Mechanisms of the salutary effects of dehydroepiandrosterone after trauma-hemorrhage: direct or indirect effects on cardiac and hepatocellular functions?

Abstract

Dehydroepiandrosterone (DHEA) is the most abundant adrenal hormone in man and has been shown to improve immune functions after trauma-hemorrhage. However, it remains unknown whether this agent has any salutary effects on the depressed organ functions under such conditions. Administration of DHEA after trauma-hemorrhage attenuates depressed cardiac and hepatocellular functions, and beneficial effects are mediated via the estrogen receptors. Male rats underwent laparotomy and were then bled to and maintained at a mean arterial pressure of 40 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 administration of DHEA (30 mg/kg of body weight) or vehicle occurred after resuscitation. At 24 hours after resuscitation, cardiac output was measured by a dye-dilution technique. Hepatocellular function, ie, the maximum velocity of indocyanine green clearance (Vmax) and the efficiency of the active transport (Km), was determined using an in vivo hemoreflectometer. Plasma levels of DHEA, sex hormone binding globulin, 17beta-estradiol, and testosterone were also determined. Moreover, additional groups of animals received a high-affinity estrogen receptor antagonist (ICI 182,780) with or without DHEA treatment. Cardiac output decreased by 12.9% at 24 hours after trauma-hemorrhage; however, it was similar to shams in DHEA-treated animals. Moreover, hepatocellular function was significantly depressed after hemorrhage (Vmax, -74.4%; Km, -62.3%), whereas DHEA treatment restored those values to sham levels. Plasma levels of 17beta-estradiol and testosterone were not significantly altered in animals receiving DHEA. The hemorrhage group treated with DHEA and ICI 182,780 showed markedly depressed cardiac and hepatocellular functions. Since DHEA treatment after trauma-hemorrhage restored the depressed 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 abolished the salutary effects of DHEA, it appears that these effects on cardiac and hepatocellular functions after trauma-hemorrhage are mediated via the estrogen receptors.