing input resistance was greater in the hypertensive group compared with the normotensive group (P < 0.05). Blockade of SK channels increased depolarizing input resistance in normotensive controls (P < 0.05) but had no effect in the hypertensive group. On termination of current pulses, a medium afterhyperpolarization potential (mAHP) was observed in most neurons of the normotensive group. In the hypertensive group, the mAHP was either small or absent. In the latter case, an afterdepolarization potential (ADP) was observed that was unaffected by apamin. Apamin treatment in the normotensive group blocked the mAHP and revealed an ADP resembling that seen in the hypertensive group. We conclude that diminished SK current likely underlies the absence of mAHPs in PVN-RVLM neurons from hypertensive rats. Both the ADP and greater depolarizing input resistance likely contribute to increased excitability of PVN-RVLM neurons from rats with AngII-Salt hypertension.
尽管有证据表明，交感节前室旁核（PVN）神经元的激活有助于盐敏感高血压的发病机制，但其中的细胞机制尚不完全清楚。最近的证据表明，小电导钙激活钾（SK）通道在调节一组关键的交感调节性 PVN 神经元的兴奋性方面起着重要作用，这些神经元的轴突投射到延髓头端腹外侧区（RVLM；即，PVN-RVLM 神经元）。在本研究中，通过向大鼠系统输注血管紧张素 II（AngII）使食用高盐（2%NaCl）饮食的大鼠产生高血压，并从逆行标记的 PVN-RVLM 神经元的脑片中进行全细胞膜片钳记录。为了确定高血压大鼠神经元中 SK 电流的幅度是否发生改变，进行了电压钳记录以分离 SK 电流。结果表明，高血压组 SK 电流幅度（P<0.05）和密度（P<0.01）显著减小。为了研究这对内在兴奋性的影响，在单独的 PVN-RVLM 神经元组中进行了电流钳记录。结果表明，高血压组中由电流注入引起的尖峰频率明显更高（P<0.05-0.01）。虽然 SK 通道阻滞剂 apamin 的浴液应用显著增加了正常血压大鼠神经元的放电（P<0.05-0.01），但在高血压组中没有观察到这种作用。在响应斜坡电流注入时，高血压组的亚阈值去极化输入电阻大于正常血压组（P<0.05）。SK 通道阻断剂增加了正常血压对照组的去极化输入电阻（P<0.05），但在高血压组中没有作用。在电流脉冲终止时，大多数正常血压组的神经元中都观察到一个中期后超极化电位（mAHP）。在高血压组中，mAHP 要么很小，要么不存在。在后一种情况下，观察到一个后去极化电位（ADP），apamin 对此没有影响。apamin 处理在正常血压组中阻断了 mAHP 并揭示了类似于高血压组中观察到的 ADP。我们得出结论，SK 电流的减少可能是高血压大鼠 PVN-RVLM 神经元中 mAHP 缺失的原因。ADP 和更大的去极化输入电阻都可能导致 AngII-盐高血压大鼠的 PVN-RVLM 神经元兴奋性增加。
