Our recent studies indicate that depletion of androgens (testosterone and dihydrotestosterone) two weeks prior to onset of hemorrhage prevents the depression of cardiac function following trauma-hemorrhage and resuscitation. Alternatively, administration of flutamide, an androgen antagonist (AA), after hemorrhage-resuscitation in non-castrated rats improves the depressed cardiac performance and hepatocellular function. Our hypothesis, therefore, is that androgens and/or low estradiol or the high ration of androgens:estradiol are directly as well as indirectly responsible for producing the depression in cardiac performance and the function of other organs after trauma-hemorrhage in males. Studies are proposed to determine the mechanism by which androgen depletion/AA improves cardiac performance and the function of other organs after hemorrhage-resuscitation. To determine if the effects of androgens and/or AA are receptor-mediated, isolated myocytes will be analyzed for androgen receptor expression, sex steroid binding capacity, receptor activation (release of heat shock protein 90 and phosphorylation), expression of transcription factors (NF-kappaB and AP-1) and alpha- and beta-myosin- heavy chain genes along with androgens, estradiol and sex hormone binding globulin levels in circulation. Since sex steroids can affect intracellular Ca/2+, [Ca/2+]i in isolated myocytes along with PKCepsilon and betaII expressions, cAMP and IP/3 levels will be measured. The gene expression and release of pro-and anti-inflammatory cytokines (TNF, IL-6, IL-4 & IL-10), and the release of catecholamines, ACTH and corticosterone will be measured to determine if they are altered by androgen depletion/AA. Isolated hearts and blood vessels will be used to determine if there are direct effects of androgen/AA on these organs. Additional studies will examine if androgen depletion/AA affects the adrenals and modifies the response of catecholamines on the heart, liver and vascularity smooth muscle. Isolated myocytes and hepatocytes will be used to examine if beta- or alpha-adrenergic receptor binding capacity/affinity are altered by androgen depletion/AA. We will also determine if AA improves the gut, lung and renal functions after hemorrhage-resuscitation and whether it decreases susceptibility to subsequent sepsis. If AA treatment (single or 3 doses) improves but does not sustain cardiovascular responses, we will administer luteinizing hormone-releasing hormone agonist, beta-estradiol, prolactin or metoclopramide to determine if they produce synergistic salutary effects. The hemodynamic parameters and organ functions to be measured include blood flow, circulating blood volume, cardiac output, left ventricular performance, vascular reactivity, liver, gut, adrenal and lung functions. The integration of cardiac function with the function of other organs and detailed mechanistic studies at the cellular and subcellular levels using physiologic, pharmacological and molecular biology techniques to identify targets for novel treatment modalities using AA or hormones should provide new information for the improved treatment of trauma victims with major blood loss and for decreasing susceptibility to subsequent sepsis.
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