Mechanisms underlying altered automic regulation of blood pressure in obesity

描述（由申请人提供）：肥胖是一种全国性的流行病，也是心血管疾病的主要原因。肥胖者表现出高血压、动脉压（AP）的压力反射控制受损以及对应激的过度升压反应，这有助于肥胖患者的终末器官损伤和发病率增加。心脏和血管系统的交感神经调节改变是肥胖相关的心血管调节障碍的组成部分，但交感神经控制缺陷的潜在机制知之甚少。肥胖Zucker大鼠（OZR）的自主神经功能缺陷与肥胖人群中观察到的类似：高血压时交感神经活动（SNA）增加，SNA中压力反射介导的变化变钝，SNA和AP与其他交感神经兴奋性反射过度增加。夸张的交感神经兴奋性反应持续存在的压力感受器反馈的情况下，这表明额外的压力反射独立的改变在OZR SNA的控制。肥胖对压力感受器反射与其他交感神经反射的相反影响可能是由于它们不同的潜在机制。压力感受性反射介导的SNA增加是由GABA能抑制从延髓尾侧腹外侧区（CVLM）撤回到驱动延髓头侧腹外侧区（RVLM）SNA的脑干神经元引起的。相反，其他交感神经兴奋性刺激通过RVLM的血管紧张素能或血管紧张素能刺激提高SNA。我们假设OZR在交感神经调节心血管功能方面存在双重缺陷：RVLM的压力反射介导的GABA能抑制受损，以及RVLM神经元对控制交感神经血管紧张素的兴奋性刺激的敏感性增强。在目标1中，我们将确定受损的压力反射是否是由于压力感受器传入功能的缺陷或脑干的变化。在目标2中，我们将确定OZR是否具有降低的RVLM的GABA能抑制。在目标3中，我们将确定是否与谷氨酸或血管紧张素II的RVLM的兴奋产生更大的增加SNA和AP在OZR，即使没有压力感受性反射。在目标4中，我们将确定OZR是否也具有由前脑发起的夸大的交感神经兴奋性反应，其激活SNA兴奋RVLM。这项建议将使用最先进的解剖学和电生理学的措施，以提供第一个机械的理解，在脑干控制与肥胖相关的自主调节的有害变化。

DESCRIPTION (provided by applicant): Obesity is a nationwide epidemic and a leading cause of cardiovascular disease. Obese people display hypertension, impaired baroreflex control of arterial pressure (AP), and exaggerated pressor responses to stress, which contribute to end-organ injury and increased morbidity in obese patients. Altered sympathetic regulation of the heart and vasculature is integral to obesity-associated impairment of cardiovascular regulation, but mechanisms underlying deficits in sympathetic control are poorly understood. Obese Zucker rats (OZR) have autonomic deficits analogous to those observed in obese people: increased sympathetic nerve activity (SNA) with hypertension, blunted baroreflex-mediated changes in SNA, and exaggerated increases in SNA and AP with other sympatho-excitatory reflexes. Exaggerated sympatho-excitatory responses persist in the absence of baroreceptor feedback, suggesting additional baroreflex-independent alterations in the control of SNA in OZR. The opposing effects of obesity upon baroreflex versus other sympathetic reflexes are likely due to their disparate underlying mechanisms. Baroreflex-mediated increases in SNA are elicited by a withdrawal of GABAergic inhibition from the caudal ventrolateral medulla (CVLM) to the brainstem neurons that drive SNA in rostral ventrolateral medulla (RVLM). In contrast, other sympatho-excitatory stimuli raise SNA by glutamatergic or angiotensinergic stimulation of the RVLM. We hypothesize that OZR have a dual deficit in sympathetic regulation of cardiovascular function: impaired baroreflex-mediated GABAergic inhibition of the RVLM, AND enhanced sensitivity of RVLM neurons to excitatory stimuli controlling sympathetic vasomotor tone. In Aim 1 we will determine if impaired baroreflexes are due to deficits in baroreceptor afferent function or changes in the brain stem. In Aim 2 we will determine if OZR have a reduced GABAergic inhibition of the RVLM. In Aim 3 we will determine whether excitation of the RVLM with glutamate or angtiotensin II produces larger increases in SNA and AP in OZR, even without baroreflexes. In Aim 4 we will determine whether OZR also have exaggerated sympatho- excitatory responses initiated by the forebrain, which activate SNA exciting the RVLM. This proposal will use state-of-the-art anatomical and electrophysiological measures to provide the first mechanistic understanding of deleterious changes in brain stem control of autonomic regulation associated with obesity.