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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]

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]

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]

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]

Nitric oxide (NO) participates in shock and poorer portal hypotensive effect to vasoconstrictors in portal hypertension with hemorrhage, the so-called splanchnic hyposensitivity. Relative adrenal insufficiency accompanies hemorrhagic shock and is found in liver disease, the ‘hepatoadrenal syndrome’, but the relevant interactions remain unsettled. Portal hypertensive rats were induced by partial portal vein ligation (PVL). Experiments were performed on the 14th day post PVL: (I) ACTH stimulation test for rats without or with hemorrhage; (II) Glypressin response (mean arterial pressure, MAP; portal pressure, PP) in rats (a) without hemorrhage or with hemorrhage, injected with (b) distilled water (DW), (c) dexamethasone 3 mg/kg; (III) To survey the dose-dependent effects of glucocorticoid without being confounded by endogenous adrenal hormone, glypressin response was surveyed in PVL rats with adrenalectomy: (a) without hemorrhage or with hemorrhage, injected with (b) DW; (c) dexamethasone 3 mg/kg; (d) dexamethasone 5 mg/kg. Plasma tumor necrosis factor-α (TNF-α) concentrations and abdominal aorta (AA), superior mesenteric artery (SMA) NO synthases (NOS) mRNA expressions were determined. The results showed that ACTH induced corticosterone release similarly in PVL rats with or without hemorrhage. In bleeding PVL rats, dexamethasone (1) down-regulated AA NOS and enhanced glypressin-induced MAP elevation; (2) did not influence glypressin-induced PP reduction; (3) reduced TNF-α. In bleeding PVL and adrenalectomized rats, high-dose dexamethasone (1) down-regulated AA/SMA NOS; (2) enhanced glypressin-induced MAP elevation and PP reduction; (3) reduced TNF-α. In conclusion, bleeding portal hypertensive rats failed to enhance corticosterone release, suggesting a relative adrenal insufficiency. High-dose dexamethasone reversed systemic hypotension and splanchnic hyporesponsiveness to glypressin in adrenalectomized PVL rats accompanied by TNF-α and NOS down-regulation, suggesting the importance of adequate adrenocorticoid supplement in portal hypertension with hemorrhage and adrenal dysfunction. [ABSTRACT FROM AUTHOR]

Abstract: Background: Previous studies have demonstrated differences among organs in terms of shock-induced vascular reactivity and a role for adenosine A2A receptors (A2ARs) in protection against ischemia/reperfusion injury. However, the contributions of A2ARs to organ-specific vascular reactivity and the protection of vascular responsiveness following shock are currently unknown. Methods: We investigated the role of A2ARs in different arteries, including the left femoral artery (LFA), thoracic aorta (TA), superior mesenteric artery (SMA), right renal artery (RRA), pulmonary artery (PA), and middle cerebral artery (MCA), in hemorrhagic-shock rats. Results: The vascular reactivities of the LFA, SMA, RRA, and MCA increased slightly during early shock and then gradually decreased, whereas those of the PA and TA decreased from the start of shock. Different blood vessels lost vascular reactivity at different rates compared with controls; the LFA had the highest rate of loss (64.51%), followed by the SMA (44.69%), TA (36.06%), PA (37.83%), and RRA (32.33%), whereas the MCA had the lowest rate (18.45%). The rate of loss of vascular reactivity in the different vessels was negatively correlated with A2AR expression levels in normal and shock conditions. The highly selective A2AR agonist CGS 21680 significantly improved vascular reactivity, hemodynamic parameters, and animal survival, whereas the specific antagonist SCH58261 further decreased the shock-induced reduction in vascular reactivity and hemodynamic parameters. Conclusions: A2ARs are involved in the regulation and protection of vascular reactivity following shock. A2AR activation may have a beneficial effect on hemorrhagic shock by improving vascular reactivity and hemodynamic parameters. [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]

Alcohol intoxication can exacerbate hemodynamic instability following hemorrhagic shock. Impairment of hormonal, neurohumoral, and immune responses can contribute to such instability; however, the relationship between blood alcohol levels and the progression of hemorrhagic shock accompanied with these responses has not been clearly demonstrated. Herein, we examined this relationship in rats treated with various dose of alcohol. After oral administration of alcohol and then hemorrhage, the recovery of mean blood pressure (MBP); increase in plasma level of norepinephrine, epinephrine, and vasopressin; and survival interval decreased in a dose-dependent manner as the blood alcohol level increased. There were no significant differences in the production of proinflammatory cytokines such as tumor necrosis factor (TNF)-a and interleukin (IL)-1ß among the groups. The present results demonstrated alcohol aggravates hemorrhagic shock in a dose-dependent manner not by alerting the immune response, but by suppressing hormonal and neurohumoral responses, thereby inhibiting hemodynamic autoregulation and shortening the survival interval. [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]

Introduction: Different vasoactive factors can modulate cardiovascular adaptation to hemorrhagic shock including Nitric Oxide (NO). In this study we investigated the effect of the NO synthase inhibitor for treatment of decompensated hemorrhagic shock in normotensive and hypertensive rats. Methods: Twenty-four male Wistar rats were divided into two groups: The normotensive and hypertensive groups. Hypertension was induced by the DOCA-Salt method for eight weeks. Then, the animals were given hemorrhagic shock by continuously withdrawing blood until the mean arterial pressure (MAP) reached to 40 mmHg. The animals were maintained in the shock state for 120 minutes. Subsequently, they were randomly assigned to L-NAME-treated and non-treated groups and monitored for 60 minutes. The survival time was recorded. Blood samples were taken before and after the shock and 60 minutes after L-NAME administration. Results: Infusion of L-NAME caused a significant increase in MAP in normotensive animals, however, slightly increased MAP in hypertensive animals. The heart rate did not significantly alter. Hemorrhage caused a marked increase in serum nitrite levels in both groups (P<0.05). L-NAME treatment significantly reduced the serum nitrite concentration in the normotensive group (P<0.05), without any change in the hypertensive group. All animals who received L-NAME treatment survived at the end of experiment. Fifty percent of the hypertensive animals died four hours after the experiment. The 72-hour survival rate was similar in the L-NAME treated groups. Conclusion: L-NAME infusion during decompensated hemorrhagic shock plays a protective role in the improvement of hemodynamic responses and short-term survival rate in normotensive animals. [ABSTRACT FROM AUTHOR]

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]

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]

Microvascular observations and measurements of the oxygen partial pressure (PO2) distribution are essential to understand tissue oxygenation. Longitudinal PO2 gradients have been reported previously, but few attempts have been made to investigate factors that can alter such a gradient. Despite its importance in hemorrhagic shock, the mesenteric microvascular PO2 distribution has never been evaluated during HH. We tested the hypothesis that the diverse hemodynamic responses of arterioles to HH would lead to changes in longitudinal PO2 gradients. The mesenteric microcirculation of anesthetized rats was studied under normovolemia (baseline) and during HH (mean arterial pressure = 50 mmHg). Diameter and blood flow of arterioles and venules of different orders were studied using intravital videomicroscopy. PO2 was determined using the phosphorescence quenching technique. During HH, blood flow was uniformly reduced in arterioles and venules, while PO2 showed a wider distribution. In arterioles, the small longitudinal PO2 gradient recorded during baseline was enhanced during HH. Two groups of vessels were observed with regard to PO2: large vessels showed PO2 levels similar to or above baseline, while small vessels showed reduced PO2. Changes in blood flow did not explain this variability, since the reduction in flow was similar for all vessels, irrespective of vessel order or type. [ABSTRACT FROM AUTHOR]