Cerebrovascular Dysfunction in Insulin Resistance

描述（由申请人提供）：胰岛素抵抗（IR）与血管功能障碍和中风有关。然而，对脑循环的影响完全未被探索。我们对IR大鼠分离的外周动脉和大脑动脉的研究结果得出以下假设：IR损害了脑循环中正常的血管扩张机制，从而加剧了中风引起的神经损伤的可能性。我们设定了3个具体目标：IR对离体脑动脉扩张剂刺激反应性影响的研究。我们将：首先，使用药理学探针检查IR对内皮依赖性扩张剂特性的影响；第二，研究IR对血管平滑肌功能的影响；第三，确定IR对动脉生理刺激反应性的影响；第四，确定停止果糖喂养后是否恢复正常的脑血管功能。具体目标2。IR中紊乱脑血管控制机制的阐明。我们将：首先，检查内皮源性因子对动脉扩张的药理和生理刺激的贡献；第二，研究IR是否影响花生四烯酸和l -精氨酸的血管代谢；第三，确定IR是否影响动脉对花生四烯酸或l -精氨酸代谢物的反应；第四，研究IR对血管平滑肌atp敏感通道或钙活化钾通道的影响；第五，确定内皮介导的扩张系统的药理学增强是否能恢复IR大鼠的正常血管功能。具体目标3。IR对实验性脑卒中后神经损伤程度影响的研究。我们将：首先，研究IR对实验性脑卒中后脑损伤的影响；其次，确定IR动物脑卒中后脑血管扩张能力受损在介导梗死体积增加中的作用；第三，确定停止果糖喂养是否能改善中风后的预后；第四，确定内皮介导的扩张系统的药理学增强是否可以预防IR大鼠的中风；第五，评估新型氧自由基清除剂减轻IR大鼠中风神经损伤的能力。我们相信，我们的研究将产生新的重要发现，这将导致改善治疗方法，以降低IR患者的发病率和死亡率。

DESCRIPTION (provided by applicant): Insulin Resistance (IR) is associated with vascular dysfunction and strokes. However, effects on the cerebral circulaton are completely unexplored. Our findings from isolated peripheral and cerebral arteries from IR rats have lead to the following hypothesis: IR impairs normal vascular dilator mechanisms in the cerebral circulaton and thereby exacerbates the potential for neurological damage due to stroke. We have created 3 specific aims: Specific Aim 1. Examination of effects of IR on responsiveness to dilator stimuli in isolated cerebral arteries. We will: First, examine effects of IR on endothelium-dependent dilator properties using pharmacological probes; Second, examine effects of IR on vascular smooth muscle function; Third, determine the effects of IR on arterial responsiveness to physiological stimuli; Fourth, determine whether restoration of normal cerebral vascular function is present after cessation of fructose feeding. Specific Aim 2. Elucidation of mechanisms of deranged cerebrovascular control mechanisms in IR. We will: First, examine the contributions of endothelium-derived factors to arterial dilation to pharmacological and physiological stimuli; Second, examine whether IR affects the vascular metabolism of arachidonic acid and L-arginine; Third, determine whether IR affects arterial responses to arachidonic acid or L-arginine metabolites; Fourth, examine effects of IR on vascular smooth muscle ATP-sensitive or calcium-activated potassium channels; Fifth, determine whether pharmacological augmentation of an endothelial-mediated dilator system restores normal vascular function in IR rats. Specific Aim 3. Examination of effects of IR on extent of neurological injury following experimental strokes. We will: First, examine effects of IR on brain injury after experimental strokes; Second, determine the role of impaired cerebral vascular dilator capacity in mediating enhanced infarct volume after stroke in IR animals; Third, determine whether cessation of fructose feeding improves outcome after stroke; Fourth, determine whether pharmacological augmentation of an endothelial-mediated dilator system protects against stroke in IR rats; Fifth, assess the ability of novel scavengers of oxygen free radicals to lessen neurological injury to stroke in IR rats. We believe that our studies will result in new and important findings that will lead to improved therapies to reduce morbidity and mortality in IR individuals.