Mechanisms Mediating Hypotension to Anthrax Lethal Toxin

描述（由申请人提供）：炭疽杆菌感染是一种致命的病理生理状况，也是主要的生物恐怖主义健康威胁。在美国，吸入性炭疽杆菌感染患者的治疗因动脉血压逐渐下降而变得复杂。为了研究炭疽杆菌导致动脉血压出现休克样降低的发病机制，美国国立卫生研究院的研究人员通过持续输注炭疽致死毒素 (LeTx) 和炭疽水肿毒素 (ETx)（这些毒素是炭疽杆菌发病机制的核心）开发了一种大鼠模型。这些研究人员报告称，LeTx 和 ETx 输注会导致低血压；然而，调节动脉血压降低的机制尚不清楚。尽管神经系统并发症是炭疽杆菌感染的一个基本组成部分，但尚无研究确定炭疽杆菌感染对交感神经流出的影响，而交感神经流出是中枢交感神经回路与心输出量、血管阻力和动脉血压调节之间的基本联系。拟议的研究将首次提出这样的假设：炭疽杆菌感染通过改变交感神经流出、心输出量、血管反应性和外周血管电导的调节来介导进行性低血压。将在大鼠中完成一项综合、多方面的实验方法，涉及交感神经、心输出量、左心室功能、α-肾上腺素能血管收缩剂、内皮依赖性和非依赖性血管舒张，以及对连续 LeTx、ETx 和联合 LeTx ETx 输注的局部血管电导测量，以解决四个问题。 1. 输注炭疽杆菌毒素是否会产生交感神经抑制作用？ 2. 输注炭疽杆菌毒素是否会导致心脏功能下降？ 3. 输注炭疽杆菌毒素是否会降低 11-肾上腺素能受体血管反应性并改变内皮依赖性和非依赖性血管舒张？ 4. 输注炭疽杆菌毒素是否会改变内脏和外周血流的分布？ LeTx 和 ETx 输注介导低血压的机制的阐述对于确定常规疗法的功效和开发针对炭疽杆菌感染的改进疗法非常重要。公共卫生相关性：炭疽杆菌感染是一种致命的病理生理状态，也是严重的生物恐怖主义健康威胁。拟议的研究旨在确定在输注炭疽致死毒素期间导致动脉血压降低的交感神经系统和心血管机制。进一步了解介导炭疽致死毒素的交感神经和心血管改变的机制对于确定传统疗法的功效和开发针对炭疽杆菌感染的改进疗法至关重要。

DESCRIPTION (provided by applicant): Bacillus anthracis infection is a deadly pathophysiological condition and a major bioterrorism health threat. The treatment of patients infected with inhalational Bacillus anthracis in the United States was complicated by progressive decreases in arterial blood pressure. To investigate the pathogenesis of the shock-like reduction in arterial blood pressure with Bacillus anthracis, investigators at the National Institutes of Health developed a rat model using continuous infusions of anthrax lethal toxin (LeTx) and anthrax edema toxin (ETx) (these toxins are central to the pathogenesis of Bacillus anthracis). These investigators reported that LeTx and ETx infusions produced hypotension; however, mechanisms mediating the depression in arterial blood pressure are not known. Although neurological complications are a fundamental component of Bacillus anthracis infections, no studies have determined the effect of Bacillus anthracis infection on sympathetic nerve outflow, the fundamental link between central sympathetic neural circuits and regulation of cardiac output, vascular resistance, and arterial blood pressure. The proposed studies will, for the first time, advance the hypothesis that Bacillus anthracis infection mediates progressive hypotension by altering regulation of sympathetic nerve outflow, cardiac output, vascular reactivity, and peripheral vascular conductance. An integrative and multifaceted experimental approach involving sympathetic nerve, cardiac output, left ventricular function, alpha-adrenergic vasoconstrictor, endothelium-dependent and -independent vasodilation, and regional vascular conductance measurements to continuous LeTx, ETx, and combined LeTx+ETx infusions will be completed in rats to address four questions. 1. Does infusion of Bacillus anthracis toxins produce sympathoinhibition? 2. Is cardiac function depressed in response to infusion of Bacillus anthracis toxins? 3. Do infusions of Bacillus anthracis toxins reduce 11-adrenergic receptor vascular responsiveness and alter endothelium-dependent and - independent vasodilation? 4. Is the distribution of visceral and peripheral blood flow altered by infusion of Bacillus anthracis toxins? The elaboration of mechanisms mediating hypotension to LeTx and ETx infusions is important for determining the efficacy of conventional therapy and the development of improved therapies in response to Bacillus anthracis infection. PUBLIC HEALTH RELEVANCE: Bacillus anthracis infection is a deadly pathophysiological state and a serious bioterrorism health threat. The proposed studies are designed to determine sympathetic nervous system and cardiovascular mechanisms responsible for the reduction in arterial blood pressure during infusion of anthrax lethal toxin. Further understanding of the mechanisms mediating sympathetic nerve and cardiovascular alterations to anthrax lethal toxin is critical for determining the efficacy of conventional therapy and the development of improved therapies for Bacillus anthracis infection.