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

Ba, Zheng F.; Wang, Haichao; Koo, Douglas J.; Ornan, David A.; Bland, Kirby I.; Chaudry, Irshad H.

doi:10.1001/archsurg.136.10.1158

Cited by 37 publications

(30 citation statements)

References 39 publications

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“…Although the sequelae of trauma and hemorrhage remain a major cause of mortality in surgical intensive care units, it is unknown whether hepatic insulin resistance occurs, and if so, what are the cellular mechanisms responsible for this resistance. In this study, a well-established rat model of trauma and hemorrhage (3,8,9,58) was used to examine changes of blood glucose and insulin levels and to determine whether hepatic insulin resistance develops. The cellular mechanisms of hepatic insulin resistance was also investigated by examining insulin signal-transduction pathways and insulin regulation of hepatic gene expression.…”

Section: Discussionmentioning

confidence: 99%

Hemorrhage induces the rapid development of hepatic insulin resistance

Wang

Kuebler

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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Hyperglycemia is an early metabolic response to trauma and hemorrhage. The role of hepatic insulin resistance to the development of this hyperglycemia is not well understood. The aim of this study was to determine whether the liver becomes insulin resistant and to identify the particular hepatic insulin signaling pathways that may be compromised following trauma and hemorrhage. Male adult rats were bled to a mean arterial pressure of 40 mmHg and maintained at that pressure for 90 min followed by resuscitation with Ringer lactate. Data showed that trauma and hemorrhage rapidly induced profound hyperinsulinemia in combination with significant hyperglycemia, suggesting the development of insulin resistance. After trauma and hemorrhage, hepatic insulin signaling via the insulin-induced phosphatidylinositol 3 (PI3)-kinase-Akt pathway was abolished, whereas ERK1/2 signaling was relatively normal. The regulation (inhibition) of a hepatic-, insulin-, and the PI3-kinase-dependent gene, IGF binding protein-1, was also lost. The present study provides convincing evidence of a rapid onset hepatic insulin resistance following a combination of trauma and hemorrhage.

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Section: Discussionmentioning

confidence: 99%

Hemorrhage induces the rapid development of hepatic insulin resistance

Wang

Kuebler

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Likewise, increase (Liu & Dillon 2002, Simoncini et al 2003 or decrease of eNOS activity by androgens has both been reported. In addition, other investigations have shown that the eNO vasodilator effect is increased (Wynne & Khalil 2003, Orshal & Khalil 2004 or decreased (Ba et al 2001, Gonzales et al 2004 by androgens. Despite all these findings, there is a lack of experimental data on the specific effects of endogenous male sex hormone in those issues, when they are studied simultaneously.…”

Section: Introductionmentioning

confidence: 95%

Orchidectomy increases expression and activity of Cu/Zn-superoxide dismutase, while decreasing endothelial nitric oxide bioavailability

Blanco-Rivero¹,

Sagredo²,

Balfagón³

et al. 2006

Journal of Endocrinology

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This study examines the effect of male sex hormones on the release, metabolism and function of endothelial nitric oxide (eNO) in rat aorta. Aortic segments from orchidectomized and control male Sprague-Dawley rats were used to measure eNO synthase (eNOS) expression, nitric oxide (NO) release, acetylcholine (ACh)-and sodium nitroprusside (SNP)-induced relaxation and Cu/Zn-superoxide dismutase (SOD) expression and activity. eNOS expression as well as basal and ACh-induced NO release were similar in arteries from both groups of rats. Basal superoxide anion production was similar in arteries from both groups, while ACh-induced superoxide anion formation was greater in arteries from orchidectomized than control rats. Orchidectomy increased the vasodilator effect induced by ACh, but did not alter that induced by SNP. SOD, a superoxide anion scavenger, did not modify the SNP-induced relaxation in aortas from control or orchidectomized rats. The membrane-permeable mimetic of SOD, tempol, increased the SNP-induced relaxation more in aortas from orchidectomized than control rats. The effect of endogenous SOD inhibitor, diethyl-dithiocarbamate, reduced the relaxation induced by SNP in segments from both groups of rats. The expression and activity of Cu/Zn-SOD were greater in aortas from orchidectomized than control rats. These data show that endogenous male sex hormone deprivation altered neither eNOS expression nor eNO release, while it increased the expression and activity of Cu/Zn-SOD. However, the predominant vascular effect of orchidectomy is to increase NO metabolism.

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“…However, clinical and laboratory studies have shown that gender differences exist in the organ and immune function after hemorrhagic shock (13,23,31). In this regard, our previous studies have shown that male sex steroids have deleterious effects and female sex steroids produce beneficial effects on cardiovascular functions after trauma-hemorrhage (5,16,31). In particular, studies have shown that administration of a single dose of estrogen after trauma and hemorrhagic shock improved cardiovascular and hepatocellular functions (18,25).…”

mentioning

confidence: 99%

Salutary effects of androstenediol on cardiac function and splanchnic perfusion after trauma-hemorrhage

Shimizu

Choudhry

Szalay

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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-Recent studies have shown that dehydroepiandrosterone (DHEA) administration after trauma-hemorrhage (T-H) improves cardiovascular function and decreases cytokine production in male animals. Although androstenediol, one of the metabolites of DHEA, is reported to have estrogen-like activity, it remains unknown whether androstenediol per se has any salutary effects on cytokines and cardiovascular function after T-H. To examine this effect, male Sprague-Dawley rats underwent laparotomy and were bled to and maintained at a mean arterial blood pressure of 35-40 mmHg for ϳ90 min. The animals were resuscitated with four times the volume of maximal bleedout volume in the form of Ringer lactate. Androstenediol (1 mg/kg body wt iv) or vehicle was administered at the end of resuscitation. Twenty-four hours after resuscitation, cardiac function and organ blood flow were measured by using 85 Sr-microspheres. Circulating levels of nitrate/nitrite and IL-6 were also determined. Cardiovascular function and organ blood flow were significantly depressed after T-H. However, these parameters were restored by androstenediol treatment. The elevated plasma IL-6 levels after T-H were also lowered by androstenediol treatment. In contrast, plasma levels of nitrate/nitrite were the highest in the androstenedioltreated T-H animals. Because androstenediol administration after T-H decreases cytokine production and improves cardiovascular function, this agent appears to be a novel and useful adjunct for restoring the depressed cardiovascular function and for cytokine production in males after adverse circulatory conditions. hemorrhagic shock; nitric oxide; nitric oxide synthase; adiol; 5-androstene-3␤,17␤-diol HEMORRHAGIC SHOCK results in a rapid decrease in cardiac output and organ blood flow. Furthermore, studies have shown that intestinal perfusion remains depressed even after the recovery of cardiac output by fluid resuscitation (29). This splanchnic hypoperfusion after hemorrhagic shock also activates the inflammatory cascade. The depressed cardiovascular function and excess production of inflammatory mediators play an important role in the development of multiple organ failure after hemorrhagic shock (20).Previous work from our laboratory has shown that left ventricular performance, cardiac output, and organ blood flow in the liver, small intestine, and kidney decreased significantly after trauma-hemorrhage (3,4,25), and plasma levels of IL-6

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

Cited by 37 publications

References 39 publications

Hemorrhage induces the rapid development of hepatic insulin resistance

Hemorrhage induces the rapid development of hepatic insulin resistance

Orchidectomy increases expression and activity of Cu/Zn-superoxide dismutase, while decreasing endothelial nitric oxide bioavailability

Salutary effects of androstenediol on cardiac function and splanchnic perfusion after trauma-hemorrhage

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