Cardiovascular protective role for activated protein C during endotoxemia in rats

We examined whether activated protein C (APC) treatment improves cardiovascular inflammation and dysfunction in endotoxemic rats. Randomized, controlled trial in an experimental laboratory of a university physiology department Male Sprague Dawley rats. Internal carotid artery and external jugular vein were catheterized under sterile conditions in rats. Instrumented rats infused or not with APC (240 mu/kg per hour) were challenged with E. coli endotoxin (10mg/kg). Four hours after endotoxin challenge rats were prepared for cardiovascular functional studies and tissue and blood analyses. Endotoxin administration induced systemic hypotension, depression of myocardial systolic performance and reduction in capillary density of the small intestine muscularis layer. Plasma levels of nitrite/nitrate, tumor necrosis factor alpha and macrophage migration inhibitory factor, mesentery venule leukocyte-endothelium interactions, heart and small intestine myeloperoxidase activities were increased in endotoxin-treated rats. APC largely prevented endotoxin-induced cardiovascular dysfunction with improved systemic hemodynamics, functional capillary density, and myocardial contractile performance. Beneficial cardiovascular effects of APC were associated with attenuation of entotoxin-induced inflammatory response in terms of plasma levels of nitrite/nitrate, tumor necrosis factor alpha, macrophage migration inhibitory factor, and endothelial cell-leukocyte activation. APC reduces systemic and tissue inflammation and preserves cardiovascular function during experimental endotoxemia.