Mechanisms Mediating Hypotension to Anthrax Lethal Toxin

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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.