Mechanisms of the salutary effects of dehydroepiandrosterone after trauma-hemorrhage - Direct or indirect effects on cardiac ann hepatocellular functions?

Background: Dehydroepiandrosterone (DHEA) is the most abundant adrenal horm one in man and has been shown to improve immune functions after trauma-hemo rrhage. However, it remains unknown whether this agent has any salutary eff ects on the depressed organ functions under such conditions. Hypothesis: Administration of DHEA after trauma-hemorrhage attenuates depre ssed cardiac and hepatocellular functions, and beneficial effects are media ted via the estrogen receptors. Design, Interventions, and Main Outcome Measures: Male rats underwent lapar otomy and were then bled to and maintained at a mean arterial pressure of 4 0 mm Hg until 40% of the maximal bleed-out volume was returned in the form of Ringer lactate (RL) solution. The animals were then resuscitated with 4 times the maximum bleed-out volume with RL for 60 minutes. Subcutaneous adm inistration of DHEA (30 mg/kg of body weight) or vehicle occurred after res uscitation. At 24 hours after resuscitation, cardiac output was measured by a dye-dilution technique. Hepatocellular function, ie, the maximum velocit y of indocyanine green clearance (V-max) and the efficiency of the active t ransport (K-m), was determined using an in vivo hemoreflectometer. Plasma l evels of DHEA, sex hormone binding globulin, 17 beta-estradiol, and testost erone were also determined. Moreover, additional groups of animals received a high-affinity estrogen receptor antagonist (ICI 182,780) with or without DHEA treatment. Results: Cardiac output decreased by 12.9% at 24 hours after trauma-hemorrh age; however, it was similar to shams in DHA-treated animals. Moreover, hep atocellular function was significantly depressed after hemorrhage (V-max,-7 4.4%; K-m, -62.3%), whereas DHEA treatment restored those values to sham le vels. plasma lea els of 17 beta-estradiol and testosterone were not signifi cantly altered in animals receiving DHEA. The hemorrhage group treated with DHEA and ICI 182,780 showed markedly depressed cardiac and hepatocellular functions. Conclusions: Since DHEA treatment after trauma-hemorrhage restored the depr essed cardiac and hepatocellular functions, it appears that DHEA is a safe and inexpensive adjunct to fluid resuscitation for restoring the depressed cardiac and hepatocellular responses after severe hemorrhagic shock in male subjects. Furthermore, since ICI 182,780 administration with DHEA abolishe d the salutary effects of DHEA, it appears that these effects on cardiac an d hepatocellular functions alter trauma-hemorrhage are mediated via the est rogen receptors.