The therapeutic efficacies of buforin II, indolicidin, and KFFKFFKFF were investigated in three rat models of septic shock: (i) rats injected intraperitoneally with 10 g of Escherichia coli O111:B4 lipopolysaccharide, (ii) rats given an intraperitoneal injection of 2 ؋ 10 10 CFU of Escherichia coli ATCC 25922, and (iii) rats in which intra-abdominal sepsis was induced via cecal ligation and single puncture. All animals were randomized to receive parenterally isotonic sodium chloride solution, 1 mg of buforin II per kg of body weight, 1 mg of indolicidin per kg, 1 mg of KFFKFFKFF per kg, and 20 mg of imipenem per kg. The main outcome measures were bacterial growth in abdominal exudate and plasma, endotoxin and tumor necrosis factor alpha (TNF-␣) concentrations in plasma, and lethality. Treatment with all peptides resulted in significant reductions in plasma endotoxin and TNF-␣ concentrations compared with those resulting from the imipenem and saline treatments. On the other hand, imipenem treatment significantly reduced the levels of bacterial growth compared with the reductions achieved with the peptide and saline treatments. All compounds reduced the rates of death compared to that for the controls. Although the peptides demonstrated lower levels of antimicrobial activity than imipenem, they exhibited the dual properties of antimicrobial and antiendotoxin agents.Severe sepsis and septic shock are major causes of morbidity and mortality in neutropenic individuals, hospitalized patients, and all immunocompromised subjects (3, 26, 28). The lipopolysaccharides (LPSs) associated with the cell membranes of gram-negative bacteria, known as endotoxin, activate host effector cells through stimulation of receptors on their surfaces (13). These target cells secrete large quantities of inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6, IL-8, platelet-activating factor, arachidonic acid metabolites, erythropoietin, and endothelin (1,2,13,17,27). LPS is composed of an O-polysaccharide chain, a core sugar, and a lipophilic fatty acid, lipid A (1, 13). Lipid A produces the signal responsible for the induction of cytokine genes. Many methods have been used to treat septic shock, including treatments with monoclonal antibodies to endotoxin, IL-1 receptor antagonists, and antioxidants and various anti-inflammatory therapies, but no treatment has produced clinically effective results (1-3, 13, 17, 26-28).Antimicrobial peptides are positively charged molecules isolated from a wide variety of animals and plants. Among these compounds, buforin II (which is isolated from the stomach of an Asian toad named Bufo bufo gargarizans), indolicidin (a 13-residue peptide isolated from cytoplasmic granules of bovine neutrophils), and KFFKFFKFF (a novel synthetic cationic peptide) have broad-spectrum antibacterial activities and outer membrane permeability-increasing properties (5,19,25). In addition, cationic peptides have received increasing attention in recent years as they also possess antiendotoxin acti...