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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]

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]

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]

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]

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]

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 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 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: 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]

Abstract: Background: Large-volume, rapid crystalloid infusion may increase endothelial cell damage and induce shear stress, potentially leading to multiple-organ dysfunction syndrome. Limited guideline data for fluid administration are currently available, especially for the aging population. The aim of the present study was to compare the degree of organ damage in conscious aging rats when different resuscitation speeds were used during the treatment of hemorrhagic shock (HS). Methods: Eighteen aging male Wistar-Kyoto rats were randomly divided into the following three groups: the control group, 30-min rapid resuscitation group, and 12-h slow resuscitation group. To mimic HS, 40% of the total blood volume was withdrawn. Fluid resuscitation (1:3) was given at 30 min after the blood withdrawal. Blood biochemical parameters including glucose, lactic acid, and lactate dehydrogenase (LDH) were measured along with the levels of serum and bronchoalveolar lavage fluid, tumor necrosis factor alpha (TNF-α), and interleukin 10 by enzyme-linked immunosorbent assay. The lungs were examined for pathologic changes, and the injury score at 24 h after HS was calculated. Results: Compared with slow-rate resuscitation, initially rapid and immediate resuscitation significantly increased the serum levels of glucose, LDH, and proinflammatory cytokines (TNF-α and interleukin 10), and bronchoalveolar lavage fluid levels of white blood cells, TNF-α, and LDH as well as produced pathologic changes in the organ. The lung injury scores were higher after induced HS in aging rats. Conclusions: The slow and continuous (12 h) fluid resuscitation rate ameliorated HS-induced organ damage in conscious aging rats. [Copyright &y& Elsevier]

Abstract: Background: To build a new and appropriate model of secondary intra-abdominal hypertension (IAH) in rats. Methods: A total of 32 female Sprague–Dawley rats were randomized into four groups. Group I: the rats were hemorrhaged to a mean arterial pressure (MAP) of 40 mm Hg for 1 h and portal hypertension was induced by partial ligation of the portal vein 1 h later; Group II: after inducing portal hypertension, hemorrhagic shock of MAP of 40 mm Hg was induced and maintained for 1 h; Group III: after inducing portal hypertension, hemorrhagic shock of MAP of 40 mm Hg was induced and maintained for 2 h; Group IV: after inducing portal hypertension, hemorrhagic shock of MAP of 40 mm Hg was induced and maintained for 2 h, and a specially designed abdominal restraint device was used. After these procedures, respectively, the collected blood was reinfused and lactated Ringer solution was continuously infused until the secondary IAH model was established. Results: No models were built in Groups I, II, and III. One rat died in Group IV after portal vein ligation, and all the remaining rats successfully developed IAH; the success rate was 87.5%. During the resuscitation period, the average time was 5.26 ± 0.59 h and the average total infusion volume was 665.5 ± 86.04 mL/kg. Conclusion: A rat model of secondary IAH was successfully established by resuscitation after a combination of inducing portal hypertension, hemorrhaging to a MAP of 40 mm Hg for 2 h, and using an abdominal restraint device. All these criteria mimic key etiological factors for the development of secondary IAH. [Copyright &y& Elsevier]

The aim of this study was to test the effect of a small volume administration of p-hydroxyphenylpyruvate (pHPP) in a rat model of profound hemorrhagic shock and to assess a possible metabolic mechanism of action of the compound. The results obtained show that hemorrhaged rats treated with 2–4% of the estimated blood volume of pHPP survived significantly longer (p<0.001) than rats treated with vehicle. In vitro analysis on cultured EA.hy 926 cells demonstrated that pHPP improved cell growth rate and promoted cell survival under stressing conditions. Moreover, pHPP stimulated mitochondria-related respiration under ATP-synthesizing conditions and exhibited antioxidant activity toward mitochondria-generated reactive oxygen species. The compound effects reported in the in vitro and in vivo analyses were obtained in the same millimolar concentration range. These data disclose pHPP as an efficient energetic substrates-supplier to the mitochondrial respiratory chain as well as an antioxidant supporting the view that the compound warrants further evaluation as a therapeutic agent. [ABSTRACT FROM AUTHOR]

Background: Acute kidney injury (AKI), a common pathological process following hemorrhagic shock, can lead to an internal milieu disorder, which is an important factor of multiple organ failure (MOF). It has been shown that the mesenteric lymph return plays a deleterious effect on MOF induced by hemorrhagic shock. In this study, we investigated the effects of mesenteric lymph duct ligation (MLDL) on gene expression profiles of renal tissue following hemorrhagic shock with fluid resuscitation. Methods: After establishment of hemorrhagic shock model and fluid resuscitation in rats of shock and shock ligation groups, the MLDL was performed in shock ligation group, and only threading under the mesenteric lymph duct in the shock group. Then, the fixed position renal tissue was taken out for homogenate in two groups at 3 h after resuscitation, the total mRNA was extracted, reversely transcribed into cDNAs and marked with Cy3 and Cy5. The cDNAs were subjected for microarray scanning with 12,028 cDNA probes; the differentially expressed genes between two groups were analyzed. Results: In the 5812 valid dates of rat genomes transcription, there were 34 known differentially expressed genes between the two groups, of which 11 genes were up-regulated whereas 23 genes were down-regulated by MLDL. These different expressed genes encoding protein function were mainly involved in signal transduction, transcription regulation, metabolism, transport, cell growth, cell cycle, cell adhesion, cell movement, cellular component, and biological process. Conclusions: The mechanism of MLDL alleviating the AKI aftershock might be associated with up- or down-regulation of the above gene expressions. [ABSTRACT FROM AUTHOR]

Abstract: Background: Lactic acidosis is a life-threatening complication of hemorrhagic shock. There is no ideal therapy for it in the clinical setting. Objective: This study was designed to investigate whether pyruvate Ringer's solution could treat hypoxic lactic acidosis associated with lethal hemorrhagic shock in rats. Methods: A total of 54 rats were subjected to hemorrhagic shock with mean arterial pressure (MAP) of 40 mm Hg for 1 h. They were then randomly divided into three groups (n = 18 each): Group N had no fluid resuscitation; Group L received lactated Ringer's solution infusion; and Group P received pyruvate Ringer's solution infusion. The survival rate was investigated after 24 h. In addition, a second set of 54 rats was selected for blood sampling, with identical methods for shock and resuscitation being followed, to determine arterial pH, blood gas analysis, lactate, pyruvate, and organs' enzyme activities at various time points. The MAP was monitored for 6 h in both populations. Results: Pyruvate Ringer's solution significantly increased the survival rate of rats subjected to fatal shock and receiving pyruvate Ringer's solution (Group P) by 1.5 times the survival rate in Group L at 24 h after fluid resuscitation (55.6% vs. 22.2%, respectively; p < 0.05). Pyruvate infusion maintained a higher MAP and fully corrected severe acidosis 1 h after resuscitation in comparison to the lactated infusion, and markedly decreased blood lactate levels and the lactate-to-pyruvate ratio 4 h after resuscitation. It also significantly improved serum markers of organ dysfunction. Conclusion: Pyruvate Ringer's solution efficiently treated hypoxic lactic acidosis and significantly increased the survival rate in rats with lethal hemorrhagic shock. Pyruvate Ringer's solution is potentially applicable to clinical resuscitation in humans. [Copyright &y& Elsevier]

Abstract: Background: Experimental hemorrhagic shock (HS) is based on controlling bleeding and the treatment of fluid resuscitation to restore tissue oxygenation and perfusion. The HS could promote ischemia/reperfusion injury, which induces a general exacerbation of the inflammatory process, initially compromising the lungs. N-acetylcysteine (NAC), an antioxidant, may attenuate ischemia/reperfusion injury. This study evaluated the effect of NAC in association with fluid resuscitation on pulmonary injury in a controlled HS model in rats. Methods: Male Wistar rats were submitted to controlled HS (mean arterial pressure of 35 mm Hg for 60 min). Two groups were constituted according to resuscitation solution administered: RLG (Ringer’s lactate solution) and RLG+NAC (Ringer’s lactate in association with 150 mg/kg NAC. A control group was submitted to catheterization only. After 120 min of resuscitation, bronchoalveolar lavage was performed to assess intra-alveolar cell infiltration and pulmonary tissue was collected for assessment of malondialdehyde, interleukin 6, and interleukin 10 and histopathology. Results: Compared with the RLG group, the RLG+NAC group showed lower bronchoalveolar lavage inflammatory cell numbers, lower interstitial inflammatory infiltration in pulmonary parenchyma, and lower malondialdehyde concentration. However, tissue cytokine (interleukin 6 and interleukin 10) expression levels were similar. Conclusion: N-acetylcysteine was associated with fluid resuscitation–attenuated oxidative stress and inflammatory cell infiltration in pulmonary parenchyma. N-acetylcysteine did not modify cytokine expression. [Copyright &y& Elsevier]

Abstract: Background: The objective of the present study was to explore the resuscitation effects of starch nanospheres solution on hemodynamics in rats with hemorrhagic shock. Methods: A total of 20 Sprague-Dawley rats were randomly divided into 2 groups: resuscitation group 1 (infusion with Ringer''s solution) and resuscitation group 2 (infusion with starch nanospheres solution) with 10 rats per group. The rats in resuscitation groups 1 and 2 were subjected to hemorrhagic shock, and resuscitation was performed with Ringer''s solution and starch nanospheres solution. The changes in the hemodynamic values of the rats in both groups were observed and recorded. Results: The hemodynamic values included the systolic blood pressure, diastolic blood pressure, mean arterial blood pressure, heart rate, and respiratory rate. After resuscitation, the systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate in resuscitation group 2 had reverted back to the base values (P > 0.05). The systolic blood pressure, diastolic blood pressure, and mean arterial pressure were lower at all points in resuscitation group 1 than in resuscitation group 2 (P < 0.05). The respiratory rate was more rapid after resuscitation at 30 and 60 min in resuscitation group 1 than in resuscitation group 2 (P < 0.05). Conclusions: Starch nanospheres solution expands the circulating blood volume and improves the hemodynamics. It also increases the effective circulating blood volume and improves the shock symptoms of effective hypovolemia. [Copyright &y& Elsevier]

Background: To investigate the effects of fluids resuscitation on pulmonary expression of aquaporin1 and aquaporin5 in a rat model of uncontrolled hemorrhagic shock and infection. Methods: Sixty Sprague-Dawley rats were randomly assigned to five groups, sham operation group (Group C) and four treated groups: no fluid resuscitation group (Group NF), groups resuscitated with Lactated Ringer's (LR),7.5% NaCl (HTS) and Hydroxyl ethyl starch (HES) respectively. Three-phased uncontrolled hemorrhagic shock and infection model was used. Phase I: Massive hemorrhage with a mean arterial pressure of 35–40 mmHg for 60 min, and followed by infection of lipopolysaccharide. Then some animals were resuscitated with solutions mentioned above, until 90 min. Phase II: At hemorrhagic shock 90 minutes, phase II of 60 minutes began with hemostasis and returning of all the initial shed blood. Phase III: Observation phase for 3.5 hours. After phase III, arterial blood gas analysis and the survival rates of the rats were recorded, Wet-to-dry lung weight ratio, BALF protein, pulmonary permeability index, and expressions of aquaporin1 and aquaporin5 were tested. Results: The expressions of aquaporin1 and aquaporin5 were decreased in treatment groups comparing with sham operation group. Group HES and Group HTS decreased pulmonary vascular permeability and Wet-to-dry lung weight ratio, improved arterial blood gas analysis and survival rates, and attenuated the decreased pulmonary expression of aquaporin1 and aquaporin5 after the “two-hit”, comparing with groups NF and LR,but these beneficial effects were blunted in group HTS. Conclusion: The expression of aquaporin1 and aquaporin5 may play important roles in formation of pulmonary edema. Resuscitation with HTS and HES, especially HES can reduce lung injury after hemorrhagic shock, partly by up-regulating the expressions of aquaporin1 and aquaporin5. [ABSTRACT FROM AUTHOR]

Hemorrhagic shock and resuscitation induces pulmonary inflammation that leads to acute lung injury. Biliverdin, a metabolite of heme catabolism, has been shown to have potent cytoprotective, anti-inflammatory, and anti-oxidant effects. This study aimed to examine the effects of intravenous biliverdin administration on lung injury induced by hemorrhagic shock and resuscitation in rats. Biliverdin or vehicle was administered to the rats 1 h before sham or hemorrhagic shock-inducing surgery. The sham-operated rats underwent all surgical procedures except bleeding. To induce hemorrhagic shock, rats were bled to achieve a mean arterial pressure of 30 mmHg that was maintained for 60 min, followed by resuscitation with shed blood. Histopathological changes in the lungs were evaluated by histopathological scoring analysis. Inflammatory gene expression was determined by Northern blot analysis, and oxidative DNA damage was assessed by measuring 8-hydroxy-2′ deoxyguanosine levels in the lungs. Hemorrhagic shock and resuscitation resulted in prominent histopathological damage, including congestion, edema, cellular infiltration, and hemorrhage. Biliverdin administration prior to hemorrhagic shock and resuscitation significantly ameliorated these lung injuries as judged by histopathological improvement. After hemorrhagic shock and resuscitation, inflammatory gene expression of tumor necrosis factor-α and inducible nitric oxide synthase were increased by 18- and 8-fold, respectively. Inflammatory gene expression significantly decreased when biliverdin was administered prior to hemorrhagic shock and resuscitation. Moreover, after hemorrhagic shock and resuscitation, lung 8-hydroxy-2' deoxyguanosine levels in mitochondrial DNA expressed in the pulmonary interstitium increased by 1.5-fold. Biliverdin administration prior to hemorrhagic shock and resuscitation decreased mitochondrial 8-hydroxy-2' deoxyguanosine levels to almost the same level as that in the control animals. We also confirmed that biliverdin administration after hemorrhagic shock and resuscitation had protective effects on lung injury. Our findings suggest that biliverdin has a protective role, at least in part, against hemorrhagic shock and resuscitation-induced lung injury through anti-inflammatory and anti-oxidant mechanisms. [ABSTRACT FROM AUTHOR]

The article presents a study which investigates the resuscitation with aged blood exacerbates liver injury in hemorrhagic anesthetized rat model. It states that the study was conducted at a research laboratory at the Hebrew University in Jerusalem, and used a prospective, controlled study and magnetic resonance imaging (MRI). Results show that stored blood showed reduction in the deformability of red blood cell (RBC).

OBJECTIVES The aim of this study was to assess the possible protective effect of montelukast against haemorrhagic shock-induced acute lung injury by interfering with inflammatory and oxidative pathways. Acute lung injury following haemorrhagic shock/resuscitation is an important contributor to late morbidity and mortality in trauma patients. Haemorrhagic shock (HS), followed by resuscitation, is considered to be an insult that frequently induces systemic inflammatory response syndrome and oxidative stress, resulting in multiple-organ dysfunction syndrome, including microvascular changes and microscopic damage termed acute lung paraynchymal injury. Montelukast is a cysteinyl leukotriene receptor antagonist that exerts an anti-inflammatory and antioxidant influence. METHODS Eighteen adult albino rats were assigned to three groups of six. In Group I, the ‘sham’ group, rats underwent all the surgical procedures but neither haemorrhagic shock nor resuscitation was carried out. Group II—the ‘HS’ induced, untreated group—was the control and underwent HS for one hour before being resuscitated with Ringer's lactate for one hour. Group III—the ‘montelukast’ group—underwent HS and treatment with montelukast (7 mg/kg i.p. injection) 30 min before the induction of HS, with the same dose repeated just before the reperfusion period. At the end of the experiment, two hours after completion of resuscitation, blood samples were collected for measurement of serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). The trachea was then isolated and bronchoalveolar lavage was carried out for measurement of leukotriene B4 (LTB4), leukotriene C4 (LTC4) and total protein. The lungs were harvested and the left lung was homogenized for measurement of malondialdehyde (MDA) and reduced glutathione (GSH) and the right lung was fixed in 10% formalin for histological examination. RESULTS Montelukast treatment (Group III) significantly reduced the total lung injury score, compared with the HS group (Group II) (P < 0.05). Montelukast also significantly decreased serum TNF-α and IL-6; lung MDA; bronchoalveolar lavage fluid (BALF) LTB4, LTC4 & total protein compared with the HS group (P < 0.05). Montelukast treatment significantly inhibited decrease in the lung GSH levels, compared with the HS group (P < 0.05). CONCLUSIONS The results of the present study reveal that montelukast may ameliorate lung injury in shocked rats by interfering with inflammatory and oxidative pathways, implicating the role of leukotrienes in the pathogenesis of haemorrhagic shock-induced lung inflammation. [ABSTRACT FROM AUTHOR]

Abstract: Background: Centhaquin is a cardiovascular active agent that significantly reduced blood lactate levels and enhanced resuscitative effect of hypertonic saline. The present study was carried out to determine the resuscitative effect of centhaquin and compare that with large-volume lactated Ringer (LR) solution in hemorrhaged rats. Materials and methods: Male, adult Sprague–Dawley rats were anesthetized with urethane, and a pressure catheter SPR-320 was placed in the left femoral artery; another pressure–volume catheter SPR-869 was placed into the left ventricle through carotid artery. Hemorrhage was induced by withdrawing blood from the right femoral artery, and the mean arterial pressure (MAP) was maintained at 35 mm Hg for 30 minutes after which resuscitation was performed using LR solution (LR-100) (100% shed blood volume), centhaquin (0.017, 0.05, and 0.15 mg/kg) dissolved in LR (100% shed blood volume), or LR-300 (300% shed blood volume). Arterial blood gases and cardiovascular parameters were determined before the induction of hemorrhage and at various times after hemorrhage. Results: It was found that survival time after resuscitation with LR-100 was 78 ± 10 min. Centhaquin in doses of 0.017 and 0.05 mg/kg significantly improved survival time to 291 ± 57 and 387 ± 39 min, respectively. Blood lactate levels (millimoles per liter) increased from 7.22 ± 0.67 at hemorrhage to 10.20 ± 0.61 at 60 min after resuscitation with LR-100. On the other hand, blood lactate levels significantly decreased to 3.55 ± 0.07 and 4.08 ± 0.28 at 60 min after resuscitation with 0.017 and 0.05 mg/kg doses of centhaquin, respectively. Centhaquin in these doses produced a 55% and 59% increase in MAP, respectively, compared with a 29% decrease by LR-100. A decrease in systemic vascular resistance of 57% and 41% was observed with 0.017 and 0.05 mg/kg doses of centhaquin, respectively, compared with a 6% decrease by LR-100. LR-100 decreased cardiac output (CO) by 28%, whereas 0.017 and 0.05 mg/kg doses of centhaquin increased it by 260% and 180%, respectively. LR-300 commonly used for resuscitation was found to increase MAP and CO. Compared with LR-300, centhaquin (0.05 mg/kg) significantly improved survival time, increased CO, and was effective in resuscitation of hemorrhaged rats. Conclusions: Centhaquin was found to be more effective than LR-300 as an effective resuscitative agent for the treatment of hemorrhagic shock in rat. [Copyright &y& Elsevier]

Abstract: Background: In vivo or in vitro hypoxic preconditioning (HPC) can protect various tissues and cells against subsequent ischemia and/or reperfusion (hypoxia and/or reoxygenation) injury. Total HPC (THPC) in animal models is largely aimed at protecting single organs; however, scant data exist on whole body protection. The present study investigated whether THPC could protect anesthetized rats against the systemic injury induced by hemorrhagic shock and resuscitation (HS/R). Methods: The 4-cycle THPC protocol consisted of 5 min of inhalation hypoxia (fraction of inspired oxygen 10%, N2 90% plus oxygen 10%) followed by 10 min of inhalation air (oxygen 21%). An acute HS/R model of anesthetized rats was used. The experiment was divided into two parts of the Severe HS/R and Moderate HS/R, differentiated by a shed blood volume of 60% or 50% (HS/R60% or HS/R50%, respectively) of the total blood volume of rats, respectively. In the Severe HS/R part, the heart rate, respiration rate, and mean arterial pressure of the rats were measured, and the survival of the rats was observed. We examined the pathomorphologic changes in the vital organs of rats and measured the arterial blood gas, heart rate, respiration rate, and mean arterial pressure of the rats in the Moderate HS/R part. Results: THPC did not result in irreversible changes or death in the rats. The rats in the THPC + HS60%/R group had a significantly greater survival rate than those in the HS60%/R group (59% versus 33%, log-rank test, chi-square = 4.356, P = 0.037). The histopathologic lung score of the rats in the HS50%/R group (1.7 ± 0.5) was significantly greater than that in the THPC + HS50%/R (1.1 ± 0.6, P = 0.046). The arterial blood gas pH was lower in the HS50%/R group than in the THPC + HS50%/R group. THPC had a greater influence on the arterial partial pressure of oxygen and carbon dioxide than on bicarbonate radical and base excess. The respiration rate in the THPC + HS/R group was faster than that in the HS/R group. No significant differences in heart rate or mean arterial pressure were seen between the THPC + HS/R and HS/R groups. Conclusions: In anesthetized rats, THPC provided early protection against the subsequent systemic injury caused by hemorrhagic shock following resuscitation. THPC might exert systemic protection by improving the function of vital organs (e.g., lungs and, perhaps, the brain). [Copyright &y& Elsevier]

Abstract: Background: We observed that centhaquin, a cardiovascular active agent, reduces blood lactate levels. Because blood lactate is an important indicator of end-organ perfusion, we determined the resuscitative effect of centhaquin in hemorrhaged rats. Materials and methods: Male, adult Sprague-Dawley rats (Harlan, Indianapolis, IN) were anesthetized with urethane, and a pressure catheter SPR-320 was placed in the left femoral artery, and a pressure–volume catheter SPR-869 was placed into the left ventricle through carotid artery. Hemorrhage was induced by withdrawing blood from the right femoral artery, and mean arterial pressure was maintained between 35 and 40 mm Hg for 30 min after which resuscitation was performed using normal saline (control), 3% hypertonic saline, or centhaquin dissolved in 3% hypertonic saline. Arterial blood pH, pO2, pCO2, lactate, hematocrit, and cardiovascular parameters were measured before the induction of hemorrhage (baseline), 30 min after induction of hemorrhagic shock, and every 60 min thereafter until the animal expired. Results: Hypertonic saline was effective in reducing blood lactate levels and improving cardiac output (CO) of hemorrhaged rats. Centhaquin dissolved in hypertonic saline produced a significantly greater decrease in blood lactate and increase in mean arterial pressure and CO compared with hypertonic saline in hemorrhaged rats. Fraction survival at 250 min was 0 when resuscitated with hypertonic saline, whereas it was 0.8 with centhaquin. Conclusions: Centhaquin significantly improved the resuscitative effect of hypertonic saline by increasing CO, reducing blood lactate, and improving survival time of hemorrhaged rats. [Copyright &y& Elsevier]

Although melatonin treatment following trauma-hemorrhage or ischemic reperfusion prevents organs from dysfunction and injury, the precise mechanism remains unknown. This study tested whether melatonin prevents liver injury following trauma-hemorrhage involved the protein kinase B (Akt)-dependent heme oxygenase (HO)-1 pathway. After a 5-cm midline laparotomy, male rats underwent hemorrhagic shock (mean blood pressure approximately 40 mmHg for 90 min) followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle, melatonin (2 mg/kg), or melatonin plus phosphoinositide 3-kinase (PI3K) inhibitor wortmannin (1 mg/kg). At 2 hr after trauma-hemorrhage, the liver tissue myeloperoxidase activity, malondialdehyde, adenosine triphosphate, serum alanine aminotransferase, and aspartate aminotransferase levels were significantly increased compared with sham-operated control. Trauma-hemorrhage resulted in a significant decrease in the Akt activation in comparison with the shams (relative density, 0.526 ± 0.031 versus 1.012 ± 0.066). Administration of melatonin following trauma-hemorrhage normalized liver Akt phosphorylation (0.993 ± 0.061), further increased mammalian target of rapamycin (mTOR) activation (5.263 ± 0.338 versus 2.556 ± 0.225) and HO-1 expression (5.285 ± 0.325 versus 2.546 ± 0.262), and reduced cleaved caspase-3 levels (2.155 ± 0.297 versus 5.166 ± 0.309). Coadministration of wortmannin abolished the melatonin-mediated attenuation of the shock-induced liver injury markers. Our results collectively suggest that melatonin prevents hemorrhagic shock-induced liver injury in rats through an Akt-dependent HO-1 pathway. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the effectiveness of normal saline, hypertonic saline, and Ringer's lactate solution followed by blood infusion in ameliorating the physiological, biochemical, and organ functions following hemorrhagic shock (HS) in rats. Materials and Methods: Anesthetized, male Sprague-Dawley rats underwent computer-controlled HS, and were randomly divided into five groups consisting of (1) sham, (2) HS without resuscitation, (3) resuscitation with normal saline, (4) resuscitation with hypertonic saline, and (5) resuscitation with Ringer's lactate solution. All resuscitated animals were infused with subsequent infusion of shed blood. Animals were continuously monitored for physiological, hemodynamic, biochemical parameters, and organ dysfunctions. Results: Non-resuscitated animals were unable to survive due to hypotension, poor oxygen metabolism, and lactic acidosis. Although these HS related parameters were corrected by all the fluids used in this study, additional blood infusion was more effective than fluid resuscitation alone. Also, hypertonic saline was more effective than Ringer's lactate solution, and normal saline was the least effective in preserving the liver and kidney functions and muscle damage. Conclusions: All crystalloid fluids were significantly more effective in reversing the HS outcome when used with blood infusion, but hypertonic salinewith blood was more effective in preventing the organ damage than Lactated Ringers solutions or normal saline in the treatment of HS. [ABSTRACT FROM AUTHOR]

Abstract: Background: Hypothermia frequently occurs during fluid resuscitation of trauma victims, especially in patients with a major blood loss. Recent studies have suggested that mild hypothermia may ameliorate hemorrhagic shock (HS) induced splanchnic damage. Objective: The aim of the present study is to compare the status of body temperature and splanchnic injury under different resuscitation speeds for HS in conscious rats. Methods: Experimental study in an animal model of HS. Twenty-four male Wistar-Kyoto rats were used in the study. To mimic HS, 40% of the total blood volume was withdrawn. Fluid resuscitation was given 30min after blood withdrawal. The rats were randomly divided into three groups; the control group, the 10-min rapid group, and the 12-h slow group. Results: Levels of blood biochemical parameters, including aspartate transferase (GOT), and alanine transferase (GPT), were measured. Levels of serum tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) were measured and levels of bronchoalveolar lavage fluid (BALF) TNF-α and nitric oxide (NO) were measured by ELISA. The lung, liver and small intestine were examined for pathological changes 48h after HS. Conclusions: Initially slow rate resuscitation with limited-volume significantly decreased body temperature, serum GOT, GPT, TNF-α, and IL-6 levels, levels of TNF-α, and NO in BALF. Moreover, the slow group had lower injury scores in the lung, liver and small intestine than the rapid group after HS. This finding suggests that mild hypothermia induced by a slow fluid resuscitation rate with limited-volume ameliorates HS-induced splanchnic damage in conscious rats. [Copyright &y& Elsevier]

Abstract: Introduction: Fluid resuscitation therapy is the initial step of treatment for hemorrhagic shock. In the present study we aimed to investigate the acute effects of acetate-balanced colloid and crystalloid resuscitation on renal oxygenation in a rat model of hemorrhagic shock. We hypothesized that acetate-balanced solutions would be superior in correcting impaired renal perfusion and oxygenation after severe hemorrhage compared to unbalanced solutions. Methods: In anesthetized, mechanically ventilated rats, hemorrhagic shock was induced by withdrawing blood from the femoral artery until mean arterial pressure (MAP) was reduced to 30mmHg. One hour later, animals were resuscitated with either hydroxyethyl starch (HES, 130/0.42kDa) dissolved in saline (HES-NaCl; n =6) or a acetate-balanced Ringer''s solution (HES-RA; n =6), as well as with acetated Ringer''s solution (RA; n =6) or 0.9% NaCl alone (NaCl; n =6) until a target MAP of 80mmHg was reached. Oxygen tension in the renal cortex (CμPO2), outer medulla (MμPO2), and renal vein were measured using phosphorimetry. Results: Hemorrhagic shock (MAP=30mmHg) significantly decreased renal oxygenation and oxygen consumption. Restoring the MAP to 80mmHg required 24.8±1.7ml of NaCl, 21.7±1.4ml of RA, 5.9±0.5ml of HES-NaCl (p <0.05 vs. NaCl and RA), and 6.0±0.4ml of HES-RA (p <0.05 vs. NaCl and RA). NaCl, RA, and HES-NaCl resuscitation led to hyperchloremic acidosis, while HES-RA resuscitation did not. Only HES-RA resuscitation could restore renal blood flow back to ∼85% of baseline level (from 1.9±0.1ml/min during shock to 5.1ml±0.2ml/min 60min after HES-RA resuscitation) which was associated with an improved renal oxygenation (CμPO2 increased from 24±2mmHg during shock to 50±2mmHg 60min after HES-RA resuscitation) albeit not to baseline level. At the end of the protocol, creatinine clearance was decreased in all groups with no differences between the different resuscitation groups. Conclusion: While resuscitation with the NaCl and RA (crystalloid solutions) and the HES-NaCl (unbalanced colloid solution) led to hyperchloremic acidosis, resuscitation with the HES-RA (acetate-balanced colloid solution) did not. The HES-RA was furthermore the only fluid restoring renal blood flow back to ∼85% of baseline level and most prominently improved renal microvascular oxygenation. [Copyright &y& Elsevier]

Abstract: Background: The aim of the present study was to test the hypothesis that balanced crystalloid resuscitation would be better for the kidney than unbalanced crystalloid resuscitation in a rat hemorrhagic shock model. Methods: Male Wistar rats were randomly assigned to four groups (n =6/group): (1) time control; (2) hemorrhagic shock control; (3) hemorrhagic shock followed by unbalanced crystalloid resuscitation (0.9% NaCl); and (4) hemorrhagic shock followed by acetate and gluconate-balanced crystalloid resuscitation (Plasma Lyte). We tested the solutions for their effects on renal hemodynamics and microvascular oxygenation, strong-ion difference, systemic and renal markers of inflammation and oxidative stress including glycocalyx degradation as well as their effects on renal function. Results: The main findings of our study were that: (1) both the balanced and unbalanced crystalloid solutions successfully restored the blood pressure, but renal blood flow was only recovered by the balanced solution although this did not lead to improved renal microvascular oxygenation; (2) while unbalanced crystalloid resuscitation induced hyperchloremia and worsened metabolic acidosis in hemorrhaged rats, balanced crystalloid resuscitation prevented hyperchloremia, restored the acid–base balance, and preserved the anion gap and strong ion difference in these animals; (3) in addition balanced crystalloid resuscitation significantly improved renal oxygen consumption (increased VO2, decreased ); and (4) however neither balanced nor unbalanced crystalloid resuscitation could normalize systemic inflammation or oxidative stress. Functional immunohistochemistry biomarkers showed improvement in L-FABP in favor of balanced solutions in comparison to the hemorrhagic group although no such benefit was seen for renal tubular injury (measured by NGAL) by giving either unbalanced or balanced solutions. Conclusions: Although balanced crystalloid resuscitation seems superior to balanced crystalloid resuscitation in protecting the kidney after hemorrhagic shock and is certainly better than not applying fluid resuscitation, these solutions were not able to correct systemic inflammation or oxidative stress associated with hemorrhagic shock. [Copyright &y& Elsevier]

Background: The acute coagulopathy of trauma is multifactorial, but generally believed to be aggravated by coexisting acidosis, hypothermia, and hemodilution. While acidosis and hypothermia have been extensively evaluated, there is a paucity of data on the independent role of hemodilution in this scenario. We therefore hypothesized that hemodilution will impair coagulation following experimental trauma and hemorrhagic shock. Methods: Adult male Spraque-Dawley rats underwent trauma and hemorrhagic shock, followed by resuscitation with 2 × SBV using normal saline (NS). Thrombelastography (TEG) was performed before and after shock. Results: In this trauma model, resuscitation resulted in a hemodilution of 50% (43% ± 4.05% versus 19.8% ± 3.96% Hct pre-shock versus post-shock , P < 0.0001). Despite the substantial hemodilution, there was no significant change in clot strength (12.96 ± 2.84 versus 11.79 ± 1.28 dynes/cm2 G pre-shock versus post-shock, P = 0.13). Similarly, the onset of coagulation (R time) was not impaired (1.68 ± 1.74 s versus 1.75 ± 0.63 s R time pre-shock versus post-shock, P = 0.45). Conclusion: In the absence of hypothermia and acidosis, hemodilution (≤50%) has a trivial effect on coagulation following trauma and hemorrhagic shock. These data call to question the commonly held belief that hemodilution per se is critical in the development of post-injury coagulopathy. [Copyright &y& Elsevier]

The article offers information on the study conducted by the authors related to fish oil that improves hemodynamic stabilization and inflammation after resuscitation in a rat model of hemorrhagic shock. It states that the study concluded that the fish oil pretreatment before fluid resuscitation showed a beneficial effect to the hemodynamic stabilization and inflammation reduction in a rat model.

BACKGROUND: Hypertensive patients have higher morbidity and mortality from hemorrhage. In this study, we investigated hemodynamic responses and serum nitrite concentrations during graded hemorrhagic shock and resuscitation in hypertensive (HT) and normotensive (NT) rats. METHODS: Thirteen male rats were divided into two groups, namely HT (n = 6) and NT (n = 7). Hypertension was induced by deoxycorticosterone acetate (DOCA)-salt method in uninephrectomized rats. After 8 weeks, graded hemorrhagic shock was induced during 34 minutes in four steps separated by 8-minute intervals (totally 16 ml/kg). The animals were kept in this condition for 120 minutes (shock period). Then, they were resuscitated with blood withdrawal. Mean arterial pressure (MAP) and heart rate (HR) were measured throughout the experiment. Blood samples were taken before and after shock induction and at the end of the shock period. RESULTS: HT rats experienced more MAP and HR reduction during the shock period and less improvement of hemodynamic response after resuscitation compared with the NT group (p < 0.05). The survival rate 72 hours post-hemorrhage in the HT group was significantly lower than the NT group (16.7% vs. 71.4%, respectively) (p < 0.05). Serum nitrite level in HT animals was lower than the NT group (2.45 ± 0.18 vs. 3.35 ± 0.26 μmol/lit, respectively; p < 0.05). In addition, it increased during the shock period in both NT and HT groups (p > 0.05). CONCLUSIONS: More reduction of MAP after hemorrhagic shock, less improvement of MAP and HR after resuscitation and low survival rate in HT animals suggested the impairment of cardiovascular system adaptation of HT animals during blood loss and it should be considered in management of hypertensive subjects. [ABSTRACT FROM AUTHOR]

Background: Studies have documented the beneficial roles of δ opioid receptor (OR) agonist for hemorrhagic shock. However, the myocardial protection roles and the mechanisms of hemodynamic stability during resuscitation of δ-OR agonist have not been explored. This study was designed to investigate myocardial protective effects and the mechanisms of high selective δ1 and δ2-OR agonists during resuscitation of acute hemorrhagic shock. Materials and Methods: Forty-eight adult male SD rats were adopted 60-min hemorrhagic shock through removing 30% (5mL) of the total blood volume, and followed by 2-h resuscitation with shed blood and L-lactated Ringer''s solution. At the end of shock and prior to resuscitation, NS, δ1-OR agonist TAN-67 (10mg/kg) and antagonist BNTX (3mg/kg), and BNTX+TAN-67, DMSO, δ2-OR agonist Deltorphin II (1mg/kg) and antagonist NTB (2mg/kg), and NTB+Deltorphin II in 0.5mL were administrated. Left ventricular function parameters were measured during the whole experimental period. Myocardial mitochondria were isolated to determine opening of mitochondrial permeability transition pore (mPTP). Morphologic changes in myocardium and mitochondria were observed by electron microscope. Results: The hemodynamic indexes in group TAN-67 and group Deltorphin II were higher than control group at each time point during resuscitation, respectively (P <0.05). TAN-67 and Deltorphin II decrease but their antagonists BNTX and NTB increase the opening of mPTP (P <0.05). Myocardial and mitochondrial damage were attenuated in group TAN-67 and group Deltorphin II. Conclusions: δ1-OR agonist TAN-67 and δ2-OR agonist Deltorphin II protect the heart by targeting the mPTP in rats with acute hemorrhagic shock. [Copyright &y& Elsevier]

The objective of this study was to determine the effectiveness of lactated Ringer's (LR) solution, sodium hydroxyethyl starch (hetastarch), and dopamine (DA) on diaphragm shortening (DS), diaphragm blood flow (DBF), diaphragm hydrogen peroxide (H2O2), and diaphragm apoptosis following hemorrhagic shock (HS). Sprague-Dawley rats were assigned to the following groups: HS, LR, LR plus DA, hetastarch, and hetastarch plus DA. After removing 40% of the blood volume, with exception of the HS group, an equal volume of resuscitation fluid was administered. The diaphragm was excised so that DBE H2O2 and apoptosis could be measured. LR did not increase DBF and DS, whereas the other fluids increased DBF and DS. H2O2 and apoptosis decreased with LR administration. H2O2 and apoptosis were decreased to a much greater extent with LR plus DA, hetastarch, and hetastarch plus DA infusions. In conclusion, LR plus DA, hetastarch, and hetastarch plus DA maintained DS and DBF, which may be attributed to the decreases in reactive oxygen species as reflected by H2O2 and apoptosis. [ABSTRACT FROM AUTHOR]

The article details a study which determined the ideal target mean arterial pressure (MAP) and tolerance time for permissive hypotension. The study included rats with uncontrolled hemorrhagic shock. It found that a target resuscitation pressure of 50-60 millimeters of mercury (mmHg) is ideal for uncontrolled hemorrhagic shock.

Abstract: Objective: To examine whether reactive oxygen species (ROS) production is affected by arterial oxygen content (CaO2) in attempted resuscitation to restore blood pressure from hemorrhagic shock (HS) or not. Methods: Under light anesthesia and spontaneous beating, 16 rats underwent HS for 80min, during which 3.0mL/100g of blood was withdrawn, followed by resuscitation attempt for 70min. At 80min, rats were randomized into a high-CaO2 group (Group 1, transfusion under fractional inspired oxygen (FIO2) of 1.0, n =8) or a low-CaO2 group (Group 2, fluid administration under FIO2 of 0.21, n =8). In each group, either blood or lactate Ringer''s (LR) solution was infused to maintain mean arterial pressure ≥75mmHg under each FIO2 concentration. CaO2, O2 utilization coefficient (UC) and plasma %CoQ9 were compared between groups. Results: Mean infused volume for attempted resuscitation was 7.6±1.0mL of blood in Group 1, and 31.4±5.5mL of LR solution in Group 2. At the end of resuscitation, CaO2 was 18.5±1.2 vol% in Group 1, almost double the 9.1±0.8 vol% in Group 2 (P <0.01). O2 UC and %CoQ9 in all rats increased from baselines of 0.25±0.12 and 7.6±1.8% to 0.44±0.13 and 9.7±1.8% after resuscitation, respectively (P <0.05 vs. baseline for each), but did not differ significantly between the groups. Conclusion: In a rat HS model, attempted resuscitation to restore blood pressure increased O2 UC as well as %CoQ9. However, the magnitude of %CoQ9 increase that represents ROS production is not affected by CaO2 during resuscitation from HS. [Copyright &y& Elsevier]

Abstract: Background: We have previously demonstrated that treatment with histone deacetylase inhibitors (HDACI), such as valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA), can improve survival after hemorrhagic shock in animal models. Hemorrhage results in hypoacetylation of proteins which is reversed by HDACI. These agents are known to acetylate insulin receptor substrate-I (IRS-I), which in turn activates the Akt survival pathway. This study investigated whether HDACI exert their beneficial effects through the Akt survival pathway. Methods: Wistar–Kyoto rats (N =21) underwent hemorrhage (60% blood loss) and were randomized into 3 groups; no resuscitation (NR), and treatment with VPA or SAHA. Kidneys were harvested at 1, 6, and 24h after HDACI treatment and analyzed for acetylated histone 3 at lysine 9 residue (Ac-H3K9), phosphorylated Akt (phospho-Akt), BAD and Bcl-2 proteins. Results: Hemorrhaged animals were in severe shock, with mean arterial pressures of 25–30mmHg and lactic acid 7–9mg/ml. Only animals treated with VPA and SAHA survived to the 6- and 24-h timepoints. Treatment with HDACI produced a biologic effect on rat kidney cells inducing acetylation of histone H3K9, which peaked after 1h of treatment, and was statistically significant in the VPA group (p =0.01) compared to NR. Phospho-Akt protein increased in the VPA group with a reciprocal decrease in the pro-apoptotic BAD protein in both groups which was statistically significant in the VPA group after 1h (p =0.007) and 24h (p =0.006) of treatment and in the SAHA group after 24h of treatment (p =0.028). Anti-apoptotic Bcl-2 protein markedly increased after 6 (p =0.04) and 24h (p =0.014) of VPA treatment. Bcl-2 also increased in the SAHA group, but failed to reach statistical significance. Conclusion: Treatment with HDACI increases phosphorylation of Akt with a subsequent decrease in the pro-apoptotic BAD protein. The above mechanism facilitates the action of anti-apoptotic protein Bcl-2. HDACI protect kidney cells subjected to hemorrhagic shock in rodents through the Akt survival pathway. [Copyright &y& Elsevier]

Introduction: The aim of this study is to evaluate whether hemorrhage and resuscitation affect liver, intestinal, and renal expressions of heat shock protein 70 (HSP70), inducible nitric oxide synthase (iNOS), and apoptosis indexes (TUNEL, caspase-3 activation) and whether the expression of these proteins can be modulated by pyrrolidine dithiocarbamate (PDTC) after a nonlethal hemorrhagic shock (HS) in rats. Methods: Forty rats were randomized into four groups: sham-operated, only HS, HS/resuscitation with blood plus normal saline (NS), and HS/resuscitation with blood/NS plus PDTC, 15 mg/kg body weight, intravenously. Rats were subjected to HS by blood removal to a mean arterial pressure of 35-40 mmHg through the femoral artery. After 1 hr of shock, the animals were resuscitated according to the experimental protocol. HSP70, iNOS, cleaved caspase-3 expression, and TUNEL were analyzed in liver, small intestine, and kidney 3 hr after resuscitation. Results: HS upregulated HSP70, iNOS, cleaved caspase-3 expression, and induced apoptosis (TUNEL) ( p < .05 to < .001). Resuscitation was not associated with further increase of their expressions. The administration of PDTC during resuscitation decreased liver, intestinal, and renal activation of iNOS and apoptosis indexes ( p < .05 to < .001), and was associated with further increase in HSP70 expression ( p < .05). Conclusions: Our results show that HS resuscitation with PDTC modulates several signaling pathways (HSP70, iNOS, TUNEL, and caspase-3) in a rat model. The results suggest that PDTC administration-by reducing apoptosis and iNOS expression-may have a potential role in minimizing organ damage after severe hemorrhage. [ABSTRACT FROM AUTHOR]

The article presents a study which identifies whether increasing levels of O-linked β-N-acetylglucosamine (O-GlcNAc) could ameliorate post trauma-hemorrhage and resuscitation (TH-R). The study which adapted the volume-controlled hemorrhagic shock model, used male adult Sprague-Dawley rats wherein their organ injuries and inflammatory responses were examined. The result shows that O-GlcNAc increasing levels could ameliorate the 24-hr survival after undergoing a trauma hemorrhage.

The article presents a study which examines the role of fluid resuscitation in the renal oxygenation of rats with hemorrhagic shock. The authors utilized three phase hemorrhagic shock model to investigate the effects of fluid resuscitation on renal oxygenation. After one hour of shock phase, rats were randomized into four groups to receive either hypertonic saline or normal saline targeting a mean arterial pressure (MAP) of 40 or 80 mmHg. Results show that high MAP-directed fluid resuscitation (80 mmHg) does not increase renal microvascular oxygen pressure compared with fluid resuscitation targeted to 40 mmHg MAP. With regards to renal oxygenation, hypertonic saline is not superior to normal saline. Also, after blood transfusion the renal oxygenation decreases.

Abstract: Background: Severe hemorrhagic shock often results in cardiac arrest due to vital organ hypoperfusion, especially of the heart. Although fluid resuscitation is the mainstay of management in hemorrhagic shock, treatment of cardiac arrest in association with severe hemorrhagic shock is unclear. Objective: This study was designed to determine the effect of early infusion of norepinephrine on hemodynamics and survival in hemorrhagic shock. Methods: Twelve Sprague-Dawley rats were bled to about 35% of estimated blood volume for 30 min and randomized to one of two groups: the study group received norepinephrine (10 μg/kg/min) in 5% dextrose solution (n = 6); the control group received the same volume of 5% dextrose (n = 6) concurrently with Lactated Ringer''s solution. After 30 min of resuscitation, half of the shed blood was transfused in both groups. Time to cardiac arrest and mean arterial pressure (MAP) were compared between the two groups. Results: MAP during the resuscitation period was higher in the norepinephrine group than in the control group. Five of 6 rats in the norepinephrine group but none of the control group survived until the transfusion period (83.3% vs. 0.0%, respectively; p = 0.003). Median time to cardiac arrest was significantly longer in the norepinephrine group (67.0 min, interquartile range [IQR] 60.0–77.0) than in controls (41.0 min, IQR 40.0–47.0; p = 0.002). Conclusions: Early use of norepinephrine in a rat model of hemorrhagic shock increased mean arterial pressure during the resuscitation period and delayed the onset of cardiac arrest. [Copyright &y& Elsevier]

Abstract: Aim of the study: Upregulation of pulmonary inflammatory molecules is crucial in mediating the development of acute lung injury induced by haemorrhagic shock. Dexmedetomidine and ketamine possess potent anti-inflammatory capacity. We sought to elucidate whether dexmedetomidine, ketamine, or dexmedetomidine–ketamine combination could mitigate acute lung injury in haemorrhagic shock rats. Methods: Fifty adult male Sprague–Dawley rats were randomized to the sham-instrumented, haemorrhagic shock (HS), HS plus dexmedetomidine (HS-D), HS plus ketamine (HS-K), or HS plus dexmedetomidine–ketamine (HS-D+K) group (n =10 in each group). Haemorrhagic shock was induced by blood withdrawing and the mean blood pressure was maintained at 40–45mmHg for 120min. Resuscitation was then performed by infusion of shed blood/saline mixtures. After monitoring for another 8h, rats were sacrificed. Results: Histology findings and lung injury score analysis revealed moderate lung injury in rats of the HS, HS-D, and HS-K groups, whereas those of the HS-D+K group revealed mild lung injury. The effects of haemorrhagic shock on increasing cell number and protein concentration in bronchoalveolar lavage fluid as well as water content, leukocyte infiltration, and myeloperoxidase activity of lung tissues were significantly attenuated by dexmedetomidine–ketamine combination but not by dexmedetomidine or ketamine alone. Dexmedetomidine–ketamine combination, but not dexmedetomidine or ketamine alone, also significantly inhibited haemorrhagic shock-induced upregulation of pulmonary inflammatory molecules, including nitric oxide, prostaglandin E2, chemokine (e.g., macrophage inflammatory protein-2), and cytokines [e.g., interleukin (IL)-1β, and IL-6]. Conclusions: Dexmedetomidine–ketamine combination mitigates acute lung injury in haemorrhagic shock rats. [Copyright &y& Elsevier]

Abstract: Background: This study was designed to determine the effects of various resuscitation fluids on pulmonary capillary leakage and pulmonary edema after HS and fluid resuscitation (HS/R) and to determine whether an antiinflammatory or antioxidative mechanism was involved. Methods: We induced HS by bleeding male Sprague–Dawley rats to a blood pressure of 30 to 40 mm Hg for 60 min. 60 min later, the rats were killed (HS group) or immediately resuscitated with L-isomer lactated Ringer''s solution (HS+LR group), shed blood (HS+BL group), or hydroxyethyl starch (HS+HES group) to maintain the blood pressure to the original value during the 60-min resuscitation period. 3 h after resuscitation, pulmonary capillary leakage and wet/dry weight ratio, levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, malondialdehyde (MDA), oxidized and reduced glutathione (GSH and GSSG), myeloperoxidase (MPO) activity, nuclear factor (NF)-κB, activator protein (AP)-1 activation, and lung microscopic and ultrastructural histological changes were measured. Results: HES and BL treatment significantly improved pulmonary capillary leakage, wet/dry weight ratio and lung injuries after HS/R. In addition, both HES and BL could attenuate the increase in TNF-α, IL-6, MPO levels and NF-κB activation. However, HES but not BL could attenuate the increase in MDA level and GSSH/GSH ratio and AP-1 activation. Conclusions: HES might attenuate pulmonary injuries by modulating pulmonary inflammatory response and oxidative stress, whereas BL attenuates pulmonary injuries by modulating pulmonary inflammatory response but not oxidative stress. [Copyright &y& Elsevier]

Abstract: Objectives: Multiple organ dysfunction resulting from hemorrhagic shock (HS) and subsequent resuscitation was mediated by several inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10). The present study was designed to investigate the protective effects of fluvastatin on these mediators after HS in rats. Methods: The experimental rats were randomly divided into three groups. The vehicle group received only vitamin K without HS, the HS-control group received vitamin K and HS, and the HS-experimental group received both vitamin K and fluvastatin (1mg/kg) before HS. HS was produced by bleeding from a femoral arterial catheter to remove 60% of total blood volume (6ml/100g BW) over 30min. The mean arterial pressure (MAP) and heart rate (HR) were monitored continuously for 12h after the start of blood withdrawal. The biochemical parameters, including arterial blood gas, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), blood urea nitrogen (BUN), creatinine (Cre), lactic dehydrogenase (LDH), creatine phosphokinase (CPK), and lactate were obtained at 30min before induction of HS and at 0, 1, 3, 6, 9 and 12h after HS. Equal volume of normal saline was given to replace blood volume loss. Cytokine levels including TNF-α and IL-10 in serum were measured at 1h after HS. Kidney, liver, lung and small intestine were removed for pathology examination at 48h after HS. Results: HS significantly increased HR, blood GOT, GPT, BUN, Cre, LDH, CPK, lactate, TNF-α and IL-10 levels, and also induced metabolic acidosis and decreased MAP in rats. Pre-treatment with fluvastatin was found to improve survival rate, preserved MAP, decreased the markers of organ injury, suppressed the release of TNF-α and increased IL-10 after HS in rats. Conclusion: Pre-treatment with fluvastatin can suppress the release of serum TNF-α and can also increase serum IL-10 level to protect HS-induced multi-organ damage in rats. [Copyright &y& Elsevier]

Hemorrhagic shock (HS) is associated with cardiac contractile dysfunction. Mast cell (MC) degranulation is hypothesized to mediate the cardiodepressant effect. Cardiac function was assessed after HS and resuscitation (HS/R) with the administration of the MC stabilizers to prevent MC degranulation. Anesthetized male Sprague-Dawley rats were randomized to sham-operated control or HS/R groups and underwent 60 min of HS followed by 2 h of resuscitated reperfusion. Animals in the HS/R groups were randomized to receive cromolyn (5 mg/kg), ketotifen (1 mg/kg), or saline 15 min before shock. Hearts were excised following HS or 2 h of reperfusion, and function was assessed on a Langendorff apparatus. A second group of randomized animals had serial blood samples taken to assess MC degranulation by quantifying levels of serum 3-hexosaminidase. Hearts were excised at 0 min (before HS) and following 60 min of US (before resuscitation) for a histological evaluation of MC density and degranulation. In vivo MC stabilization using ketotifen and cromolyn improved cardiac peak systolic pressure (P < 0.05), contractility (P < 0.05), and relaxation (P < 0.05) compared with that of HS controls. Serum β-hexosaminidase increased during HS/R and was inhibited by MC stabilization (P < 0.05). Degranulation was inhibited when assessed by histochemistry and immune fluorescence. The inhibition of MC degranulation can significantly improve cardiac function following HS/R. [ABSTRACT FROM AUTHOR]