POTASSIUM CHANNELS AND CEREBRAL HEMODYNAMICS AFTER BRAIN

创伤性伤害是婴儿和儿童死亡的主要原因，头部受伤的死亡率大大增加。虽然对成人脑损伤的影响已经进行了广泛的研究，但对新生儿/婴儿脑损伤的研究却很少。先前的数据显示，新生儿与幼猪相比，大脑血液下降和动脉收缩更多，这支持了新生儿对脑损伤非常敏感的观点。此外，对几种一氧化氮依赖性扩张器刺激的反应在损伤后迟钝或逆转为收缩。血管舒张可通过多种机制介导，包括生理条件下脑血管控制中的cGMP、cAMP和K+通道，但其在病理条件下的作用尚不清楚。这一建议是基于初步数据，内源性和合成的K+通道激活剂在脑损伤后的扩张被钝化。因此，本研究提出的假设是，脑损伤后，K+通道功能受损导致脑血流动力学改变，导致脑血管功能和神经元病理受损。为了解决这一假设，将追求三个具体目标：1)表征脑损伤对K+通道活性的影响，作为年龄和时间的函数；2)确定脑损伤后K+通道活性改变的机制，作为年龄和时间的函数；3)确定脑损伤后K+通道功能受损与脑血流动力学改变之间关系的功能意义，作为年龄和时间的函数。封闭颅窗技术将应用于新生猪和幼猪，测量头动脉直径，收集脑脊液，通过放射免疫分析血管活性代谢物。脑损伤的组织化学和免疫组织化学指标，如甲酚紫和微管相关蛋白2，将用于表征新生儿和幼猪脑损伤的影响。这些研究可能会导致脑损伤儿童的治疗方法。

Traumatic injury is the leading cause of death of infants and children and mortality is greatly increased in the presence of head injury. While the effects of brain injury have been investigated extensively in the adult, less is known about brain injury in the newborn/infant. Previous data have shown that cerebral blood fell and pial arteries constricted more in newborn vs. juvenile pigs, supporting the idea that the newborn is exquisitely sensitive to brain injury. Additionally, responses to several nitric oxide dependent dilator stimuli were either blunted or reversed to constricted following the insult. Relaxation of blood vessels can be mediated by several mechanisms, including cGMP, cAMP, and K+ channels in cerebrovascular control under physiologic conditions, less is known concerning their contributions under pathologic conditions. This proposal is based on preliminary data that dilation by endogenous and synthetic K+ channel activators are blunted after brain injury. Therefore, the hypothesis is addressed by the proposed research is that impaired K+ channel function contributes to altered cerebral hemodynamics resulting in impaired cerebrovascular function and neuronal pathology following brain injury. To address this hypothesis, three specific aims will be pursued: 1) characterize the effect of brain injury on K+ channel activity as a function of age and time, 2) determine the mechanism of altered K+ channel activity following brain injury as a function of age and time and 3) determine the functional significance of the relationship between impaired K+ channel function and altered cerebral hemodynamics following brain injury as a function of age and time. The close cranial window technique will be use din newborn and juvenile pigs to measure pial artery diameter and collect CSF for vasoactive metabolite analysis via radioimmunoassay. Histochemical and immunohistochemical indices of brain damage such as cresyl violet and microtuble associated protein 2 will be used to characterize the effects of brain injury in the newborn and juvenile pig. These studies may lead to therapies for brain injured children.