U-74, 500A inhibition of burn-induced cardiac dysfunction

Abstract

Our previous studies suggest that oxygen-derived free radicals, particularly the hydroxyl radical, play a major role in cardiac dysfunction which is characteristic of burn injury. In this present study, we examined the effects of U-74,500A (U7), a 21-aminosteroid, nonglucocorticoid on ventricular contraction and relaxation recovery from burn injury. Parameters measured included left ventricular pressure (LVP) and the maximal rate of LVP rise (+dP/dt max) and fall (−dP/dt max). Full-thickness burns comprising 45% of the total body surface area (burn groups, N = 69) or 0% for controls (Group 1, N = 8) were produced in guinea pigs. In Group 2, 20 burned guinea pigs were not fluid resuscitated (vehicle only) and served as untreated burns; in Group 3, 11 burned guinea pigs received U7 alone (2.5 mg/kg in 0.01 N HCl iv). Eleven burned guinea pigs were resuscitated with vehicle plus 4 ml lactated Ringer's (LR)/kg/% burn for 24 hr (Group 4); in Group 5, 14 guinea pigs were treated with U7 as described for Group 3 followed immediately by LR for 24 hr as described for Group 4. In Group 6, U7 was administered immediately postburn as described for Group 3; and LR resuscitation, begun 1 hr postburn, was continued for 24 hr ( N = 14). Compared to controls, untreated burn injury significantly impaired cardiac function as indicated by a fall in LVP (74 ± 3 vs 60 ± 4 mm Hg, P < 0.05) and ± dP/dt max (1126 ± 51 vs 1011 ± 39 and 1159 ± 53 vs 993 ± 59 mm Hg/sec, P < 0.05, respectively). Neither fluid resuscitation with LR alone or U7 alone improved burn-induced cardiac dysfunction. In contrast, U7 given postburn and followed with either immediate or delayed fluid resuscitation significantly improved cardiac contractile function. Hearts treated with U7 and fluid resuscitation delayed for 1 hr postburn generated left ventricular function curves (LVP and + dP/dt max plotted vs LV end-diastolic volume) comparable to those calculated for control hearts. These data suggest that antagonizing free radical mediated, iron catalyzed lipid peroxidation improves cardiac function after burn injury, indicating a therapeutic role for the 21-aminosteroids in burn shock.