Mechanisms underlying altered automic regulation of blood pressure in obesity

肥胖患者血压自动调节改变的机制

• 批准号: 7320218
• 负责人: ANN M SCHREIHOFER
• 金额: $ 34.73万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7320218
• 关键词: Animal Model; Arts; Attenuated; Baroreflex; Brain Stem; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Conscious; Diving; Epidemic; Feedback; Figs - dietary; Glutamates; Heart; Hypertension; Hypothalamic structure; Impairment; Injection of therapeutic agent; Injury; Invasive; Measures; Mediating; Morbidity - disease rate; Nerve; Neurons; Nucleus solitarius; Obesity; Obesity associated cardiovascular disease; Organ; PAG gene; Patients; Pressoreceptors; Prosencephalon; Reaction; Reflex action; Regulation; Research Personnel; Source; Stimulus; Stress; Testing; Vasomotor; Withdrawal; Zucker Rats; afferent nerve; blood pressure regulation; gamma-Aminobutyric Acid; human PAG protein; midbrain central gray substance; paraventricular nucleus; pressure; programs; receptor; response

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.

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）的压力感受反射控制受损以及对压力的升压反应过度，这会导致肥胖患者的终末器官损伤并增加发病率。心脏和脉管系统交感神经调节的改变是肥胖相关心血管调节受损的重要组成部分，但交感神经控制缺陷的潜在机制尚不清楚。肥胖 Zucker 大鼠 (OZR) 具有与肥胖人群类似的自主神经缺陷：高血压时交感神经活动 (SNA) 增加，压力反射介导的 SNA 变化减弱，以及 SNA 和 AP 与其他交感兴奋反射的过度增加。在没有压力感受器反馈的情况下，过度的交感兴奋反应持续存在，这表明 OZR 中 SNA 的控制存在额外的与压力反射无关的改变。肥胖对压力反射与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。压力感受反射介导的 SNA 增加是通过取消从尾侧腹外侧延髓 (CVLM) 到驱动头端腹外侧延髓 (RVLM) 中 SNA 的脑干神经元的 GABA 能抑制而引起的。相反，其他交感神经兴奋性刺激通过 RVLM 的谷氨酸能或血管紧张素能刺激来提高 SNA。我们假设 OZR 在心血管功能的交感调节方面存在双重缺陷：压力感受反射介导的 RVLM GABA 能抑制受损，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反射受损是否是由于压力感受器传入功能缺陷或脑干变化所致。在目标 2 中，我们将确定 OZR 是否降低了 RVLM 的 GABA 抑制。在目标 3 中，我们将确定即使没有压力反射，用谷氨酸或血管紧张素 II 激发 RVLM 是否会导致 OZR 中 SNA 和 AP 的较大增加。在目标 4 中，我们将确定 OZR 是否也具有由前脑引发的夸大交感兴奋反应，从而激活 SNA 兴奋 RVLM。该提案将使用最先进的解剖学和电生理学措施，首次从机制上理解与肥胖相关的自主神经调节的脑干控制的有害变化。