Search

Pre-hospital potentially preventable trauma related deaths are mainly due to hypoperfusion-induced tissue hypoxia leading to irreversible organ dysfunction at or near the point of injury or during transportation prior to receiving definitive therapy. The prolyl hydroxylase domain (PHD) is an oxygen sensor that regulates tissue adaptation to hypoxia by stabilizing hypoxia inducible factor (HIF). The benefit of PHD inhibitors (PHDi) in the treatment of anemia and lactatemia arises from HIF stabilization, which stimulates endogenous production of erythropoietin and activates lactate recycling through gluconeogenesis. The results of this study provide insight into the therapeutic roles of MK-8617, a pan-inhibitor of PHD-1, 2, and 3, in the mitigation of lactatemia in anesthetized rats with polytrauma and hemorrhagic shock. Additionally, in an anesthetized rat model of lethal decompensated hemorrhagic shock, acute administration of MK-8617 significantly improves one-hour survival and maintains survival at least until 4 h following limited resuscitation with whole blood (20% EBV) at one hour after hemorrhage. This study suggests that pharmaceutical interventions to inhibit prolyl hydroxylase activity can be used as a potential pre-hospital countermeasure for trauma and hemorrhage at or near the point of injury. [ABSTRACT FROM AUTHOR]

Preserving vascular function is crucial for preventing multiorgan failure and death in ischemic and low-pressure states such as trauma/hemorrhagic shock (T/HS). It has recently been reported that inhibiting circulating proteases released from the bowel to the circulation during T/HS may preserve vascular function and improve outcomes following T/HS. This study aimed to evaluate the role of the serine protease inhibitor gabexate mesilate (GM) in preserving vascular function during T/HS when given enterally. We studied the vascular reactivity of mesenteric arteries from male Wistar rats treated with enteral GM (10 mg/kg) (GM-treated, n = 6) or control (Shock-control, n = 6) following (T/HS) using pressure myography. Concentration–response curves of endothelial-dependent and endothelial-independent agonists (e.g., acetylcholine, sodium nitroprusside) ranging from 10−10 to 10−5 M were performed. In a second set of experiments, ex-vivo arteries from healthy rats were perfused with plasma from shocked animals from both groups and vascular performance was similarly measured. Arteries from the GM-treated group demonstrated a preserved concentration–response curve to the α1 adrenergic agonist phenylephrine compared to arteries from Shock-control animals (− logEC50: − 5.73 ± 0.25 vs. − 6.48 ± 0.2, Shock-control vs. GM-treated, p = 0.04). When perfused with plasma from GM-treated rats, healthy arteries exhibited an even greater constriction and sensitivity to phenylephrine (− logEC50: − 6.62 ± 0.21 vs. − 7.13 ± 0.21, Shock-control vs. GM-treated, p = 0.02). Enteral GM also preserved the endothelium-dependent vascular response to agonists following T/HS and limited syndecan-1 shedding as a marker of glycocalyx compromise (41.84 ± 9 vs. 17.63 ± 3.97 ng/mL, Shock-control vs. GM-treated, p = 0.02). Syndecan-1 cleavage was correlated with plasma trypsin-like activity (r2 = 0.9611). Enteral gabexate mesilate was able to maintain vascular function in experimental T/HS, which was reflected by improved hemodynamics (mean arterial pressure 50.39 ± 7.91 vs. 64.95 ± 3.43 mmHg, Shock-control vs. GM treated, p = 0.0001). Enteral serine protease inhibition may be a potential therapeutic intervention in the treatment of T/HS. [ABSTRACT FROM AUTHOR]

Purpose: Hydrogen gas (H2) inhalation improved the survival rate of hemorrhagic shock. However, its mechanisms are unknown. We hypothesized that H2 protected the endothelial glycocalyx during hemorrhagic shock and prolonged survival time. Methods: 83 Sprague–Dawley rats were anesthetized with isoflurane. The animals were randomly assigned to 5 groups: room air with no shock, 1.2% H2 with no shock, room air with shock (Control-S), 1.2% H2 with shock (H21.2%-S), and 3.0% H2 with shock (H23.0%-S). Shock groups were bled to a mean arterial pressure of 30–35 mmHg and held for 60 min, then resuscitated with normal saline at fourfold the amount of the shed blood volume. Results: The syndecan-1 level was significantly lower in the H21.2%-S [8.3 ± 6.6 ng/ml; P = 0.01; 95% confidence interval (CI), 3.2–35.8] than in the Control-S (27.9 ± 17.0 ng/ml). The endothelial glycocalyx was significantly thicker in the H21.2%-S (0.15 ± 0.02 µm; P = 0.007; 95% CI, 0.02–0.2) than in the Control-S (0.06 ± 0.02 µm). The survival time was longer in the H21.2%-S (327 ± 67 min, P = 0.0160) than in the Control-S (246 ± 69 min). The hemoglobin level was significantly lower in the H21.2%-S (9.4 ± 0.5 g/dl; P = 0.0034; 95% CI, 0.6–2.9) than in the Control-S (11.1 ± 0.8 g/dl). However, the H23.0%-S was not significant. Conclusions: Inhalation of 1.2% H2 gas protected the endothelial glycocalyx and prolonged survival time during hemorrhagic shock. Therapeutic efficacy might vary depending on the concentration. [ABSTRACT FROM AUTHOR]

To investigate the effect of intravenous Vitamin C (VC) on hemorrhagic shock (HS)-associated rat renal injury and the involved mechanism. Thirty SD rats were randomly assigned to the sham surgery (sham), hemorrhagic shock (HS), HS+100 mg/kg VC (H + VL), HS+500 mg/kg VC (H + VH) and HS+100 mg/kg VC + EX527 (H + VL + E) groups. Tissue and blood samples were collected 6 h after surgery. Kidney pathological changes were scored. Creatinine (CRE), blood urea nitrogen (BUN), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) levels in serum and Vitamin C levels and superoxide dismutase (SOD) activity and the ability to suppress hydroxyl radical (RAFHR) in plasma were measured. The expression of Sirtuin1 (SIRT1), Acetyl-NF-κB (Ace-NF-κB), heme oxygenase-1 (HO-1), TNF-α, and IL-1β in tissues was analyzed by ELISA or western-blot. In the HS group, the kidney pathological score and CRE, BUN, TNF-α, and IL-1β levels in serum were significantly higher than in the Sham group ( P  < 0.05), while SOD and RAFHR were significantly decreased in the plasma ( P  < 0.05). SOD activity and SIRT1 expression were remarkably lower in the kidney in the HS group than in the Sham group ( P  < 0.05), while MDA, TNF-α, and IL-1β concentrations and Acetyl-NF-κB andHO-1 expression in the kidney showed a noteworthy increase compared to the Sham group ( P  < 0.05). Compared to the HS group, VC treatment led to a remarkable reduction in the kidney pathological score and CRE,BUN,TNF-α, and IL-1β levels ( P  < 0.05), and a significant increase in Vitamin C, SOD, and RAFHR levels in the plasma ( P  <  0.05 ). Additionally, MDA, TNF-α, IL-1β and Acetyl-NF-κB expression levels were decreased in the kidney ( P < 0.05), while SOD, SIRT1 and HO-1 levels were notably enhanced. There were no differences between the H + VL and H + VH groups aside from plasma Vitamin C levels. The effect of Vitamin C was decreased after the addition of EX527, which inhibits SIRT1. Intravenous Vitamin C might attenuate HS-related renal injury via the SIRT1 pathway, and it appears that there were no differences in the effects between the high and low doses. [ABSTRACT FROM AUTHOR]

Background Uncontrolled hemorrhage (UH) remains the most common cause of death on the battlefield. This study examined the pathophysiological characteristics of UH in rats acutely exposed to high altitude. Material and methods Rats raised at sea level were randomly divided into two groups. Rats in the high-altitude group were exposed to hypobaric hypoxia in a hypobaric chamber (simulating 4000 m above sea level) for 2 d and then were performed a hemorrhagic shock protocol in the hypobaric chamber. Rats that underwent the same hemorrhage procedure at sea level were used as control. Anesthetized rats were bled to maintain their mean arterial pressure at 45 mmHg for 1 h. The distal quarter of the tail was amputated to allow free blood loss. After 1 h, the tail cut was ligated to induce hemostasis. mean arterial pressure, acid–base balance, blood loss, and survival were recorded. Rats were killed, and tissues were obtained for histological analysis. Results Rats in the high-altitude group suffered less uncontrolled blood loss, more severe acidosis (lower pH and base excess), and inferior tissue oxygen supply (lower oxygen saturation and higher arterial lactate concentration) during the hemorrhage periods compared with the control group. Survival rates were significantly lower in the high-altitude group than those in the control group ( P < 0.05), which was consistent with the results of pathological tissue injury. Conclusions In this rat model of hemorrhagic shock, acute high-altitude exposure resulted in decreased UH but more serious hemorrhagic shock injuries than that at sea level. [ABSTRACT FROM AUTHOR]

Aims This study was designed to investigate the protective effects of centrally administered erythropoietin (EPO) on brain oxidative stress and inflammatory markers to protect the kidneys during hemorrhagic shock (HS). Main methods Animals were assigned into three groups ( n = 6). Sham rats were subjected to cannulation of femoral artery and vein as well as stereotaxic surgery. In HS group, 50% of total blood volume was withdrawn and resuscitation was started 2 h later. In EPO group, stereotaxic surgery in lateral ventricle was performed one week before induction of HS for administration of EPO (2 IU) just before resuscitation. Plasma samples, kidney and brain tissues were allocated after a further 3 h in all animals. Key findings There was a significant increase in survival rate in the EPO group (69.3%) compared to the HS group (35.7%). Brain EPO administration significantly attenuated the rises in BUN, plasma Cr and NGAL, brain and renal MDA content and also increased SOD activity in the kidney and brain compared to the HS group. Brain, plasma and kidney TNF-α and IL-6 levels were significantly reduced by EPO compared to HS group. EPO increased the phosphorylation of Akt on Ser473 and eNOS mRNA expression in the kidney tissue compared to the HS group. Significance In conclusion, centrally administered EPO reduced pro-inflammatory and oxidative stress indices in the kidney and reduced apoptosis by activation of the Akt/eNOS signaling pathway. Hence, it can be hypothesized that EPO may play a major role in the central regulation of renal system as a neuromodulator. [ABSTRACT FROM AUTHOR]

Background: The hypertonic saline (HTS) solutions have recently gained widespread acceptance in control of shock. Aim of the work: The aim of this work is to study the use of hypertonic saline with the resuscitation fluids in rats with induced hemorrhagic shock to evaluate the impact of this solution on the extent of early bacterial translocation, blood pressure, and histopathological liver changes. Materials and methods: sixty phenobarbital anesthetized rats were involved in this study where they were allowed to bleed. Arterial pressure was maintained below 50 mm Hg for 30 minutes. They were randomized into 2 groups, each of 30 rats. Resuscitation in group I was done by using Lactated Ringer's (LR) solution (60 ml/Kg) and in group II HTS 7.5% in a dose of 4 ml/kg body weight was added to Lactated Ringer's (LR) solution (60 ml/Kg). Regular monitoring of blood pressure was done and blood samples were withdrawn 1, 30, and 90 minutes and 6 hours after commencement of the resuscitation and sent for blood culture for both aerobic and anaerobic growths. After 24 hours the liver was resected and sent for histological examination. Results: The mean arterial blood pressure in group I before resuscitation was found to be about 48±11 mm Hg and it was raised to a mean of 90±8 mm Hg after 2 hours of resuscitation with LR alone. In group II, the mean arterial blood pressure was found to be 49±5 mm Hg and it was efficiently controlled by HTS with LR and 2 hours after commencement of resuscitation it was elevated to 114±10 mm Hg. The blood cultures were positive in 3.3% of the rats of group II and in 40% of rats of group I. Escherichia coli were the most commonly isolated organism. Histopathological findings showed inflammatory process and early severe hepatocyte degeneration of the liver of group I rats and these changes were absent or minimal in group II. Conclusion: hypertonic saline was found to be effective for decreasing the rate of early bacterial translocation to blood and also for more efficient restoring of the mean arterial pressure in rats with induced hemorrhagic shock; in addition, HTS infusion minimizes the inflammatory and degenerative process in liver. [ABSTRACT FROM AUTHOR]

Objective: ET-26 HCl is a promising sedative–hypnotic anesthetic with virtually no effect on adrenocortical steroid synthesis. However, whether or not ET-26 HCl also has a sufficiently wide safety margin and hemodynamic stability similar to that of etomidate and related compounds remains unknown. In this study, the effects of ET-26 HCl, etomidate and propofol on therapeutic index, heart rate (HR), mean arterial pressure (MAP), maximal rate for left ventricular pressure rise (Dmax/t), and maximal rate for left ventricular pressure decline (Dmin/t) were investigated in healthy rats and a rat model of uncontrolled hemorrhagic shock (UHS). Methods: 50% effective dose (ED50) and 50% lethal dose (LD50) were determined after single bolus doses of propofol, etomidate, or ET-26 HCl using the Bliss method and the up and down method, respectively. All rats were divided into either the normal group and received either etomidate, ET-26 HCl or propofol, (n = 6 per group) or the UHS group and received either etomidate, ET-26 HCl or propofol, (n = 6 per group). In the normal group, after preparation for hemodynamic and heart-function monitoring, rats were administered a dose of one of the test agents twofold-higher than the established ED50, followed by hemodynamic and heart-function monitoring. Rats in the UHS group underwent experimentally induced UHS with a target arterial pressure of 40 mmHg for 1 hour, followed by administration of an ED50 dose of one of the experimental agents. Blood-gas analysis was conducted on samples obtained during equilibration with the experimental setup and at the end of the experiment. Results: In the normal group, no significant differences in HR, MAP, Dmax/t and Dmin/t (all P > 0.05) were observed at any time point between the etomidate and ET-26 HCl groups, whereas HR, MAP and Dmax/t decreased briefly and Dmin/t increased following propofol administration. In the UHS group, no significant differences in HR, MAP, Dmax/t and Dmin/t were observed before and after administration of etomidate or ET-26 HCl at ED50 doses (all P > 0.05). Administration of propofol resulted in brief, statistically significant reductions in HR and Dmax/t, with a brief increase in Dmin/t (P ˂ 0.05), while no significant differences in MAP were observed among the three groups. The blood-lactate concentrations of rats in the ET-26 HCl group were significantly lower than those in etomidate and propofol groups (P ˂ 0.05). Conclusions: ET-26 HCl provides a similar level of hemodynamic stability to that obtained with etomidate in both healthy rats, and rat models of UHS. ET-26 HCl has the potential to be a novel induction anesthetic for use in critically ill patients. [ABSTRACT FROM AUTHOR]

Background Oxidative stress induced by hemorrhagic shock (HS) is known to initiate a systemic inflammatory response, which leads to subsequent acute lung injury. This study is aimed to assess the efficacy of exendin-4 (Ex-4) in attenuating lung injury in a rat model of HS and resuscitation (HS/R). Methods HS was induced in sodium pentobarbital–anesthetized adult male Wistar rats by withdrawing blood to maintain a mean arterial pressure of 30-35 mm Hg for 50 min. Then, the animals received Ex-4 (5 μg/kg) or vehicle (saline) intravenously and were resuscitated with a volume of normal saline 1.5 times that of the shed blood volume. Mean arterial pressure was measured throughout the experiment, and acid-base status, oxidative stress, inflammation, and lung injury were evaluated at 2 h after resuscitation. Results Ex-4 infusion reduced the methemoglobin content, the malondialdehyde content, the myeloperoxidase activity, and the expression of tumor necrosis factor-α and interleukin-6 in the lungs. The histologic injury was also markedly decreased in the Ex-4 group compared with the vehicle group. Conclusions Ex-4 ameliorates the oxidative stress, inflammatory response, and subsequent acute lung injury occurring after HS/R. Although future studies are required to elucidate the underlying mechanism, our results indicate that Ex-4 infusion may be a promising strategy for improving lung injury in the treatment of HS. [ABSTRACT FROM AUTHOR]

Hemorrhagic shock (HS) is associated with an excessive activation of inflammation, contributing to multiple organ failure in numerous medical or surgical conditions. To explore the therapeutic potential of crocin, a natural compound with anti-inflammatory properties, we administered crocin to rats during resuscitation following HS induced by withdrawing blood. Compared with control animals which were sham-treated, HS-operated rats showed organ damages as manifested by enhanced markers of multiple organ dysfunctions. Crocin treatment substantially reduced these parameters in rats subjected to HS, suggesting an alleviation of tissue injuries such as in the kidney, liver, pancreas, and muscle. The activation of NF-κB (nuclear factor κB) pathway in lung tissue by HS, as shown by increased nuclear translocation of p65 and IκBα phosphorylation, was diminished by crocin treatment. The crocin administration also significantly decreased the serum levels of proinflammatory cytokine TNF-α (tumor necrosis factor-α) and interleukin (IL)-6, whereas increased the level of anti-inflammatory cytokine IL-10 in HS-operated rats. These studies indicate that crocin administration may reduce inflammation-driven tissue damage in patients with HS. [ABSTRACT FROM AUTHOR]

The effects of polymerized porcine hemoglobin (pPolyHb) on hemodynamic stability and maintenance of mesenteric microvascular function were explored in a rat model of hemorrhagic shock (HS). Following controlled hemorrhage, rats were infused with equal volumes of either pPolyHb, hetastarch (HES), or red blood cell (RBC). The results showed that pPolyHb was superior to HES and RBC in restoring hemodynamic stability and reversing anaerobic metabolism. We observed a reduction in the diameter of mesenteric microvasculature after HS. Resuscitation with pPolyHb and RBC was able to restore the diameters of the venules and arterioles, whereas HES failed to restore the diameters during the observation period. [ABSTRACT FROM AUTHOR]

We aimed to evaluate the effect of natural antioxidant crocin in alleviating hemorrhagic shock (HS)-induced organ damages. HS rats were treated with crocin during resuscitation. Mortality at 12 h and 24 h post resuscitation was documented. HS and resuscitation induced organ injuries, as characterized by elevated wet/dry ratio, quantitative assessment ratio, blood urea nitrogen, creatinine, aspartate aminotransferase and alanine aminotransferase, whereas rats received crocin treatment demonstrated improvements in all the above characteristics. This protective effect coincided with reduced malondialdehyde and increased glutathione in both serum and lung tissues, indicating attenuated oxidative stress in crocin-treated rats. Myeloperoxide levels in lung, kidney and liver were also reduced. Crocin can potentially be used to protect organs from HS-induced damages during resuscitation due to its anti-oxidative role. [ABSTRACT FROM AUTHOR]

Background To overcome the problems of previously reported hemoglobin-based oxygen carriers, we developed a stabilized nonpolymeric cross-linked tetrameric hemoglobin solution (YQ23). The aims of this study were to investigate the oxygen carrying and releasing properties of this novel hemoglobin-based oxygen carrier and to determine whether it has beneficial effects for hemorrhagic shock. Methods Using a hemorrhagic shock model in Sprague–Dawley rats and mini-pigs, we tested the effects of infusing 0.1, 0.3, and 0.5 g/kg YQ23 on animal survival, tissue oxygen delivery (DO 2 ) and consumption (VO 2 ), hemodynamics parameters, and liver, renal, and cardiac function. Results YQ23 infusion increased the survival rate of rats and pigs with severe hemorrhagic shock in a dose-dependent manner. Moreover, it improved the hemodynamic parameters, cardiac output, DO 2 and VO 2 , and the mitochondrial respiratory function of vital organs. Among the three doses of YQ23, 0.5 gHb/kg YQ23 achieved a similar beneficial effect as whole blood. Conclusions This study indicated that the novel cross-linked tetrameric hemoglobin YQ23 has good oxygen carrying and releasing properties and exhibits beneficial effects on hemorrhagic shock in rats and pigs by improving the oxygen carrying and delivery function of blood, which maintains organ function. [ABSTRACT FROM AUTHOR]

Traumatic brain injury and hemorrhagic shock is associated with blood-brain barrier (BBB) breakdown and edema formation. Recent animal studies have shown that fresh frozen plasma (FFP) resuscitation reduces brain swelling and improves endothelial function compared to isotonic NaCl (NS). The aim of this study was to investigate whether pooled and pathogen-reduced plasma (OctaplasLG® [OCTA]; Octapharma, Stockholm, Sweden) was comparable to FFP with regard to effects on brain water content, BBB permeability, and plasma biomarkers of endothelial glycocalyx shedding and cell damage. After fluid percussion brain injury, hemorrhage (20 mL/kg), and 90-min shock, 48 male Sprague-Dawley rats were randomized to resuscitation with OCTA, FFP, or NS ( n = 16/group). Brain water content (wet/dry weight) and BBB permeability (transfer constant for 51Cr-EDTA) were measured at 24 h. Plasma osmolality, oncotic pressure, and biomarkers of systemic glycocalyx shedding (syndecan-1) and cell damage (histone-complexed DNA) were measured at 0 and 23 h. At 24 h, brain water content was 80.44 ± 0.39%, 80.82 ± 0.82%, and 81.15 ± 0.86% in the OCTA, FFP, and NS groups (lower in OCTA vs. NS; p = 0.026), with no difference in BBB permeability. Plasma osmolality and oncotic pressures were highest in FFP and OCTA resuscitated, and osmolality was further highest in OCTA versus FFP ( p = 0.027). In addition, syndecan-1 was highest in FFP and OCTA resuscitated ( p = 0.010). These results suggest that pooled solvent-detergent (SD)-treated plasma attenuates the post-traumatic increase in brain water content, and that this effect may, in part, be explained by a high crystalloid and colloid osmotic pressure in SD-treated plasma. [ABSTRACT FROM AUTHOR]

Background The plasmin/plasminogen inhibitor tranexamic acid (TXA) is mainly used in elective surgeries with a higher blood loss to avoid uncontrolled bleeding. Recently, TXA has also been shown to reduce mortality in trauma patients. It is assumed that its beneficial effects are principally caused by its antifibrinolytic properties. We hypothesize that TXA also improves survival in a modified Wigger's model of hemorrhagic shock by a mechanism other than antifibrinolysis. Materials and methods Male Wistar rats were intermittently bled until the mean arterial blood pressure was dropped to 25-30 mm Hg (severe shock). After shock induction, the animals received either 0.14-0.15 mL TXA (30 mg/kg) i.v. or the equivalent volume of 0.9% NaCl given as bolus. Adjacent to the shock period, the rats were resuscitated with Ringer's solution within 30 min and observed for another 150 min unless the animals died earlier. Results In the animals treated with TXA, survival was clearly prolonged and acid–base parameters showed some differences as compared to the animals receiving only NaCl. In the model used, coagulation slightly declined, but an increased fibrinolysis was not observed. Conclusions Since in the applied shock model fibrinolysis is negligible, we postulate that TXA is capable of providing protection against hemorrhagic shock independent from its antifibrinolytic properties. [ABSTRACT FROM AUTHOR]

Background Severe hemorrhage shock and resuscitation are a systemic ischemia–reperfusion phenomenon which can induce learning and memory deficit in human and rats. Sevoflurane postconditioning has been proved to offer neuroprotection under different setting of cerebral ischemia–reperfusion in rats. The aim of this study was to investigate whether sevoflurane postconditioning could improve spatial learning and memory ability after hemorrhage shock and resuscitation in rats. Methods Thirty-five male rats were randomized into five groups: sham group, shock group, low concentration (sevo1, 1.2%), middle concentration (sevo2, 2.4%), and high concentration (sevo3, 3.6%) of sevoflurane postconditioning groups. The spatial learning and memory ability of rats were measured by Morris water maze 3 d after the operation. The expression of choline acetyltransferase (CHAT) and acetylcholinesterase (ACHE) in the hippocampus CA1 region was observed by immunohistochemistry method after the Morris water maze test. Results The ability of spatial learning and memory of rats and the expression of CHAT was significantly declined, while the expression of ACHE increased in the shock group compared with the sham group ( P < 0.05). Sevoflurane postconditioning with the concentrations of 2.4% and 3.6% significantly ameliorated the spatial learning and memory ability and increased the expression of CHAT and decreased the expression of ACHE in hippocampal CA1 region when compared with shock group ( P < 0.05). Conclusions Postconditioning with sevoflurane at the concentrations of 2.4% and 3.6% which improved the ability of spatial learning and memory after hemorrhage shock and resuscitation in rats may involve the protection of the cholinergic neurons in hippocampal CA1 region. [ABSTRACT FROM AUTHOR]

Hemorrhagic shock (HS) induces a compensatory endocrine and cytokine response which aims to restore homeostasis. This response can be modulated by general anesthetics. To our knowledge, no studies have evaluated if etomidate modulates this response in experimental HS. After being premedicated with buprenorphine (0.05 mg/kg subcutaneously), male Wistar rats were anaesthetized with 5% isoflurane and divided into three groups: G1 (control, n = 16), G2 (n = 13), and G3 (n = 14). G2 and G3 were subjected to HS by collecting 30% of their blood volume and resuscitated 90 min later with the collected blood and normal saline, in a 1:3 ratio, respectively. G3 received etomidate (1 mg/kg IV) before HS. Blood gas analysis, adrenocorticotropic hormone (ACTH), corticosterone, and plasma levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10 and of TNF-α, IL-6, and IL-10 mRNA obtained through real-time polymerase chain reaction (RT-PCR) were measured at 0, 90, 150, and 240 min after HS induction. Compared with G2, etomidate-treated animals had significantly lower corticosterone, PO2, PO2/FiO2, base excess and HCO3, and higher TNF-α, IL-6, IL-10, and TNF-α mRNA levels (P <0.05). Etomidate-treated rats showed impaired adrenal and increased cytokine response to HS and evidence of worse tissue oxygenation and lung dysfunction. Based on these results, and until further studies are performed to confirm if these findings occur in clinical patients, we suggest that etomidate should be used cautiously in HS. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the resuscitative efficacy and the effect on reperfusion injury of two site-specific PEGylated human serum albumins modified with linear or branched PEG20kDa, compared with saline, 8% human serum albumin and 25% human serum albumin, in a hemorrhagic shock model.Setting: Laboratory.Subjects: Male Wistar rats.Design: Prospective study.Interventions: Rats were bled to hemorrhagic hypovolemic shock and resuscitated with different resuscitation fluids.Measurements and Main Results: The mean arterial pressure and blood gas variables were measured. Hemorheology analysis was performed to evaluate the influence of resuscitation on RBCs and blood viscosity. The microvascular state was indirectly characterized in terms of monocyte chemotactic protein-1 and endothelial nitric oxide synthase that related to shear stress and vasodilation, respectively. The levels of inflammation-related factors and apoptosis-related proteins were used to evaluate the reperfusion injury in lungs. The results showed that PEGylated human serum albumin could improve the level of mean arterial pressure and blood gas variables more effectively at the end of resuscitation. poly(ethylene glycol) modification was able to increase the viscosity of human serum albumin to the level of effectively enhancing the expression of monocyte chemotactic protein-1 and endothelial nitric oxide synthase, which could promote microvascular perfusion. The hyperosmotic resuscitative agents including both 25% human serum albumin and PEGylated human serum albumins could greatly attenuate lung injury. No significant therapeutic advantages but some disadvantages were found for Y shaped poly(ethylene glycol) modification over linear poly(ethylene glycol) modification, such as causing the decrease of erythrocyte deformability.Conclusions: Linear high molecular weight site-specific PEGylated human serum albumin is recommended to be used as a hyperosmotic resuscitative agent. [ABSTRACT FROM AUTHOR]

Cardiac trauma has been recognized as a complication associated with blunt chest trauma involving coronary artery injury, myocardium contusion and myocardial rupture. Secondary cardiac injuries after trauma supposed to be a critical factor in trauma patients, but the mechanism is not fully explored. Overproduction of TNF-alpha had been reported in multiple trauma animals, this induces oxidative stress resulting in cardiac apoptosis. Apoptosis gradually increases after trauma and reaches to a maximum level in 12 h time. TNF-alpha increases the expression of NFkB, and induces the expression of caspase-3 and resulted in cell apoptosis. The effect can be attenuated by non-selective caspase inhibitor and IL10. Fas induced cardiac apoptosis and hypertrophy in ischemic heart disease. In this study, we demonstrated a trauma-hemorrhagic shock (THS) model in rats and resuscitated rats by lactated Ringer’s (L/R) solution after shock in different hours (0 hour, 4 hours, 8 hours). NFkB gradually increased after the first 8 hours of shock, and can be reduced by fluid resuscitation. NFkB is known as a downstream pathway of Fas related apoptosis, we found Fas ligand, caspase-8 levels elevate after shock, and can be reduced by resuscitation. In addition, resuscitation can activate insulin-like growth factor (IGF-1)/Akt pathway, at the same time. It can block mitochondrial damage by decrease the effect of tBid. In conclusion, THS can induce secondary cardiac injury. Fas showed to be an important element in caspase cascade induced myocardium apoptosis. By L/R fluid resuscitation, the suppression of caspase cascade and activation of IGF-I/Akt pathway showed antiapoptotic effects in traumatic heart of rats. [ABSTRACT FROM AUTHOR]

Background: Lactate, acetate, and gluconate are anions used in balanced resuscitation fluids, of which lactate and acetate are considered bicarbonate precursors. This study investigated the role of the liver in the ability of balanced and unbalanced solutions to correct acid-base alterations and renal haemodynamics and microvascular oxygenation in a rat model of resuscitated haemorrhagic shock.Methods: Ringer's lactate, Ringer's acetate, PlasmaLyte, or normal saline were administered following haemorrhagic shock in the presence or absence of a 70% partial liver resection. Renal haemodynamics and microvascular oxygenation (by oxygen-dependent quenching of phosphorescence) were measured as well as concentrations of lactate, gluconate, and acetate in plasma and urine. Kidney wet and dry weight was also assessed.Results: Partial liver resection resulted in increased liver enzymes compared with control and shock groups (P < 0.01). Haemorrhagic shock decreased systemic and renal perfusion and reduced microvascular kidney oxygenation with lactic acidosis (P < 0.01). Resuscitation with balanced fluids did not fully restore renal oxygenation (P < 0.01). Ringer's acetate and PlasmaLyte increased bicarbonate content and restored pH better than Ringer's lactate or saline after partial liver resection (P < 0.01). Liver resection caused an increase in plasma gluconate after PlasmaLyte resuscitation (P < 0.05).Conclusions: Acetate-buffered balanced fluids show superior buffering effects compared with Ringer's lactate or saline. Gluconate is partially metabolized by the liver, although it does not contribute to acid-base control because of its excretion in urine. Acetate is metabolized regardless of liver function and may be the most efficient bicarbonate precursor. Lactate infusion tends to overwhelm the metabolism capacity of the residual liver. [ABSTRACT FROM AUTHOR]

Introduction Resuscitation after hemorrhagic shock (HS) could result in increased pro-inflammatory cytokines and then multiple organ dysfunctions. Calcitriol exerts pleiotropic effects in a wide variety of target tissues and has a role against anti-inflammation. The present study was aimed to investigate the modulatory effects of calcitriol on the pathophysiological and inflammatory markers following HS in rats. Materials and methods By withdrawing 60% of the total blood volume over 30 min via a femoral artery catheter in rats, HS was induced. Afterwards, 10 ng/kg calcitriol was injected intravenously in rats. After performing these procedures, hemodynamic status of mean arterial pressure (MAP) and heart rate (HR) were continuously monitored for 12 h. Hemoglobin, lactic dehydrogenase (LDH), creatine phosphokinase (CPK), liver and renal function were measured at 30 min before the induction of HS and 0, 1, 3, 6, 9, and 12 h after HS, while an equal volume of normal saline as replacement fluid. At 1 and 12 h after inducing HS, serum levels of tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were measured, and the livers, kidneys and lungs were taken out and then examined histo-pathologically at 48 h after inducing HS. Results Hemoglobin and MAP were significantly decreased, liver and renal function were significantly impaired, but HR and the levels of LDH, CPK, TNF-α and IL-6 were significantly increased after HS in rats. After being treated with calcitriol following HS resulted in better survival rate, lower serum levels of TNF-α and IL-6, and lesser hepatic, renal, and pulmonary histo-pathologic scores of injury in rats. Conclusion Being treated with calcitriol after HS could ameliorate the pro-inflammatory reactions by modulating the effects of cytokines, which lead to prevention of subsequent major organ damages. [ABSTRACT FROM AUTHOR]

This study tested the hypothesis that the hypothalamus participates in the decompensatory phase of hemorrhage by measuring Fos immunoreactivity and by inhibiting neuronal activity in selected hypothalamic nuclei with lidocaine or cobalt chloride. Previously, we reported that inactivation of the arcuate nucleus inhibited, but did not fully prevent, the fall in arterial pressure evoked by hypotensive hemorrhage. Here, we report that hemorrhage (2.2 ml/100 g body weight over 20 min) induced Fos expression in a high percentage of cells in the paraventricular, supraoptic and arcuate nuclei of the hypothalamus as shown previously. Lower densities of Fos immunoreactive cells were also found in the medial preoptic area (mPOA), anterior hypothalamus, lateral hypothalamus (LH), dorsomedial hypothalamus, ventromedial hypothalamus (VMH) and posterior hypothalamus. Bilateral injection of lidocaine (2%; 0.1 μl or 0.3 μl) or cobalt chloride (5 mM; 0.3 μl) into the tuberal portion of the LH immediately before hemorrhage was initiated reduced the magnitude of hemorrhagic hypotension and bradycardia significantly. Lidocaine injection into the VMH also attenuated the fall in arterial pressure and heart rate evoked by hemorrhage although inactivation of the mPOA or rostral LH was ineffective. These findings indicate that hemorrhage activates neurons throughout much of the hypothalamus and that a relatively broad area of the hypothalamus, extending from the arcuate nucleus laterally through the caudal VMH and tuberal LH, plays an important role in the decompensatory phase of hemorrhage. [ABSTRACT FROM AUTHOR]

Background Vascular hyporeactivity in severe hemorrhagic shock could induce refractory hypotension and is an important cause of death. The global acute inflammatory response induced in shock triggers the over-expression of reactive oxygen species, NO, ET1 and TNF-α, which play essential roles in the pathology of vascular hyporeactivity. This leads to a hypothesis that inhibition of the complement system, the mediator of the inflammatory cascade, might be a promising therapeutic exploration for vascular hyporeactivity. Methods We use cobra venom factor (CVF) and the soluble form of CR1 (sCR1) which deplete or inhibit complement C3 respectively to examine its role in vascular hyporeactivity in a conscious hemorrhagic shock rat model. Results We first confirmed the over-activation of C3 during shock and the down-regulation effects of CVF and sCR1 on C3. Then, both CVF and sCR1 could significantly mitigate the over-expression of serum NO, ET-1, TNF-α and reactive oxygen species. Finally, the vascular reactivity of superior mesenteric arteries (SMA) was examined in vitro, which confirmed the massive reduction of vascular reactivity in shock, which was significantly rescued by both CVF and sCR1. Conclusions Inhibition of C3 might improve the reactivity of SMA to norepinephrine during hemorrhagic shock possibly through the downregulation of NO, ET1, TNF-α and reactive oxygen radicals. [ABSTRACT FROM AUTHOR]

Background The mechanisms of early traumatic-induced coagulopathy are not well understood. Our aim was to examine the role of platelets and fibrinogen to early coagulopathy in the rat after hemorrhagic shock. Methods Adult Sprague-Dawley rats were anesthetized and randomly assigned to: 1) Baseline, 2) Hemorrhage or 3) Shock (n = 10 each). Controlled phlebotomy occurred over 20 min and animals were left in shock 60 min. Coagulation was assessed using PT, aPTT, ROTEM and ELISAs. Results PT and aPTT increased 5 to 7 times following hemorrhage and shock. Prolongation of EXTEM and INTEM clotting times, lower clot elasticity and increased EXTEM lysis index (LI) indicated a hypocoagulopathy. After 20 min hemorrhage, LI(30–60) in FIBTEM was ~ 100%, EXTEM 83–87% and APTEM 80–82% indicating a platelet contribution to the coagulopathy with no hyperfibrinolysis. After 60 min shock, the situation was reversed with fibrinogen loss being a contributor. This apparent switch from a platelet- to a fibrinogen-based coagulopathy, with fibrinolysis, was supported by ≥ 15% in maximum lysis (ML), a threefold increase in plasma PAI-1 after hemorrhage, and undetectable levels after shock. Curiously, the relative contribution of fibrinogen/platelet ratio to clot amplitude, determined from FIBTEM/EXTEM A10 ratio (and MCF), remained unchanged at ~ 1:5 for baseline, hemorrhage and shock despite a progressive hypocoagulopathy. Significant increases in P-selectin, acidosis and lactate indicated systemic endothelial damage and tissue hypoperfusion. Conclusions Hypocoagulopathy following severe hemorrhage and shock in the rat appeared to involve a two-step process of platelet dysfunction followed by fibrinogen impairment, possibly linked to progressive endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Background We have recently shown that inhibition of peptidylarginine deiminase (PAD) improves survival in a rodent model of lethal cecal ligation and puncture. The roles of PAD inhibitors in hemorrhagic shock (HS), however, are largely unknown. The goal of this study was to investigate the effects of YW3-56, a novel PAD inhibitor, on survival after severe HS. Methods Mouse macrophages were exposed to hypoxic conditions followed by reoxygenation in the presence or absence of YW3-56. Enzyme-linked immunosorbent assay (ELISA) was performed to measure levels of secreted tumor necrosis factor α and interleukin-6 in the culture medium. Cell viability was determined by methyl thiazolyl tetrazolium assay. In the survival experiment, anesthetized male Wistar–Kyoto rats ( n = 10/group) were subjected to 55% blood loss, and treated with or without YW3-56 (10 mg/kg, intraperitoneally). Survival was monitored for 12 h. In the nonsurvival experiment, morphologic changes of the lungs were examined. Levels of circulating cytokine-induced neutrophil chemoattractant 1 (CINC-1) and myeloperoxidase (MPO) in the lungs were measured by ELISA. Expression of lung intercellular adhesion molecules-1 (ICAM-1) was also determined by Western blotting. Results Hypoxia/reoxygenation (H/R) insult induced tumor necrosis factor α and interleukin-6 secretion from macrophages, which was significantly attenuated by YW3-56 treatment. YW3-56 treatment also increased cell viability when macrophages were exposed to H/R up to 6/15 h and improved survival rate from 20% to 60% in lethal HS rat model. Compared to the sham groups, pulmonary MPO activity and ICAM-1 expression in the HS group were significantly increased, and acute lung injury was associated with a higher degree of CINC-1 levels in serum. Intraperitoneal delivery of YW3-56 significantly reduced pulmonary MPO and ICAM-1 expression and attenuated acute lung injury. Conclusions Our results demonstrate for the first time that administration of YW3-56, a novel PAD inhibitor, can improve survival in a rat model of HS and in a cell culture model of H/R. The survival advantage is associated with an attenuation of local and systemic pro-inflammatory cytokines and the protection against acute lung injury after hemorrhage. Thus, PAD inhibition may represent a novel and promising therapeutic strategy for severe HS. [ABSTRACT FROM AUTHOR]

Maintenance of cerebral viability and function is an important goal of critical care in victims of injury due to ischemia and hypovolemia. As part of the multiple organ dysfunction syndrome, the brain function after trauma is influenced by the systemic inflammatory response. We investigated the effect of EF24, an anti-inflammatory bis-chalcone, on cerebral bioenergetics in a rat model of 45% hemorrhagic shock. The rats were treated with EF24 (0.4 mg/kg) or EF24 with an artificial oxygen carrier liposome-encapsulated hemoglobin (LEH). The volume of LEH administered was equal to the shed blood. The brain was collected after 6 h of shock for biochemical assays. EF24 treatment showed significant recovery of ATP, phosphocreatine, and NAD/NADH ratio. It also increased citrate synthase activity and cytochrome c oxidase subunit IV expression which were reduced in shock brain. Furthermore, it reduced the shock-induced accumulation of pyruvate and pyruvate dehydrogenase kinase-1 expression, suggesting that EF24 treatment improves cerebral energetics by restoring perturbed pyruvate metabolism in the mitochondria. These effects of EF24 were associated with reduced poly(ADP-ribose) polymerase cleavage and a significant improvement in the levels of nerve growth factor and brain-derived neurotrophic factor in shock brain. Co-administration of LEH with EF24 was only marginally more effective as compared to the treatment with EF24 alone. These results show that EF24 treatment sets up a pro-survival phenotype in shock by resurrecting cerebral bioenergetics. Since EF24 was effective in the absence of accompanying fluid resuscitation, it has potential utility as a pre-hospital pharmacotherapy in shock due to accidental blood loss. [ABSTRACT FROM AUTHOR]

This study investigated the cardiovascular effects of nesfatin-1 in normotensive rats and animals subjected to hypotensive hemorrhage. Hemorrhagic hypotension was induced by withdrawal 2 mL blood/100 g body weight over a period of 10 min. Acute hemorrhage led to a severe and long-lasting decrease in mean arterial pressure (MAP) and heart rate (HR). Intracerebroventricularly (i.c.v.) administered nesfatin-1 (100 pmol) increased MAP in both normotensive and hemorrhaged rats. Nesfatin-1 also caused bradycardia in normotensive and tachycardia in hemorrhaged rats. Centrally injected nesfatin-1 (100 pmol, i.c.v.) also increased plasma catecholamine, vasopressin and renin concentrations in control animals and potentiated the rise in all three cardiovascular mediators produced by hemorrhage. These findings indicate that centrally administered nesfatin-1 causes a pressor response in conscious normotensive and hemorrhaged rats and suggest that enhanced sympathetic activity and elevated vasopressin and renin concentrations mediate the cardiovascular effects of the peptide. [ABSTRACT FROM AUTHOR]

Our study intended to determine the effects on oxygen uptake ( V ˙ O 2 ) of restoring a normal rate of O 2 delivery following blood transfusion (BT) after a severe hemorrhage (H). Spontaneously breathing urethane anesthetized rats were bled by removing 20 ml/kg of blood over 30 min. Rats were then infused with their own shed blood 15 min after the end of H. At mid-perfusion, half of the rats received a unique infusion of the decoupling agent 2,4-dinitrophenol (DNP, 6 mg/kg). V ˙ O 2 and arterial blood pressure (ABP) were continuously measured throughout the study, along with serial determination of blood lactate concentration [La]. Animals were euthanized 45 min after the end of reperfusion; liver and lungs were further analyzed for early expression of oxidative stress gene using RT-PCR. Our bleeding protocol induced a significant decrease in ABP and increase in [La], while V ˙ O 2 dropped by half. The O 2 deficit progressively accumulated during the period of bleeding reached −114 ± 53 ml/kg, just before blood transfusion. Despite the transfusion of blood, a significant O 2 deficit persisted (−82 ± 59 ml/kg) 45 min after reperfusion. This slow recovery of V ˙ O 2 was sped up by DNP injection, leading to a fast recovery of O 2 deficit after reperfusion, becoming positive (+460 ± 132 ml/kg) by the end of the protocol, supporting the view that O 2 supply is not the main controller of V ˙ O 2 dynamics after BT. Of note is that DNP also enhanced oxidative stress gene expression (up-regulation of NADPH oxidase 4 in the lung for instance). The mechanism of slow recovery of O 2 requirement/demand following BT and the resulting effects on tissues exposed to relatively high O 2 partial pressure are discussed. [ABSTRACT FROM AUTHOR]

Background: Metabolic derangement is a key hallmark of major traumatic injury. The recent introduction of mass spectrometry-based metabolomics technologies in the field of trauma shed new light on metabolic aberrations in plasma that are triggered by trauma and hemorrhagic shock. Alteration in metabolites associated with catabolism, acidosis and hyperglycemia have been identified. However, the mechanisms underlying fluxes driving such metabolic adaptations remain elusive. Methods: A bolus of U-13C-glucose was injected in Sprague–Dawley rats at different time points. Plasma extracts were analyzed via ultra-high performance liquid chromatography-mass spectrometry to detect quantitative fluctuations in metabolite levels as well as to trace the distribution of heavy labeled carbon isotopologues. Results: Rats experiencing trauma did not show major plasma metabolic aberrations. However, trauma/hemorrhagic shock triggered severe metabolic derangement, resulting in increased glucose levels, lactate and carboxylic acid accumulation. Isotopologue distributions in late Krebs cycle metabolites (especially succinate) suggested a blockade at complex I and II of the electron transport chain, likely due to mitochondrial uncoupling. Urate increased after trauma and hemorrhage. Increased levels of unlabeled mannitol and citramalate, metabolites of potential bacterial origin, were also observed in trauma/hemorrhagic shock rats, but not trauma alone or controls. Conclusions: These preliminary results are consistent with observations we have recently obtained in humans, and expand upon our early results on rodent models of trauma and hemorrhagic shock by providing the kinetics of glucose fluxes after trauma and hemorrhage. Despite the preliminary nature of this study, owing to the limited number of biological replicates, results highlight a role for shock, rather than trauma alone, in eliciting systemic metabolic aberrations. This study provides the foundation for tracing experiments in rat models of trauma. The goal is to improve our understanding of substrate specific metabolic derangements in trauma/hemorrhagic shock, so as to design resuscitative strategies tailored toward metabolic alterations and the severity of trauma. [ABSTRACT FROM AUTHOR]

5(S),6(R)-7-trihydroxymethyl heptanoate (BML-111) is an lipoxin A4 receptor agonist, which modulates the immune response and attenuates hemorrhagic shock-induced acute lung injury. However, the role of BML-111 in sepsis and in the intestinal mucosal barrier are not well understood. Therefore, the present study was designed to investigate the effect of BML-111 on the intestinal mucosal barrier in a rat model of sepsis. Furthermore, the molecular mechanism of action of BML-111 was evaluated. The cecal ligation and puncture-induced rat model of sepsis was constructed, and BML-111 was administered at three different doses. The results revealed that BML-111 suppressed the elevation of the pro-inflammatory cytokines tumor necrosis factor-α and interleukin-6, while enhancing the elevation of the anti-inflammatory cytokine transforming growth factor-β in the intestine. In addition, BML-111 significantly upregulated rat defensin-5 mRNA expression levels and downregulated the induction of cell apoptosis as well as caspase-3 activity in the intestine. All these results demonstrated that BML-111 exerted protective effects on the intestinal mucosal barrier in sepsis. Further, it was indicated that alterations in the expression of toll-like receptor (TLR)2 and TLR4 may be one of the molecular mechanisms underlying the protective effect of BML-111. The present study therefore suggested that BML-111 may be a novel therapeutic agent for sepsis. [ABSTRACT FROM AUTHOR]

This study examined the effects of polyethylene oxide (PEO) on the survival rate, hemodynamics, blood gas indexes, lactic acid levels, microcirculation, and inflammatory cytokine levels in rats subjected to severe hemorrhagic shock. The shocked rats were resuscitated with either Ringer's lactate solution or 20 ppm of PEO in Ringer's lactate solution for 1 h. It was found that infusion of PEO effectively improved the survival, metabolic acidosis, oxygen delivery, hyperlactacidemia, tissue perfusion, and inflammatory responses of rats subjected to hemorrhagic shock. In addition, we found, for the first time, that PEO showed protective effects on hepatic and renal injury, as evidenced by the significant decreases in the elevated levels of alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and creatinine caused by shock induction after infusion of PEO ( p < 0.05, 60 min post-resuscitation by comparison with pre-resuscitation). All of these findings indicate that PEO exhibits strong therapeutic effects under conditions of severe hemorrhagic shock,which also provides theoretical and experimental bases for the clinical use of PEO. [ABSTRACT FROM AUTHOR]

Background: Insulin has been shown to exert positive inotropic effects in several in vivo ex vivo models and in human hearts. Resuscitation following hemorrhagic shock results in myocardial contractile dysfunction. However, the optimal timing for treatment with insulin for the cardioprotection effects is unclear. Objectives: The objective of this study was to test the hypothesis that treatment with insulin before resuscitation provides better cardioprotection than treatment with insulin after resuscitation. Materials and Methods: Rats were assigned to 3 experimental groups (n = 6 per group): (1) Hemorrhagic shock and resuscitation, (2) hemorrhagic shock resuscitated then treated with insulin and (3) hemorrhagic shock treated with insulin before resuscitation. Rats were hemorrhaged for 60 min to rach mean arterial blood pressure of 40 mmHg. Rats were resuscitated in vivo by reinfusion of the shedded blood to restore normotension and monitored for 60 min. Rats were treated or not with insulin 200 μU/g body weight intramuscularly either before or after resuscitation. The maximum of the left ventricular developed pressure (+dP/dt) was measured for 60 min in the isolated perfused hearts using the Langendorff method. Blood samples were obtained for measurements of tumor necrosis factor-alpha (TNF-α). Results: Treatment with insulin before resuscitation following hemorrhagic shock significantly elevated max dP/dt compared with insulin treatment after resuscitation and the untreated group. TNF-α levels were lower in the insulin treatment before resuscitation compared to the treatment after resuscitation and the untreated group. Conclusion: Insulin treatment before resuscitation following hemorrhagic shock provides better cardiac protection than treatment with insulin after resuscitation, as evidenced by the improved myocardial contractility, preservation of myocardial structure. The mechanism of cardiac protection involves decrease in the inflammatory response to shock by lowering the levels of TNF. [ABSTRACT FROM AUTHOR]

Background Therapeutic hypothermia (hypo) and valproic acid (VPA, a histone deacetylase inhibitor) have independently been shown to be protective in models of trauma and hemorrhagic shock but require logistically challenging doses to be effective. Theoretically, combined treatment may further enhance effectiveness, allowing us to use lower doses of each modality. The aim of this study was to determine whether a combination of mild hypo and VPA treatments would offer better cytoprotection compared with that of individual treatments in a hemorrhage model. Materials and methods Male Sprague-Dawley rats were subjected to 40% volume-controlled hemorrhage, kept in shock for 30 min, and assigned to one of the following treatment groups: normothermia (36°C-37°C), hypo (30 ± 2°C), normothermia + VPA (300 mg/kg), and hypo + VPA (n = 5 per group). After 3 h of observation, the animals were sacrificed, liver tissue was harvested and subjected to whole cell lysis, and levels of key proteins in the prosurvival Akt pathway were measured using Western blot. Results Activation of the proapoptotic protein cleaved caspase-3 was significantly lower in the combined treatment group relative to normothermia (P < 0.05). Levels of the prosurvival Bcl-2 was significantly higher in the combined treatment group relative to sham, normothermia, and normothermia + VPA groups (P < 0.005). The downstream prosurvival protein phospho-GSK-3ß was significantly higher in the sham, hypo, and combined treatment groups compared with that in normothermia groups with or without VPA (P < 0.05). Levels of the prosurvival ß-catenin were significantly higher in the combined treatment group relative to normothermia (P < 0.01). Conclusions This is the first in vivo study to demonstrate that combined treatment with VPA and hypo offers better cytoprotection than these treatments given independently. [ABSTRACT FROM AUTHOR]

Background Vascular hyporesponsiveness is an important pathophysiological feature of some critical conditions such as hemorrhagic shock. Many proteins and molecules are involved in the regulation of the pathologic process, however the mechanism has still remained unclear. Our study was intended to look for the related protein markers involved in the regulation of vascular reactivity after hemorrhagic shock. Methods Differential in-gel electrophoresis and tandem mass spectrometry were applied to quantify the differences of protein expression in the superior mesenteric arteries from hemorrhagic shock and normal rats. Results A total of 2317 differentially expressed protein spots in the superior mesenteric arteries of rats before and after hemorrhagic shock were found, and 146 protein spots were selected for tandem mass spectrometry identification. Thirty-seven differentially expressed proteins were obtained, including 3 uncharacterized proteins and 34 known proteins. Among them, heat shock protein beta-1 and calmodulin were the known proteins involved in the occurrence of vascular hyporesponsiveness. Bioinformatics analysis results showed that 18 proteins were related to vasoconstriction, 11 proteins may be involved in other vascular functions such as regulation of angiogenesis and endothelial cell proliferation. Conclusions The changes of vascular responsiveness after hemorrhagic shock in rats may be associated with the upregulation or downregulation of previously mentioned protein expressions. These findings may provide the basis for understanding and further study of the mechanism and treatment targets of vascular hyporeactivity after shock. [ABSTRACT FROM AUTHOR]

Background Traumatic brain injury (TBI) is often associated with uncontrolled hemorrhagic shock (UHS), which contributes significantly to the mortality of severe trauma. Studies have demonstrated that permissive hypotension resuscitation improves the survival for uncontrolled hemorrhage. What the ideal target mean arterial pressure (MAP) is for TBI with UHS remains unclear. Methods With the rat model of TBI in combination with UHS, we investigated the effects of a series of target resuscitation pressures (MAP from 50-90 mm Hg) on animal survival, brain perfusion, and organ function before hemorrhage controlled. Results Rats in 50-, 60-, and 70-mm Hg target MAP groups had less blood loss and less fluid requirement, a better vital organ including mitochondrial function and better cerebral blood flow, and animal survival (8, 6, and 7 of 10, respectively) than 80- and 90-mm Hg groups. The 70-mm Hg group had a better cerebral blood flow and cerebral mitochondrial function than in 50- and 60-mm Hg groups. In contrast, 80- and 90-mm Hg groups resulted in an excessive hemodilution, a decreased blood flow, an increased brain water content, and more severe cerebral edema. Conclusions A 50-mm Hg target MAP is not suitable for the resuscitation of TBI combined with UHS. A 70 mm Hg of MAP is the ideal target resuscitation pressure for this trauma, which can keep sufficient perfusion to the brain and keep good organ function including cerebral mitochondrial function. [ABSTRACT FROM AUTHOR]

Background: Hemorrhagic shock (HS) is the major cause of death from trauma. Hemorrhagic shock may lead to cellular hypoxia and organ damage. Our previous findings showed that HS induced a cardiac apoptosis pathway and synergistically caused myocardial cell damage in diabetic rats under trauma-induced HS. Tetramethylpyrazine (TMP) is a major biologically active ingredient purified from the rhizome of Ligusticum wallichii (called Chuang Xiong in Chinese). Chuan Xiong rescued cells from synergistic cardiomyoblast cell injury under high-glucose (HG) conditions plus hypoxia. TMP is one of the most important active ingredients that elevated the survival rate in ischemic brain injury and prevented inducible NO synthase expression to have anti-inflammatory effects against cell damage in different cell types. Method: Here, we further investigate whether TMP can protect against hypoxic (<1% oxygen) conditions in H9c2 cardiomyoblast cells for 24 hrs. Results: Our results showed that hypoxia mediated through HIF-1α/JNK/p38 activation significantly elevated the levels of the hypoxia-related proteins HIF-1α, BNIP3 and IGFBP3, further enhanced the pro-apoptotic protein Bak and upregulated downstream Caspase 9 and 3, resulting in cell death. All of these phenomena were fully recovered under TMP treatment. We observed that TMP exerted this effect by activating the IGF1 receptor survival pathway, dependent primarily on PI3K/Akt. When PI3K (class I) was blocked by specific siRNA, the hypoxia-induced activated caspase 3 and cell apoptosis could not be reversed by TMP treatment. Conclusion: Our results strongly suggest that TMP could be used to restore hypoxia-induced myocardial cell apoptosis and cardiac hypoxic damage. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Introduction: During hemorrhagic shock (HS), the kidneys are one of the primary target organs involved. Oxidative stress is shown to be enhanced in different models of acute kidney injury (AKI). Remote ischemic preconditioning (RPC) by brief limb ischemia is considered to be a safe method to protect different organs from further damage. In this study, we investigated the effects of brief hind limb occlusion on protection against AKI and whether this protection is related to a reduction in oxidative stress. Materials and Methods: Twenty one rats were divided into three groups of seven rats. Shamoperated animals underwent surgical procedures, without hemorrhage. HS was induced by bleeding from a femoral arterial catheter to remove 44% of total blood volume. In RPC group, four cycles of lower limb ischemic preconditioning (5 min ischemia followed by 5 min reperfusion) were performed immediately before HS. Three hours later, plasma and renal tissue samples were collected for renal function monitoring and oxidative stress assessment. Results: Compared with the sham group, HS resulted in renal dysfunction, significantly increased blood urea nitrogen (BUN), plasma creatinine (Cr) and renal malondialdehyde (MDA) levels as well as decreased superoxide dismutase (SOD) activity in the kidneys (P 0.05). In the RPC group, renal function was significantly improved. Plasma Cr and BUN and renal MDA levels were significantly lower in RPC group comparing to HS group (P 0.05). Renal SOD activity was significantly higher in RPC group compared to HS group (P 0.05). Conclusion: These results demonstrate that induction of brief periods of lower limb ischemic preconditioning improves kidney function, restores SOD activity and reduces oxidative stress injury caused by hemorrhagic shock. [ABSTRACT FROM AUTHOR]

Disturbance of immunity is an important factor to modulate inflammatory responses after severe shock. Post-shock mesenteric lymph (PSML) return plays an adverse role in multiple organ injuries induced by the hemorrhagic shock, and the inflammatory factors are involved in this process. However, whether the PSML can exacerbate immune dysfunctions that modulate inflammatory response to the hemorrhagic shock remains unknown. In the present study, the effects of PSML drainage on the distribution of T lymphocyte subgroup, the release of inflammatory factors, and apoptosis of thymocytes were investigated; the effect of PSML on the specific parameters of cellular immune function was also determined. Results showed that PSML drainage reduced the increased levels of CD3+, CD3 + CD4+, CD4 + CD25+ lymphocytes, IFN-γ, and the ratios of CD3 + CD4+/CD3 + CD4− in blood of the shocked rats at 3 h after resuscitation; PSML drainage also abolished the decreased IL-4 level and restored the higher ratio of IFN-γ/IL-4 to normal levels. Tissue injury, including enlarged intermembrance space and edema with congestion in the medulla, increased apoptotic cells and bax expression, decreased number of cells in the S phase, and bcl-2 expression were observed in the thymus after hemorrhagic shock. PSML drainage reversed these effects. In particular, PSML drainage increased the proliferation index and decreased p53 expression of thymocytes. These results suggest that hyperimmunity occurred at early stages of hemorrhagic shock with resuscitation and that PSML drainage could markedly improve cellular immune function that is responsible for the reduced inflammatory responses. [ABSTRACT FROM AUTHOR]

Methods: Male rats were ‘pretreated’ with phosphate-buffered saline (PBS; i.p.) or LPS (1 mg/kg; i.p.) 24 h prior to HS. Mean arterial pressure (MAP) was maintained at 30 ± 2 mmHg for 90 min or until 25% of the shed blood had to be re-injected to sustain MAP. This was followed by resuscitation with the remaining shed blood. Four hours after resuscitation, parameters of organ dysfunction and systemic inflammation were assessed. Results: HS resulted in renal dysfunction, and liver and muscular injury. At a first glance, LPS preconditioning attenuated organ dysfunction. However, we discovered that HS-rats that had been preconditioned with LPS (a) were not able to sustain a MAP at 30 mmHg for more than 50 min and (b) the volume of blood withdrawn in these animals was significantly less than in the PBS-control group. This effect was associated with an enhanced formation of the nitric oxide (NO) derived from inducible NO synthase (iNOS). Thus, a further control group in which all animals were resuscitated after 50 min of hemorrhage was performed. Then, LPS preconditioning aggravated both circulatory failure and organ dysfunction. Most notably, HS-rats pretreated with LPS exhibited a dramatic increase in NF-κB activation and pro-inflammatory cytokines. Conclusion: In conclusion, LPS preconditioning predisposed animals to an earlier vascular decompensation, which may be mediated by an excess of NO production secondary to induction of iNOS and activation of NF-κB. Moreover, LPS preconditioning increased the formation of pro-inflammatory cytokines, which is likely to have contributed to the observed aggravation of organ injury/dysfunction caused by HS. [ABSTRACT FROM AUTHOR]

Introduction: During hemorrhagic shock (HS), the kidneys are one of the primary target organs involved. Oxidative stress is shown to be enhanced in different models of acute kidney injury (AKI). Remote ischemic preconditioning (RPC) by brief limb ischemia is considered to be a safe method to protect different organs from further damage. In this study, we investigated the effects of brief hind limb occlusion on protection against AKI and whether this protection is related to a reduction in oxidative stress. Materials and Methods: Twenty one rats were divided into three groups of seven rats. Shamoperated animals underwent surgical procedures, without hemorrhage. HS was induced by bleeding from a femoral arterial catheter to remove 44% of total blood volume. In RPC group, four cycles of lower limb ischemic preconditioning (5 min ischemia followed by 5 min reperfusion) were performed immediately before HS. Three hours later, plasma and renal tissue samples were collected for renal function monitoring and oxidative stress assessment. Results: Compared with the sham group, HS resulted in renal dysfunction, significantly increased blood urea nitrogen (BUN), plasma creatinine (Cr) and renal malondialdehyde (MDA) levels as well as decreased superoxide dismutase (SOD) activity in the kidneys (P0.05). In the RPC group, renal function was significantly improved. Plasma Cr and BUN and renal MDA levels were significantly lower in RPC group comparing to HS group (P0.05). Renal SOD activity was significantly higher in RPC group compared to HS group (P0.05). Conclusion: These results demonstrate that induction of brief periods of lower limb ischemic preconditioning improves kidney function, restores SOD activity and reduces oxidative stress injury caused by hemorrhagic shock. [ABSTRACT FROM AUTHOR]

Background To investigate protective effects of pyruvate-enriched peritoneal dialysis solution (P-PDS), compared with lactate-PDS (L-PDS), on the intestinal mucosal barrier in peritoneal resuscitation (PR) from severe hemorrhagic shock (HS) in rats. Materials and methods Fifty male SD rats were randomly divided into five groups (n = 10): group sham, group control (HS without fluid resuscitation), group intravenous resuscitation (IVR) (HS with IVR only), group L-PDS (HS with IV infusion plus PR with L-PDS), and group P-PDS (HS with IV infusion plus PR with P-PDS). HS was induced by hemorrhage with mean arterial pressure 40 mm Hg for 60 min. In three groups with fluid rehydration, IVR included shed blood and dl-lactate Ringer solution equal to two times the volume of shed blood during 60 min; in two groups with PR, 20 mL of L-PDS, or P-PDS were infused when IV infusion started after HS into the peritoneal cavity in 20 min, respectively. Blood samples were taken for determinations of pH, base excess, PaCO2, PaO2, and D-LA 60 min post fluid resuscitation. After rats were sacrificed, a segment of intestine was harvested for the detection of expressions of intestinal barrier proteins: zonula occludens-1 (ZO-1) and phosphorylated vasodilator-stimulated phosphoprotein (p-VASP) by Western blot and immunohistochemistry. Intestinal morphologic alterations were also observed. Results Blood pH, base excess, and PaO2 were higher, whereas PaCO2 and D-LA were lower in group P-PDS than in other three HS groups (P < 0.05 and P < 0.01, respectively). Severe acidosis was nearly corrected in group P-PDS. Intestinal barrier proteins ZO-1 and p-VASP were significantly preserved in group P-PDS than in group L-PDS (P < 0.05) although they were improved in group L-PDS in comparison with other two HS groups (P < 0.05 or P < 0.01). Expressions of barrier proteins by Western blotting in group P-PDS were reversed to normal. The score of intestinal epithelial damage index was reduced in group L-PDS, compared with other two HS groups (P < 0.05), however, it was significantly lower in group P-PDS than in group L-PDS (P < 0.05). Conclusions Pyruvate was superior to lactate in PDS in the correction of severe acidosis with PR. P-PDS was more preservative of expressions of intestinal ZO-1 and p-VASP and mucosal barrier function, compared with L-PDS in PR from severe HS in rats. [ABSTRACT FROM AUTHOR]

Background Hydrogen-rich saline provides a high concentration of hydrogen, which selectively reduces levels of hydroxyl radicals and alleviates acute oxidative stress in many models. We investigated the protective effects and mechanisms of three different hydrogen-rich liquid resuscitation preparations on lung injury-induced uncontrolled-hemorrhagic shock (UHS) in rats. Materials and methods A UHS rat model was prepared using the method of Capone et al. of arterial bleeding and tail amputation. Healthy male Wistar rats were randomly divided into seven groups (10 per group) to receive: sham treatment; Ringer solution; hydrogen-rich Ringer solution (H-Ringer solution); hydroxyethyl starch (HES); hydrogen-rich hydroxyethyl starch (H-HES); hypertonic saline/hydroxyethyl starch (HSH); and hydrogen-rich hypertonic saline/hydroxyethyl starch (H-HSH). At 72 h after successful resuscitation, lung tissue was Hematoxylin Eosin stained to score any pathologic changes. We also determined wet-to-dry (W/D) lung weight ratios and lung tissue concentrations of interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-10, malondialdehyde (A), and superoxide dismutase (SOD) and myeloperoxidase (MPO) activities. Results Compared with the non-H groups, polymorphonuclear neutrophil accumulation in alveoli in the H groups was significantly reduced (P value), and capillary leakage and wall edema were ameliorated. Compared with the sham group, pathologic pulmonary injury scores, W/D ratios, IL-6, TNF-α, IL-10, A concentrations, and MPO activity in the other groups were all increased, whereas SOD activity was decreased (P < 0.01). Comparing the H-Ringer, H-HES, and H-HSH groups respectively with the Ringer, HES, and HSH groups, pathologic pulmonary injury scores, W/D ratios, IL-6, TNF-α, A concentrations, and MPO activity were all reduced, whereas IL-10 concentrations and SOD activity were increased (P < 0.01). Conclusions Each hydrogen-rich liquid resuscitation preparation could protect the lung against acute injury secondary to UHS. These mechanisms may be associated with hydrogen inhibiting the release of pro-inflammatory cytokines, promoting anti-inflammatory cytokine release, and reducing oxidative damage. [ABSTRACT FROM AUTHOR]

Background Bradykinin (BK) has many biological effects in inflammation, allergy, and septic shock. Studies have shown that low doses of BK can induce vascular relaxation and high doses can induce vascular contraction in many pathophysiological conditions, but the role and mechanisms that high doses of BK have on vascular contraction in hemorrhagic shock are not clear. Methods With hemorrhagic-shock rats and hypoxia-treated superior mesenteric artery (SMA), we investigated the role and mechanisms of high doses of BK-induced vascular contraction in hemorrhagic shock. Results High doses of BK (500-50,000 ng/kg in vivo or 10-10 to 10-5 mol/L in vitro) dose dependently induced vascular contraction of SMA and increased the vascular calcium sensitivity in normal and hemorrhagic-shock rats. Less than 10-10 mol/L of BK induced vascular dilation BK-induced increase of vascular contractile response and calcium sensitivity was reduced by denudation of the endothelium, 18α-glycyrrhetic acid (an inhibitor of myoendothelial gap junction) and connexin 43 antisense oligodeoxynucleotide. Further studies found that high concentrations of BK-induced vascular contraction in hemorrhagic shock was closely related to the activation of Rho A-Rho kinase pathway and Protein Kinase C (PKC) α and ε. Conclusions High doses of BK can induce vascular contraction in hemorrhagic shock condition, which is endothelium and myoendothelial gap junction dependent. Cx43-mediated activation of Rho A-Rho kinase and Protein Kinase C (PKC) pathway plays a very important role in this process. This finding provided a new angle of view to the biological role of BK in other pathophysiological conditions such as hemorrhagic shock or hypoxia. [ABSTRACT FROM AUTHOR]

Introduction: Hemorrhagic shock causes more circulatory disturbances and mortality in hypertensive than normotensive subjects. In the late phase of hemorrhagic shock, nitric oxide (NO) overproduction leads to vascular decompensation. In this study, we evaluated the effect of inducible NO synthase (iNOS) inhibitor, aminoguanidine (AG), on hemodynamic parameters and serum nitrite concentration in decompensated hemorrhagic shock model in normotensive and hypertensive male rats. Materials and Methods: Twenty-four male rats were divided into hypertensive and normotensive groups (n = 12 each). Hypertension was induced by subcutaneous injection of deoxycorticoesterone acetate (DOCA), 30 mg/kg in uninephrectomized rats. Decompensated hemorrhagic shock was induced by withdrawing blood until the mean arterial pressure (MAP) reached 40 mmHg. After 120 min, each group was assigned to aminguanidine (100 mg/kg) and control group. Hemodynamic parameters were monitored for next 60 min. Blood samples were taken before and after shock period and 60 min after treatment. Survival rate was monitored for 72 h. Results: Infusion of AG in normotensive animals caused a transient increase in MAP and increase of heart rate, whereas it did not affect those parameters in hypertensive animals. Hemorrhagic shock caused a significant rise in serum nitrite concentration in normotensive and hypertensive rats and infusion of AG did not significantly change it in both groups. No significant differences observed in survival rate between AG-treated and not treated groups. Conclusion: It seems that inhibition of iNOS with AG does not have beneficial effects on hemodynamatic parameters and survival rate during decompensated hemorrhagic shock in normotensive and hypertensive animals. [ABSTRACT FROM AUTHOR]

Background The aim of this study was to investigate the effect of volume-controlled hemorrhage and hypothermia on rats with blunt chest trauma, evaluating bacterial translocation (BT), lung tissue malondialdehyde (MDA), nitric oxide (NO) levels, and erythrocyte deformability (ED). Methods In our study, 10 animals each were included in 6 groups. Groups were as follows: a group with blunt chest trauma only (Group T), a group with hemorrhage only (Group H), a normothermic group with comorbidity of trauma and hemorrhage (Group NT), a mild hypothermic group with trauma and hemorrhage (Group MH), a moderate hypothermic group with trauma and hemorrhage (Group MoH), and a control group (Group C). Sodium pentobarbital (50 mg/kg, intraperitoneally) anesthesia was administered. Thoracic trauma was generated using kinetic energy at the middle of the chest (2.45 J). Stage 3 hemorrhagic shock was initiated. After 24 hours, the rats were killed and red blood cell deformability, BT development in the liver, spleen, and mesenteric lymph nodes, and NO and MDA levels in lung tissue, kept at –80°C, were measured. Results In Groups MH and MoH, there was no difference in ED values, though they were lower than those in Group NT (p < 0.05). BTwas more prevalent in Group NT than in the other groups. In Group NT, the growth of BT was greater than in other groups (p < 0.05). The level of NO in Group H was higher than in the control group (p < 0.05). In Group MoH, the level of MDA was lower than in Group MH (p < 0.05). Conclusion Hypothermia seems to demonstrate protective effects on ED and BT by reducing oxidative stress. The protective effects of therapeutic hypothermia on ED may be due to the effect of reducing NO and/or MDA. There was no difference in effect between mild and moderate hypothermia in terms of the formation of ED and BT. [ABSTRACT FROM AUTHOR]

Studies have shown that local application of platelet-derived growth factor (PDGF) can be used for the treatment of acute and chronic wounds. We investigated if systemic application of PDGF has a protective effect on acute hemorrhagic shock in rats in the present study. Using hemorrhagic shock rats and isolated superior mesenteric arteries, the effects of PDGF-BB on hemodynamics, animal survival, and vascular reactivity as well as the roles of the gap junction proteins connexin (Cx)40 and Cx43, PKC, and Rho kinase were observed. PDGF-BB (1-15 μg/kg iv) significantly improved the hemodynamics and blood perfusion to vital organs (liver and kidney) as well as vascular reactivity and improved the animal survival in hemorrhagic shock rats. PDGF recovering shock-induced vascular hyporeactivity depended on the integrity of the endothelium and myoendothelial gap junction. Cx43 antisense oligodeoxynucleotide abolished these improving effects of PDGF, whereas Cx40 oligodeoxynucleotide did not. Further study indicated that PDGF increased the activity of Rho kinase and PKC as well as vascular Ca2+ sensitivity, whereas it did not interfere with the intracellular Ca2+ concentration in hypoxiatreated vascular smooth muscle cells. In conclusion, systemic application of PDGF-BB may exert beneficial effects on hemorrhagic shock, which are closely related to the improvement of vascular reactivity and hemodynamics. The improvement of PDGF-BB in vascular reactivity is vascular endothelium and myoendothelial gap junction dependent. Cx43, Rho kinase, and PKC play very important role in this process. These findings suggest that PDGF may be a potential measure to treat acute clinical critical diseases such as severe trauma, shock, and sepsis. [ABSTRACT FROM AUTHOR]

Background: Hemorrhagic shock (HS) following trauma is a leading cause of death among persons under the age of 40. During HS the body undergoes systemic warm ischemia followed by reperfusion during medical intervention. Ischemia/reperfusion (I/R) results in a disruption of cellular metabolic processes that ultimately lead to tissue and organ dysfunction or failure. Resistance to I/R injury is a characteristic of hibernating mammals. The present study sought to identify circulating metabolites in the rat as biomarkers for metabolic alterations associated with poor outcome after HS. Arctic ground squirrels (AGS), a hibernating species that resists I/R injury independent of decreased body temperature (warm I/R), was used as a negative control. Methodology/principal findings: Male Sprague-Dawley rats and AGS were subject to HS by withdrawing blood to a mean arterial pressure (MAP) of 35 mmHg and maintaining the low MAP for 20 min before reperfusing with Ringers. The animals’ temperature was maintained at 37±0.5°C for the duration of the experiment. Plasma samples were taken immediately before hemorrhage and three hours after reperfusion. Hydrophilic and lipid metabolites from plasma were then analyzed via 1H–NMR from unprocessed plasma and lipid extracts, respectively. Rats, susceptible to I/R injury, had a qualitative shift in their hydrophilic metabolic fingerprint including differential activation of glucose and anaerobic metabolism and had alterations in several metabolites during I/R indicative of metabolic adjustments and organ damage. In contrast, I/R injury resistant AGS, regardless of season or body temperature, maintained a stable metabolic homeostasis revealed by a qualitative 1H–NMR metabolic profile with few changes in quantified metabolites during HS-induced global I/R. Conclusions/significance: An increase in circulating metabolites indicative of anaerobic metabolism and activation of glycolytic pathways is associated with poor prognosis after HS in rats. These same biomarkers are absent in AGS after HS with warm I/R. [ABSTRACT FROM AUTHOR]

Abstract: Haemorrhagic shock is a life threatening condition, and, as such, it is important to understand the mechanisms taking part in its reversal. In the 1990s, it was shown that activation of serotonin 1A receptors is responsible for the circulatory decompensation and development of the sympathoinhibitory phase. In previous reports, it was demonstrated that activation of serotonin 1A receptors induces resuscitative effects in haemorrhaged rats. However, the effectory mechanisms still require further investigation. The aim of the present study was to determine whether the sympathetic nervous system participates in the effects of serotonin through central serotonin 1A receptors in haemorrhagic shock in rats. In order to determine the role of the sympathetic nervous system alpha-1-, alpha-2-, and beta-adrenergic receptor agonists – prazosin, yohimbine and propranolol, respectively, were used. We found that stimulation of the central serotonin 1A receptors by the administration of a selective agonist – 8-hydroxy-2-(di-n-propylamino)tetralin, 1-(2,5-dimethoxy-4-iodophenyl)-aminopropane (8-OH-DPAT) into the lateral brain ventricle is connected with the activation of compensation mechanisms leading to the increase in the heart rate and blood pressure. The current results demonstrate that the stimulation of peripheral alpha-1-, alpha-2- and beta-adrenergic receptors plays an essential role in the resuscitative effect triggered by the stimulation of central serotonin 1A receptors. [Copyright &y& Elsevier]

Background: Kidney injury commonly occurs following hemorrhagic shock. This study aims to observe the effects of mesenteric lymph duct ligation (MLDL) on the adenosine triphosphate (ATP) levels and the cell membrane adenosine triphosphatase (ATPase) activity in the kidneys of rats subjected to hemorrhagic shock. Methods: Wistar rats were assigned into sham, shock, and ligation groups. The hemorrhagic shock model was established in the shock and ligation groups, and MLDL was performed in the ligation group after resuscitation. Renal homogenates were prepared to determine the ATP and ATPase levels at 90 min after hemorrhage and at 0, 1, 3, 6, 12, and 24 h after resuscitation. Results: The ATP levels, and the Na+-K+-ATPase, Mg2+-ATPase, Ca2+-ATPase, and Ca2+-Mg2+-ATPase activities in the renal tissue of the shock group were lower than those in the sham group at the multiple time points. Furthermore, the corresponding values in the ligation group were significantly higher than those in the shock group at multiple time points. Conclusion: MLDL improves energy metabolism and enhances the ATPase activity in the kidneys of hemorrhagic shock rats, along with other mechanisms that alleviate renal injury after hemorrhagic shock. [ABSTRACT FROM AUTHOR]