Despite advances in the management of the septic patient, a large number of such patients die of the ensuing septic shock and multiple organ failure. This mortality might be decreased by a better understanding of the mediators responsible for the transition from the early, hyperdynamic to the late, hypodynamic phase of sepsis so that early detection and modulation of those factors can prevent progressive cell and organ dysfunction. Our studies have indicated that upregulation of adrenomedullin (AM), a recently identified potent vasodilatory peptide, is responsible for initiating the hyperdynamic phase of sepsis. Although vascular AM hyporesponsiveness plays a major role in the transition from the hyperdynamic to hypodynamic phase of sepsis, the reduction of the level of the novel specific AM binding protein (i.e., AMBP-1) and its binding capacity, rather than AM receptors, appear to be the culprit f1or the vascular hyporesponsiveness. Since co-administration of AM and AMBP-1 prevents the occurance of hypodynamic sepsis and reduces mortality, we hypothesize that inadequate interaction between AMBP-1 and AM due to the reduction of AMBP-1 plays an important role in the devlopment of the hypodynamic response, multiple organ failure, and mortality during ther progression of sepsis. Thus we propose two specific aims. Aim 1: To determine mechanisms responsible for producing the vascular AM hyporesponsiveness in sepsis. We will examine how sepsis affects AMBP-1 biosynthesis, its binding capacity, and AM bioactivity. The role of proinflammatory cytokines (TNF-a, IL-1B) and endotoxin will be examined. Studies are proposed to determine whether Kupffer cell activation suppresses AMBP-1 synthesis and release. Aim II: To determine mechanisms by which administration of AM/AMBP-1 maintains cardiovascular stability in sepsis. We will examine whether AM/AMBP-1 affects Amreceptor binding capacity, signal transduction pathways, and endothelial constitutive nitric oxide synthase (ecNOS). The role of inhibition of vascular endothelial cell apoptosis and shedding as well as TNF-A and IL-B production in producing AM/AMBP-1's beneficial effects will be studied. Moreover, the effects of delayed infusion of AM/AMBP-1 on organ function and survival will be assessed. The proposed studies should provide useful information which will allow us not only to understand the mechanisms responsible for transition from the hyperdynamic to hypodynamic sepsis, but also for maintaining cardiovascular stability and preventing organ failure and mortality.
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