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

肥胖导致短期血压控制受损的机制

基本信息

批准号：
10001951
负责人：
ANN M SCHREIHOFER
金额：
$ 35.42万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10001951
关键词：
Adult Affect Age Baroreflex Blood Glucose Blood Pressure Brain Stem Cardiovascular system Cell Nucleus Clinic Clinical Development Estrogens Excess Dietary Salt Female Food Glutamates Heart Rate Human Hyperglycemia Hyperphagia Hypertension Impairment Individual Ingestion Intervention Life Mediating Metabolic syndrome Nerve Neurons Obesity Organ Outcome Ovariectomy Patients Physiological Population Process Prosencephalon Rattus Reflex action Regulation Risk Risk Factors Sodium Chloride Stroke Thinness Treatment Efficacy Zucker Rats adult obesity autonomic reflex blood pressure regulation combat glycemic control hypertension treatment improved individual response insight male neuronal excitability novel obesity treatment paraventricular nucleus pressure prevent public health relevance response restoration risk minimization salt intake standard care young adult

项目摘要

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.

项目总结