Because TNF is an important mediator of septic shock and TNF challenges simulate the cardiac abnormalities of septic shock, we propose to investigate the mechanism of TNF-induced cardiac dysfunction in the canine model. In order to determine specific effects of TNF on cardiac dysfunction, animals will be administered TNF intravenously rather than an intraperitoneal septic clot. After TNF infusion, we will serially examine the ultrastructure, biochemical, and molecular abnormalities of the canine heart. The in vivo physiologic effects of various doses of TNF will be correlated with tissue abnormalities, because myocardial depression may resolve in 24 hours or persist for more that 10 days depending on the TNF dose. Based on data from previous studies, we plan to administer 3 doses of TNF: TNF vehicle (control), a low dose (30 mg/kg/bw) to examine an effect on the heart that reverses in 24 hours, and a high dose on TNF (100 mg/kg/bw) to examine an effect that persists for greater than 10 days.
