Attenuation of Vascular Endothelial Dysfunction by Testosterone Receptor Blockade After Trauma and Hemorrhagic Shock

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Abstract
PREVIOUS STUDIES have shown that vascular endothelial cell dysfunction occurs during hemorrhagic shock and persists despite fluid resuscitation.1-3 Vascular endothelial cells play a critical role in the maintenance of tissue perfusion.4 It is therefore important to investigate potential therapeutic approaches for maintaining endothelial cell function after hemorrhagic shock. In this regard, studies have been conducted to examine the role of sex hormones in the pathophysiology of trauma and severe hemorrhage (hereafter referred to as trauma-hemorrhage).5-8 It has been demonstrated that proestrus female animals show a normal or even enhanced immune response after trauma-hemorrhage, whereas male animals exhibit a depressed immune response.6 Furthermore, since gonadectomy before induction of trauma-hemorrhage in male animals prevents the occurrence of immune depression,7 male sex hormones might play an inhibitory role in posttraumatic immune responses. Furthermore, flutamide, a nonsteroidal testosterone receptor antagonist, has been shown to restore depressed immune function to normal in male subjects after trauma-hemorrhage.5,8 With regard to organ function, testosterone receptor blockade after trauma-hemorrhage has been shown to improve depressed cardiac, hepatic, and adrenal functions in male rats.9,10 However, it remains unknown whether the salutary effects of this agent are related to the attenuation of depressed endothelial cell function (ie, the production of vascular endothelium-derived nitric oxide [EDNO]) and the subsequent improvement in tissue perfusion and oxygen use in male subjects under such conditions. The aims of this study, therefore, were to determine (1) whether testosterone receptor blockade with flutamide after trauma-hemorrhage attenuates depressed endothelium-dependent vascular relaxation and (2) whether this agent also improves blood flow in, oxygen delivery to, and oxygen consumption in the liver, small intestine, and kidneys in male rats after trauma-hemorrhage and resuscitation.