REGULATION OF MUSCLE BLOOD FLOW IN OLDER WOMEN AND MEN

描述（由申请人提供）：本研究的长期目标是确定人类衰老对运动骨骼肌血流调节的影响及其对功能能力的影响。我们以前的研究产生了新的结果，表明在健康的老年女性和男性中，大肌肉运动（腿部自行车）期间活动肌肉血流量的调节随着年龄的变化而改变。具体而言，老年女性表现出的证据，一个显着的限制，在腿部血管舒张在次极量运动，而在老年男性有证据表明，腿部血管收缩反应增强。这些性别特异性改变可能会损害老年人满足日常功能和代谢需求的能力。这项修订后的竞争性更新的目标是调查负责这些年龄和性别特异性改变的中央和地方机制。具体目标1将确定在非耐力训练的老年女性和男性中，中枢机制（心输出量）在次极量运动期间限制腿部灌注的程度。在腿部血液供应受限的情况下，中央（腿部循环）或外周（单膝伸肌运动或腿部循环+通过盐水输注增强心脏前负荷），我们假设老年女性将表现出腿部血管舒张的限制，而老年男性将表现出心输出量和腿部血管舒张之间的平衡改变，相对于年轻人，分别。具体目标2将定义局部机制，负责运动腿部血流动力学随年龄的性别差异。这一系列的研究将检查腿部动脉血管的结构和机械性能（假设2），减少的影响（假设3）和增强（假设4A：缺血性握力，IHG）运动期间腿部充血、内皮介导的血管舒张的交感神经调节（假设4 B;联合NO/PG阻断），以及这些机制在调节腿部运动充血中的相互作用（假设4C; NO/PG阻断+ IHG）。根据初步结果，我们预测，与男性相比，女性腿部内皮介导的血管舒张和血管顺应性将有更大的年龄相关性降低。我们将通过测量全身和腿部血流来研究这些目的（多普勒超声）、动脉压（股动脉导管或臂袖）和局部氧合（NIRS）在年轻（20-30岁）及以上（60-75岁）的男性和女性在腿部锻炼，适当考虑年龄和性别差异的腿部肌肉质量（DXA），股四头肌力量，和腿部动脉结构（峰值小腿传导性、动态动脉顺应性）。这些研究的结果将通过定义运动期间腿部血流调节的年龄和性别差异的中央和局部机制来扩展先前奖项的发现，从而为未来旨在优化老年女性和男性肌肉血液供应和功能能力的干预性研究奠定基础。

DESCRIPTION (provided by applicant): The long-range goal of this research is to determine the effects of human aging on the regulation of blood flow to exercising skeletal muscles and its consequent impact on functional capacity. Our previous studies yielded novel results suggesting that the regulation of active muscle blood flow during large muscle exercise (leg cycling) is altered with age in healthy older women and men. Specifically, older women exhibit evidence of a significant limitation to vasodilation in the legs during submaximal exercise; whereas in older men there is evidence for augmented leg vasoconstrictor responsiveness. These sex-specific alterations could impair the ability of older adults to meet daily functional and metabolic demands. The goals of this revised competitive renewal are to investigate the central and local mechanisms responsible for these age and sex-specific alterations. Specific Aim 1 will determine the extent to which central mechanisms (cardiac output) limit leg perfusion during submaximal exercise in non-endurance trained older women and men. During conditions in which blood supply to the leg is limited centrally (leg cycling) or peripherally (single knee extensor exercise or leg cycling+augmented cardiac preload via saline infusion), we hypothesize that older women will exhibit a limit to leg vasodilation, whereas older men will demonstrate an altered balance between cardiac output and leg vasodilation, relative to their younger counterparts, respectively. Specific Aim 2 will define the local mechanisms responsible for sex differences in exercising leg hemodynamics with aging. This series of studies will examine structural and mechanical properties of the leg arterial vasculature (hypothesis 2), the effects of diminished (hypothesis 3) and enhanced (hypothesis 4A: ischemic handgrip, IHG) sympathetic modulation of leg hyperemia, endothelium-mediated vasodilation during exercise (hypothesis 4B; combined NO/PG blockade), and the interaction of these mechanisms in regulating leg exercise hyperemia (hypothesis 4C; NO/PG blockade + IHG). Based on preliminary results, we predict that women will have greater age-associated reductions in endothelium-mediated vasodilation and vascular compliance in the legs compared to men. We will investigate these aims by measuring systemic and leg blood flow (Doppler ultrasound), arterial pressure (femoral catheter or brachial cuff) and local oxygenation (NIRS) in younger (20-30 yr) and older (60-75 yr) men and women during leg exercise, with appropriate consideration for age and sex differences in leg muscle mass (DXA), quadriceps strength, and leg arterial structure (peak calf conductance, dynamic arterial compliance). The results of these studies will extend the findings from the previous award by defining the central and local mechanisms underlying age- and sex-differences in leg blood flow regulation during exercise, thereby setting the stage for future interventional studies aimed at optimizing muscle blood supply and functional capacity in older women and men.