Reeves Stephen R, Gozal David
Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louiseville, KY 40202, USA
Exp Physiol. 2007 Nov;92(6):1057-66. doi: 10.1113/expphysiol.2007.038489. Epub 2007 Aug 3.
Protein kinase C (PKC) is a broadly expressed and critically important signalling protein with a wide range of functional roles, including central components of respiratory control. For example, systemic and targeted administration of PKC inhibitors within the nucleus of the solitary tract (nTS) markedly attenuates peak hypoxic ventilatory responses (HVR). Protein kinase C activation in phrenic motor nucleus has also been implicated in some forms of acute respiratory plasticity, such as phrenic long-term facilitation (pLTF), a persistent enhancement of phrenic motor output following acute intermittent hypoxia. To further examine the role of PKC within the nTS, the selective PKC antagonist bisindolylmaleimide I (BIM I) was microinjected in the area corresponding to the nTS via bilateral osmotic pumps in normoxic adult male Sprague-Dawley rats; control animals received bisindolylmaleimide V (BIM V, inactive analogue). In one series of experiments, hypoxic challenges (fractional inspired ) were conducted in unrestrained animals (n = 8 per group). No differences in baseline ventilation emerged; however, peak HVR was attenuated following BIM I (P < 0.01), primarily owing to reductions in respiratory frequency increases (P < 0.01). In a second series of experiments, integrated phrenic nerve activity was recorded in anaesthetized, vagotomized, paralysed and ventilated rats exposed to three 5 min hypoxic episodes separated by 5 min hyperoxia . During baseline conditions, no differences emerged in phrenic nerve output; however, phrenic nerve output measured during the initial hypoxic exposure was significantly attenuated in BIM I-treated rats (P < 0.01). In contrast, both groups of animals displayed significant pLTF (BIM I versus BIM V; n.s.). Thus, we conclude that PKC activation within the nTS is critically involved in the central response to acute hypoxia, but does not appear to play a role in either eliciting or maintaining pLTF.
蛋白激酶C（PKC）是一种广泛表达且至关重要的信号蛋白，具有多种功能作用，包括呼吸控制的核心组成部分。例如，在孤束核（nTS）内全身和靶向给予PKC抑制剂会显著减弱峰值低氧通气反应（HVR）。膈运动核中的蛋白激酶C激活也与某些形式的急性呼吸可塑性有关，如膈神经长期易化（pLTF），即急性间歇性低氧后膈运动输出的持续增强。为了进一步研究PKC在nTS中的作用，在常氧成年雄性Sprague-Dawley大鼠中，通过双侧渗透泵将选择性PKC拮抗剂双吲哚基马来酰亚胺I（BIM I）微量注射到对应于nTS的区域；对照动物接受双吲哚基马来酰亚胺V（BIM V，无活性类似物）。在一系列实验中，对未束缚的动物（每组n = 8）进行低氧刺激（吸入分数）。基线通气无差异；然而，BIM I处理后峰值HVR减弱（P < 0.01），主要是由于呼吸频率增加的减少（P < 0.01）。在第二系列实验中，在麻醉、迷走神经切断、麻痹和通气的大鼠中记录膈神经综合活动，这些大鼠暴露于三个5分钟的低氧发作，中间间隔5分钟的高氧。在基线条件下，膈神经输出无差异；然而，在BIM I处理的大鼠中，首次低氧暴露期间测量的膈神经输出显著减弱（P < 0.01）。相比之下，两组动物均显示出显著的pLTF（BIM I与BIM V比较；无显著性差异）。因此，我们得出结论，nTS内的PKC激活在对急性低氧的中枢反应中起关键作用，但似乎在引发或维持pLTF中不起作用。
