The investigator asserts that mortality ensuing after septic shock and multiple organ failure could be prevented if septic mediators/factors responsible for the transition from the early hyperdynamic to the late hypodynamic sepsis were fully identified. Studies by the investigator have shown: 1) an upregulation of adrenomodulin (ADM) during early sepsis, 2) an emergence of the hyperdynamic phase in normal animals treated with ADM and 3) prevention of the hyperdynamic phase in animals treated with ADM antibodies. The investigator hypothesizes that ADM regulation causes hyperdynamic circulation and that a subsequent loss of vascular responsiveness to ADM is the cause of the transition from the hyperdynamic to the hypodynamic phase of sepsis. Furthermore, the hypothesis implies that modulation of the ADM responsiveness by pharmacologic agents would prevent the transition and allow for the maintenance of cardiovascular stability and other organ functions, and thus reduce late septic mortality. The studies are to determine: 1) the mechanisms of the ADM upregulation after cecal-ligation-puncture peritonitis, 2) the mechanism by which vascular hyporesponsiveness to ADM occurs during sepsis, and 3) whether pentoxifyline or ATP-MgC12 could allow for maintenance of vascular responsiveness to ADM so that cardiovascular and other organ functions might become stable. The proposed studies would measure plasma and tissue levels of ADM and other mediators such as redundant cytokines, endotoxin and catecholamines, gene expression of ADM and its receptor, cyclic AMP adenylate cyclase, and G proteins. The investigator points out the proposed work should provide useful information to better understand the mechanism of the hyperdynamic to hypodynamic sepsis transition, and for maintaining hemodynamic stability during sepsis and thus preventing septic shock and multiple organ failure.
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