Objective: We examined whether activated protein C (APC) treatment improves cardiovascular inflammation and dysfunction in endotoxemic rats.
Design and setting: Randomized, controlled trial in an experimental laboratory of a university physiology department
Subjects: Male Sprague Dawley rats.
Interventions: Internal carotid artery and external jugular vein were catheterized under sterile conditions in rats. Instrumented rats infused or not with APC (240 microg/kg per hour) were challenged with E. coli endotoxin (10 mg/kg). Four hours after endotoxin challenge rats were prepared for cardiovascular functional studies and tissue and blood analyses.
Measurements and results: 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.
Conclusion: APC reduces systemic and tissue inflammation and preserves cardiovascular function during experimental endotoxemia.