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

项目摘要 安·M·施莱霍费尔 肥胖损害自主神经反射对平均动脉压(MAP)的短期调节，导致 地图的不稳定。与高血压无关，MAP变异性增加是高血压的主要危险因素 结束器官损伤和中风。改善高血压但不能升高MAP变异性的治疗 使患者面临心血管不良后果的风险。该项目使用肥胖的Zucker大鼠(OZR)来 确定在环境中产生改变的自主神经反射的细胞和系统机制 代谢综合征。像肥胖的人一样，成年的OZR会变得高胰岛素血症，血糖控制不佳。 他们还发生交感神经驱动的高血压，交感神经压力感受性反射控制减弱。 与瘦Zucker大鼠比较活动量(SNA)和心率(HR)。处理的其他交感神经抑制反射 成人OZR的孤束核(NTS)也受到损害，这与OZR的发生发展相一致。 NTS对谷氨酸能激活的生理反应减弱。相比之下，谷氨酸能激活 延髓头端腹外侧区(RVLM)产生与发病相一致的增强的生理反应 增强的交感-兴奋性反射。后一种情况的发生与压力反射受损无关。 也增加了地图的可变性。成年男性高血压或血糖控制受损的改善 OZR均能部分恢复压力感受性反射对HR的控制，但NTS功能和其他交感神经的命运-- 抑制性反射尚不为人所知。此外，这些治疗是否也抑制了增强的RVLM 激活和交感兴奋反射是未知的。女性OZR会患上代谢综合征，但 压力反射受损出现的时间较晚，远远超出了高血压的发展阶段。治疗的疗效 在男性中使用，而在女性OZR中NTS，RVLM和其他交感反射的功能未知。 中心假设：在男性OZR中，血糖控制不良会抑制NTS神经元的谷氨酸能激活 接受迷走神经输入以削弱交感神经抑制反射，这种状态会因高血压而加剧。 此外，我们假设同时摄入过量盐分和吞噬功能亢进会增强谷氨酸能。 激活RVLM产生夸大的交感-兴奋反射，可能进一步破坏MAP的稳定。 虽然雌性大鼠可能发生盐诱导的RVLM敏化，但我们假设雌激素可以增强 NTS在代谢综合征早期对抗交感神经抑制反射受损的功能。 我们建议确定肥胖如何影响单独记录的NTS和RVLM神经元对 男性和女性OZR的外周和前脑的输入与年龄匹配的LZR相比。我们还将 确定减少盐摄入量、血糖控制不良或MAP是否会改变NTS和RVLM功能 与OZR的交感反射恢复一致。这个项目将为肥胖问题提供新的见解-- 并确定高血压和高血糖的标准治疗方法是否 足以恢复临床上未评估的脑干功能和交感神经反射。

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.