Mechanisms for impaired short-term control of blood pressure with obesity

项目摘要 Ann M.施赖霍费尔 肥胖损害自主神经反射对平均动脉压（MAP）的短期调节， MAP的不稳定性。与高血压无关，MAP变异性增加是高血压的主要危险因素。 终末器官损伤和中风改善高血压但不增加MAP变异性的治疗 使患者处于不利心血管结果的风险中。该项目使用肥胖Zucker大鼠（OZR）， 确定细胞和系统机制，产生改变自主反射的设置 代谢综合征像肥胖的人一样，成年OZR变得高胰岛素血症，血糖控制不良。 他们还发展交感神经驱动的高血压，交感神经的压力反射控制减弱 活动（SNA）和心率（HR）与瘦Zucker大鼠相比。处理的其他交感神经抑制反射 通过孤束核（NTS）也受到损害，在成年OZR，符合发展 减少对NTS的神经递质激活的生理反应。相反， 延髓头端腹外侧区（RVLM）产生与发作一致的增强的生理反应 交感神经兴奋性反射增强后一种情况的发生独立于受损的压力反射 也增加了MAP变异性。成年男性高血压或血糖控制受损的改善 OZR各自部分恢复HR的压力反射控制，尽管NTS功能和其他交感神经功能的命运。 抑制性反射是未知的。此外，这些治疗是否也抑制了RVLM的增加， 激活和交感神经兴奋性反射是未知的。女性OZR会出现代谢综合征，但 受损的压力感受性反射出现较晚，远远超过高血压的发展。治疗的功效 在男性中使用，而在女性OZR中NTS、RVLM和其他交感神经反射的功能尚不清楚。 中心假设：在雄性OZR中，血糖控制不良抑制了NTS神经元的多巴胺能激活 接受迷走神经输入，损害交感神经抑制反射，这种状态会因高血压而加剧。 此外，我们推测，同时摄入过量的盐与暴食增强 RVLM的激活产生可进一步使MAP不稳定的过度交感神经兴奋性反射。 虽然雌性大鼠可能会产生盐诱导的RVLM致敏，但我们假设雌激素增强了RVLM的致敏性。 NTS功能对抗代谢综合征早期阶段的交感神经抑制反射损伤。 我们建议确定肥胖如何影响单独记录的NTS和RVLM神经元对 输入从周边和前脑在男性和女性OZR相比，年龄匹配的LZR。我们还将 确定减少盐摄入、血糖控制不良或MAP是否会改变NTS和RVLM功能 与OZR中交感神经反射的恢复一致。该项目将为肥胖症提供新的见解- 相关的自主神经功能缺损，并确定高血压和高血糖的标准治疗是否 足以恢复改变的脑干功能和交感神经反射，这些在临床上没有评估。

Project Summary Ann M. Schreihofer Obesity impairs short-term regulation of mean arterial pressure (MAP) by autonomic reflexes, contributing to the destabilization of MAP. Independent of hypertension, increased variability of MAP is a major risk factor for end organ damage and stroke. Treatments that ameliorate hypertension but not elevated variability of MAP leave patients at risk for adverse cardiovascular outcomes. This project uses obese Zucker rats (OZR) to determine cellular and systemic mechanisms that produce altered autonomic reflexes in the setting of metabolic syndrome. Like obese humans, adult OZR become hyperinsulinemic with poor glycemic control. They also develop sympathetically-driven hypertension with diminished baroreflex control of sympathetic nerve activity (SNA) and heart rate (HR) compared to lean Zucker rats. Other sympatho-inhibitory reflexes processed through the nucleus tractus solitarius (NTS) are also impaired in adult OZR, coincident with the development of reduced physiological responses to glutamatergic activation of the NTS. In contrast, glutamatergic activation of the rostral ventrolateral medulla (RVLM) produces enhanced physiological responses coincident with the onset of augmented sympatho-excitatory reflexes. This latter condition occurs independent of impaired baroreflexes and also increases MAP variability. Amelioration of hypertension or impaired glycemic control in adult male OZR each partially restores baroreflex control of HR, although the fates of NTS function and other sympatho- inhibitory reflexes are not known. Furthermore, whether these treatments also dampen augmented RVLM activation and sympatho-excitatory reflexes is unknown. Female OZR develop metabolic syndrome, but impaired baroreflexes emerge later, well beyond the development of hypertension. The efficacy of treatments used in males and the functions of NTS, RVLM, and other sympathetic reflexes are unknown in female OZR. Central hypotheses: In male OZR, poor glycemic control dampens glutamatergic activation of NTS neurons receiving vagal inputs to impair sympatho-inhibitory reflexes, and this state is exacerbated by hypertension. Further, we hypothesize that simultaneous ingestion of excess salt with hyperphagia augments glutamatergic activation of the RVLM to yield exaggerated sympatho-excitatory reflexes that could further destabilize MAP. Although female rats may develop salt-induced sensitization of the RVLM, we hypothesize estrogen enhances NTS function to combat impairment of sympatho-inhibitory reflexes in early stages of metabolic syndrome. We propose to determine how obesity impacts responses of individually recorded NTS and RVLM neurons to inputs from the periphery and forebrain in male and female OZR compared to age-matched LZR. We will also determine whether reducing salt intake, poor glycemic control, or MAP alters NTS and RVLM function coincident with restoration of sympathetic reflexes in OZR. This project will provide novel insights into obesity- related autonomic deficits and determine whether standard treatments for hypertension and hyperglycemia are adequate to restore altered brainstem function and sympathetic reflexes that are not evaluated in the clinic.