Gozal D, Graff G R, Torres J E, Khicha S G, Nayak G S, Simakajornboon N, Gozal E
Constance S. Kaufman Pediatric Pulmonary Research Laboratory, Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
J Appl Physiol (1985). 1998 Feb;84(2):641-8. doi: 10.1152/jappl.1998.84.2.641.
Although protein kinase C (PKC) is an essential component of multiple neurally mediated events, its role in respiratory control remains undefined. The ventilatory effects of a systemically active PKC inhibitor (Ro-32-0432; 100 mg/kg i.p.) were assessed by whole body plethysmography during normoxia, hypoxia (10% O2), and hyperoxia (100% O2) in unrestrained Sprague-Dawley rats. A sustained expiratory time increase occurred within 8-10 min of injection in room air[mean 44.8 +/- 5.2 (SE) % ], was similar to expiratory time prolongations after Ro-32-0432 administration during 100% O2 (45.5 +/- 8.1%; not significant), and was associated with mild minute ventilation (VE) decreases. Hypercapnic ventilatory responses (5% CO2) remained unchanged after Ro-32-0432. During 10% O2, VE increased from 122.6 +/- 15.6 to 195.7 +/- 10.1 ml/min in vehicle-treated rats (P < 0.001). In contrast, marked attenuation of VE hypoxic responses occurred after Ro-32-0432 [86.2 +/- 6.2 ml/min in room air to 104.1 +/- 7.1 ml/min in 10% O2; pre- vs. post-Ro32-0432, P < 0.001 (analysis of variance)]. Overall, PKC activity was reduced and increases with hypoxia were abolished in the particulate subcellular fraction of brain tissue after Ro-32-0432 treatment, indicating that this compound readily crosses the blood-brain barrier. We conclude that systemic PKC inhibition elicits significant centrally mediated expiratory prolongations and ventilatory reductions as well as blunted ventilatory responses to hypoxia but not to hypercapnia. We postulate that PKC plays an important role in signal transduction pathways within brain regions underlying respiratory control.
尽管蛋白激酶C（PKC）是多种神经介导事件的重要组成部分，但其在呼吸控制中的作用仍不明确。通过全身体积描记法，在无束缚的Sprague-Dawley大鼠处于常氧、低氧（10% O₂）和高氧（100% O₂）状态下，评估了一种全身活性PKC抑制剂（Ro-32-0432；100 mg/kg腹腔注射）的通气效应。在室内空气中注射后8 - 10分钟内出现持续的呼气时间延长[平均值为44.8 +/- 5.2（标准误）%]，这与在100% O₂期间给予Ro-32-0432后的呼气时间延长情况相似（45.5 +/- 8.1%；无显著差异），并且与轻微的分钟通气量（VE）降低相关。Ro-32-0432给药后高碳酸通气反应（5% CO₂）保持不变。在10% O₂期间，给予溶剂的大鼠的VE从122.6 +/- 15.6增加到195.7 +/- 10.1 ml/分钟（P < 0.001）。相比之下，Ro-32-0432给药后VE低氧反应明显减弱[在室内空气中为86.2 +/- 6.2 ml/分钟，在10% O₂中为104.1 +/- 7.1 ml/分钟；Ro-32-0432给药前与给药后相比，P < 0.001（方差分析）]。总体而言，Ro-32-0432治疗后，脑组织颗粒亚细胞组分中的PKC活性降低，并且低氧引起的PKC活性增加被消除，这表明该化合物很容易穿过血脑屏障。我们得出结论，全身性PKC抑制会引发显著的中枢介导的呼气延长和通气减少，以及对低氧而非高碳酸的通气反应减弱。我们推测PKC在呼吸控制相关脑区的信号转导通路中起重要作用。
