The objectives of the studies are: 1) to elucidate the molecular mechanisms underlying the role of brain dynorphin/kappa opiate receptor systems in mediating the CNS response to hypotension; 2) to characterize the temporal and regional alterations in immediate early gene, stress protein and cytokine expression in the brain and correlate such changes with gene expression for opiate peptides and with the cardiovascular and histologic response to hemorrhage; 3) to characterize the presence and regional activation of programmed cell death in the brain; and 4) to facilitate the development of improved molecular and pharmacologic therapeutic approaches to shock. Preliminary studies have documented that endogenous opiates, most notably dynorphin, appear to be involved in the central regulation of cardiovascular function during hemorrhagic shock. Molecular investigations will continue along this line with selected areas of brain dysfunction identified. The investigators will examine the therapeutic efficacy of the k-opioid receptor antagonist, nor- binaltorphimine, the calcium channel blocker, (s)-emopamil, the IL-1 receptor antagonist, IL1-RA, and the antibody to TNFa alone or in combination. The studies are to enhance current understanding of the molecular sequelae of hypotension and low flow states that accompany shock and trauma so as to foster the development of more effective pharmacologic and genetic therapeutic approaches to treating shock.
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