Mechanisms underlying altered automic regulation of blood pressure in obesity

描述(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。肥胖者表现为高血压、压力感受性反射控制动脉压(AP)受损和对应激反应过度，导致终末器官损伤和肥胖症患者发病率增加。心脏和血管的交感神经调节改变是肥胖相关的心血管调节功能受损的组成部分，但交感神经控制缺陷的潜在机制尚不清楚。肥胖的Zucker大鼠(OZR)具有与肥胖者相似的自主神经缺陷：伴高血压的交感神经活动(SNA)增加，压力反射介导的SNA变化迟钝，以及SNA和AP随其他交感兴奋反射的夸大增加。在没有压力感受器反馈的情况下，夸大的交感-兴奋反应仍然存在，这表明OZR中SNA的控制发生了额外的压力感受器非依赖性改变。肥胖对压力感受器反射和其他交感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增加是由延髓尾侧腹外侧区(CVLM)的GABA能抑制撤销到驱动延髓头端腹外侧区(RVLM)SNA的脑干神经元引起的。相反，其他交感兴奋刺激通过谷氨酸或血管紧张素能刺激RVLM而提高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：压力感受性反射介导的GABA能抑制RVLM，以及RVLM神经元对控制交感血管舒缩张力的兴奋性刺激的敏感性增强。在目标1中，我们将确定压力感受器反射受损是由于压力感受器传入功能的缺陷还是脑干的变化。在目标2中，我们将确定OZR是否降低了对RVLM的GABA能抑制。在目标3中，我们将确定在没有压力反射的情况下，谷氨酸或血管紧张素II刺激RVLM是否会在OZR中产生更大的SNA和AP增加。在目标4中，我们将确定OZR是否也有由前脑启动的夸大交感兴奋反应，这激活了SNA兴奋RVLM。这项建议将使用最先进的解剖学和电生理学方法，首次从机制上理解与肥胖相关的自主神经调节脑干控制的有害变化。

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.