icatibant and Burns

Of the 450,000 burn patients each year, 50% have a positive blood alcohol content, and this predisposes them to worsened clinical outcomes. Despite high prevalence and established consequences, the mechanisms responsible for alcohol-mediated complications of postburn remote organ damage are currently unknown. To this end, mice received a single dose of alcohol (1.12 g/kg) or water by oral gavage and were subjected to a 15% total body surface area burn. Animals with a burn alone lost ∼5% of their body weight in 24 h, whereas intoxicated and burned mice lost only 1% body weight (P < 0.05) despite a 17% increase in hematocrit (P < 0.05) and a 57% increase in serum creatinine (P < 0.05) over burn injury alone. This retention of water weight despite increased dehydration suggests that intoxication at the time of a burn causes a shift in fluid compartments that may exacerbate end-organ ischemia and damage as evidenced by a 3-fold increase in intestinal bacterial translocation (P < 0.05), a 30% increase (P < 0.05) in liver weight-to-body weight ratio, and an increase in alveolar wall thickness over a burn alone. Furthermore, administration of the bradykinin antagonist HOE140 30 min after intoxication and burn restored fluid balance and alleviated end-organ damage. These findings suggest that alcohol potentiates postburn remote organ damage through shifts in fluid compartments mediated by bradykinin.

Topics: Animals; Bacterial Translocation; Bradykinin; Bradykinin B2 Receptor Antagonists; Burns; Central Nervous System Depressants; Creatinine; Dehydration; Ethanol; Hematocrit; Humans; Ischemia; Male; Mice

Peptide kinins are potent vasoactive agents in the microcirculation that might be released after burn injury. The present study was designed to test the hypothesis that Icatibant (JE 049), a potent, selective peptidomimetic bradykinin-B2 receptor antagonist, would reduce the cardiovascular pathology occurring in sheep exposed to 40% total body surface area (TBSA), third-degree burn. Female sheep were surgically prepared for chronic study. After 5 to 7 days' recovery from the operative procedure, they were randomized to five groups: sham (n = 6, noninjured, nontreated), medicated sham (n = 4, noninjured, treated with 20 microg kg h Icatibant), control (n = 7, 40% TBSA third-degree burn, nontreated), Icatibant-4 (n = 6, 40% TBSA third-degree burn, treated with 4 microg kg h Icatibant [low dose]), Icatibant-20 (n = 8, 40% TBSA third-degree burn, treated with 20 microg kg h Icatibant [high dose]). Prefemoral lymph flow (milliliters per hour) remained constant in the sham and medicated sham groups but increased after injury: control (0 h, 3.9 +/- 0.5; 24 h, 28 +/- 4.2; 48 h, 33.0 +/- 8.1). The increased fluid flux was associated with enhanced protein flux. Both low and high doses of Icatibant significantly reduced the microvascular fluid flux: Icatibant-4 (0 h, 5.3 +/- 0.6; 24 h, 17.5 +/- 3.5; 48 h, 20.3 +/- 3.4); Icatibant-20 (0 h, 5.3 +/- 1.1; 24 h, 15.2 +/- 2; 48 h, 17.6 +/- 4.1). Total prefemoral protein leak was reduced in all treatment groups. The low dose of Icatibant significantly reduced prefemoral lymph flow without adversely affecting the hemodynamic changes observed after burn injury in sheep, suggesting that the bradykinin antagonist would reduce edema formation and improve fluid management of thermally injured patients.

Topics: Animals; Blood Flow Velocity; Bradykinin; Bradykinin B2 Receptor Antagonists; Burns; Capillary Permeability; Edema; Female; Fluid Therapy; Neutrophils; Random Allocation; Sheep

1. Scald injury in Sv129+C57BL/6 mice induced a temperature and time dependent oedema formation as calculated by the extravascular accumulation of [(125)I]-albumin. Oedema formation was suppressed in NK(1) knockout mice compared to wildtypes at 10 (P<0.01) and 30 min (P<0.001). However, at 60 min a similar degree of extravasation was observed in the two groups. 2. Kinin B(1) (des-Arg(10) Hoe 140; 1 micromol kg(-1)) and B(2) (Hoe 140; 100 nmol kg(-1)) antagonists caused an inhibition of oedema in wildtype mice at 10 and 30 min (P<0.001), but not at 60 min or at 30 min in NK(1) receptor knockout mice. 3. The inhibition of thermic oedema by des-Arg(10) Hoe 140 was reversed by des-Arg(9) bradykinin (0.1 micromol kg(-1); P<0.01) and also observed with a second B(1) receptor antagonist (des-Arg(9) Leu(8) bradykinin; 3 micromol kg(-1); P<0.01). Furthermore des-Arg(10) Hoe 140 had no effect on capsaicin (200 microg ear(-1)) ear oedema, but this was significantly reduced with Hoe 140 (P<0.05). 4. Scalding induced a large neutrophil accumulation at 4 h, as assessed by myeloperoxidase assay (P<0.001). This was not suppressed by NK(1) receptor deletion or kinin antagonists. 5. These results confirm an essential role for the NK(1) receptor in mediating the early, but not the delayed phase of oedema formation or neutrophil accumulation in response to scalding. The results also demonstrate a pivotal link between the kinins and sensory nerves in the microvascular response to burn injury, and for the first time show a rapid involvement of the B(1) receptor in murine skin.

Topics: Administration, Topical; Animals; Bradykinin; Bradykinin Receptor Antagonists; Burns; Capsaicin; Cell Movement; Dermatitis; Edema; Hot Temperature; Injections, Intravenous; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Piperidines; Quinuclidines; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin; Receptors, Neurokinin-1; Tachykinins; Time Factors

The new and highly potent B2 bradykinin (BK) antagonist Hoe 140 was tested for its ability to inhibit oedema of rat paws induced by scalding and carrageenan. The data show that Hoe 140 inhibits scalding and carrageenan oedema for more than four and six hours, respectively. Based on its potency against actions of endogenously generated kinins Hoe 140 is appropriate to investigate the role of kinins in human inflammatory diseases.

Topics: Animals; Bradykinin; Burns; Carrageenan; Edema; Hot Temperature; Inflammation; Kinins; Male; Rats; Rats, Sprague-Dawley; Time Factors