Kynurenic acid attenuates multiorgan dysfunction in rats after heatstroke

Aim:

To assess whether systemic delivery of kynurenic acid improves the outcomes of heatstroke in rats.

Methods:

Anesthetized rats were divided into 2 major groups and given vehicle solution (isotonic saline 0.3 mL/kg rat weight) or kynurenic acid (30–100 mg in 0.3 mL saline/kg) 4 h before the start of thermal experiments. They were exposed to an ambient temperature of 43 °C for 68 min to induce heatstroke. Another group of rats were exposed to room temperature (26 °C) and used as normothermic controls. Their core temperatures, mean arterial pressures, serum levels of systemic inflammatory response molecules, hypothalamic values of apoptotic cells and neuronal damage scores, and spleen, liver, kidney and lung values of apoptotic cells were determined.

Results:

The survival time values during heatstroke for vehicle-treated rats were decreased from the control values of 475–485 min to new values of 83–95 min. Treatment with KYNA (30–100 mg/kg, iv) 4 h before the start of heat stress significantly and dose-dependently decreased the survival time to new values of 152–356 min (P<0.05). Vehicle-treated heatstroke rats displayed hypotension, hypothalamic neuronal degeneration and apoptosis, increased serum levels of tunor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and interleukin-10 (IL-10), and spleen, liver, kidney, and lung apoptosis. KYNA preconditioning protected against hypotension but not hyperthermia and attenuated hypothalamic neuronal degeneration and apoptosis during heatstroke. KYNA preconditioning attenuated spleen, kidney, liver, and lung apoptosis and up-regulated serum IL-10 levels but down-regulated serum TNF-α and ICAM-1 levels during heatstroke.

Conclusion:

Our results suggest that systemic delivery of kynurenic acid may attenuate multiorgan dysfunction in rats after heatstroke.     

Geranylgeranylacetone preconditioning may attenuate heat‐induced inflammation and multiorgan dysfunction in rats

Objectives Geranylgeranylacetone, an acyclic isoprenoid, is a non‐toxic inducer of heat shock protein (HSP)70. HSP70 overproduction is associated with heat tolerance in rats. This study aimed to investigate whether geranylgeranylacetone preconditioning of rats reduced heat‐induced inflammation and multiple organ dysfunction. Methods Anaesthetised rats were given vehicle or geranylgeranylacetone (800 mg/kg) orally. After 48 h they were exposed to ambient temperature of 43°C for 70 min to induce heatstroke. Another group of rats kept at room temperature were used as normothermic controls. Key findings Vehicle‐treated rats all succumbed to heat stress; their survival time was 25 ± 4 min. Pretreatment with geranylgeranylacetone significantly increased survival time to 92 ± 15 min. Compared with normothermic controls, all vehicle‐treated heatstroke rats displayed hepatic and renal dysfunction (e.g. increased plasma levels of serum urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase) and active inflammation (e.g. increased plasma and brain levels of interleukin‐1β, tumour necrosis factor‐α and interleukin‐6). These heat‐stress response indicators were all significantly suppressed by geranylgeranylacetone pretreatment. In addition, the plasma and brain levels of interleukin‐10 (an anti‐inflammatory cytokine) and brain levels of HSP70 were significantly increased after geranylgeranylacetone preconditioning during heatstroke. Conclusions Geranylgeranylacetone preconditioning attenuates heat‐induced inflammation and multiorgan dysfunction in rats.     

The flavonoid baicalin protects against cerebrovascular dysfunction and brain inflammation in experimental heatstroke

The present study was performed to assess the prophylactic effect of baicalin, a flavonoid compound, in an animal model of heatstroke. Anesthetized rats, immediately before the start of heat stress, were divided into two major groups and given the following: vehicle solution (1mL per kg body weight) or baicalin (10-40mg per kg body weight) intravenously. They were exposed to ambient temperature of 43 degrees C to induce heatstroke. Another group of rats was exposed to room temperature (24 degrees C) and used as normothermic controls. Their physiologic and biochemical parameters were continuously monitored. When the vehicle-pretreated rats underwent heat stress, their survival time values were found to be 20-28min. Pretreatment with intravenous doses of baicalin significantly improved survival during heatstroke (65-248min). As compared to those of normothermic controls, all vehicle-pretreated heatstroke animals displayed higher levels of core temperature, intracranial pressure, and nitric oxide metabolite (NO(2)(-)), glutamate, glycerol, lactate/pyruvate ratio, and dihydroxybenzoic acid (DHBA) in hypothalamus. In addition, both serum and hypothalamic levels of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) as well as plasma levels of creatinine, serum urea nitrogen, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase and alkaline phosphatase were elevated after heatstroke onset. In contrast, all vehicle-pretreated heatstroke animals had lower levels of mean arterial pressure, cerebral perfusion pressure, cerebral blood flow, and brain PO(2). Administration of baicalin before the start of heat exposure significantly reduced the hyperthermia, intracranial hypertension, and the increased levels of NO(2)(-), glutamate, glycerol, lactate/pyruvate ratio, and DHBA in the hypothalamus that occurred during heatstroke. The heatstroke-induced increased levels of IL-1beta and TNF-alpha in both the serum and hypothalamus, and renal and hepatic dysfunction were suppressed by baicalin pretreatment. In contrast, both the serum and hypothalamic levels of IL-10 were significantly elevated by baicalin during heatstroke. We successfully demonstrated that baicalin can be used as a prophylactic agent for heatstroke. In particular, baicalin may protect against cerebrovascular dysfunction and brain inflammation in heatstroke.     

Inhibition of neuronal nitric oxide synthase causes attenuation of cerebrovascular dysfunction in experimental heatstroke

The present study was performed to assess the prophylactic effect of 7-nitroindazole (7-NI), an inhibitor of neuronal nitric oxide synthase (nNOS), in an animal model of heatstroke. Anesthetized rats, immediately before the start of heat stress, were divided into two major groups and given the following: vehicle solution (1 mL per kg body weight) or 7-NI (5-20mg/mL per kg body weight) intraperitoneally. They were exposed to ambient temperature of 43 degrees C to induce heatstroke. Another group of rats were exposed to room temperature (24 degrees C) and used as normothermic controls. Their physiologic and biochemical parameters were continuously monitored. When the vehicle-pretreated rats underwent heat stress, their survival time values were found to be 21-25 min. Pretreatment with intraperitoneal doses of 7-NI significantly improved survival during heatstroke (55-164 min). As compared to those of normothermic controls, all vehicle-pretreated heatstroke animals displayed higher levels of core temperature, intracranial pressure, nitric oxide metabolite (NO(2)(-)), glutamate, glycerol, lactate/pyruvate ratio, neuronal damage score and nNOS expression in the hypothalamus, and tumor necrosis factor-alpha (TNF-alpha) in the serum. In contrast, all vehicle-pretreated heatstroke animals had lower levels of mean arterial pressure, cerebral perfusion pressure, cerebral blood flow, and brain PO(2). Administration of 7-NI before the start of heat exposure significantly reduced the hyperthermia, intracranial hypertension, nNOS-dependent NO(2)(-), glutamate, glycerol, lactate/pyruvate ratio, and neuronal damage score in the hypothalamus, as well as overproduction of TNF-alpha in the serum that occurred during heatstroke. The data show that reduction of nNOS-dependent NO(2)(-) with 7-NI causes attenuation of cerebrovascular dysfunction, hyperthermia, and TNF-alpha overproduction during heatstroke in the rat.     

Hyperbaric oxygen improves survival in heatstroke rats by reducing multiorgan dysfunction and brain oxidative stress

Hyperbaric oxygen has been found to be beneficial in treating heatstroke animals. We attempted to further assess the possible mechanism of therapeutic protection offered by hyperbaric oxygen in experimental heatstroke. Anesthetized rats, immediately after the onset of heatstroke, were randomized into the following groups and given: a) hyperbaric oxygen (100% O(2) at 253 kPa for 1 h); or b) normal air. They were exposed to 43 degrees C temperature to induce heatstroke. When the untreated rats underwent heat stress, their survival time values were found to be 20-24 min. Resuscitation with hyperbaric oxygen increased the survival time to new values of 152-176 min. All untreated heatstroke rats displayed cerebrovascular dysfunction (evidenced by hypotension, intracranial hypertension, and cerebral hypoperfusion, hypoxia, and ischemia), hypercoagulable state (evidenced by increased levels of activated partial thromboplastin time, prothrombin time, and D-dimer, but decreased values of platelet count and protein C in plasma), and tissue ischemia/injury (evidenced by increased levels of creatinine, serum urea nitrogen, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase in plasma, and dihydrobenzoic acid, lipid peroxidation, and oxidized-form glutathione/reduced-form of glutathione ratio in hypothalamus). The cerebrovascular dysfunctions, hypercoagulable state, tissue ischemia/injury, and brain oxidative stress that occurred during heatstroke were all suppressed by hyperbaric oxygen therapy. The current results indicate that hyperbaric oxygen therapy may resuscitate rats that had a heatstroke by decreasing multiple organ dysfunction and brain oxidative stress.     

Prevention and repair of circulatory shock and cerebral ischemia/injury by various agents in experimental heatstroke

The current report summarized animal models of heatstroke experimentation that advance our current knowledge of therapeutic effects on cerebrovascular dysfunction, hypercoagulable state and/or systemic inflammation with various agents in the setting of heatstroke. This was a narrative review of selected published primary basic literature from MEDLINE for 1973-2006. It was found that rodents shared with humans almost the same heatstroke reactions such as hyperpyrexia, hypotension, hyperventilation, pulmonary edema, hepatic and renal failure, hypercoagulable state, metabolic acidosis, systemic inflammation, and cerebral ischemia, injury and dysfunction. Therefore, the rodent model would allow testing of new therapeutic strategies for heatstroke. It was found that brain cooling produced by infusion of cold (4 degrees C) normal saline via the jugular vein or whole body cooling improved survival during heatstroke by reducing cerebrovascular dysfunction, multiple organ failure, systemic inflammation and hypercoagulable state. However, even under the absence of brain or whole body cooling, these heatstroke reactions still could be reversed by treating with the following agents: (1) free radical scavengers; (2) human recombinant protein C: (3) platonin; (4) hyperbaric oxygen; (5) hydroxyethyl starch, hypertonic solution, or human albumin; (6) glucocorticoids; (7) interleukin-1 receptor antagonists; (8) L-arginine; (9) estrogen; and (10) human umbilical cord blood cells or CD +34 cells. Before initiation of heat stress, prior manipulations with one of the following measures were found to be able to protect against heatstroke syndromes: (1) systemic delivery of inducible nitric oxide synthase inhibitors, mu-opioid receptor antagonists, endothelin-1A receptor antagonists, dopaminergic or serotoninergic nerve depletor or receptor antagonists, or glutamate receptor antagonists; or (2) heat shock protein 72 preconditioning.     

Chronic hypoxia preconditioning increases survival in rats suffering from heatstroke

1. In the present study, we assessed the protective effects of chronic hypoxia preconditioning against heatstroke-induced injury in urethane-anaesthetized rats. Heatstroke was induced by exposing the animals to an ambient temperature of 42 degrees C. The time at which both the mean arterial pressure (MAP) and local cerebral blood flow (CBF) in the striatum began to decrease from peak levels was taken as the onset of heatstroke. Control rats were exposed to a temperature of 24 degrees C. 2. Mean arterial pressure, CBF, blood pH, PaO2, PaCO2 and survival time (the interval between onset of heatstroke and cardiac arrest) after heat stress were all lower than in control rats (in which 'survival time' was defined as > 360 min). However, blood lactate concentrations were greater in rats exposed to heat. Rats placed at high altitude (HA), when exposed to the same heat stress (42 degrees C) survived much longer (113 +/- 26 min; n = 8) than rats maintained at sea level (SL; 20 +/- 2 min; n = 8). 3. After the onset of heatstroke, blood pH and lactate concentrations were found to be significantly higher and lower, respectively, in HA rats than in SL rats. 4. Western blot assay revealed that chronic hypoxia preconditioning induced heat shock protein (HSP) 72 expression in both the kidneys and lungs. 5. Thus, it appears that the observed benefit of chronic hypoxia preconditioning is related to attenuation of tissue acidification and elevations of HSP72 expression in both kidneys and lungs during heatstroke.     

盲肠结扎穿孔脓毒症大鼠巨噬细胞炎症蛋白-1α水平变化的研究

目的研究脓毒症大鼠早期肺泡灌洗液巨噬细胞炎症蛋白-1α(MIP-1α)水平的变化及其与脓毒症的关系。方法 60只SD大鼠随机分成A组假手术组,n=30、B组脓毒症组,n=30,A组仅行盲肠探查术,B组采用盲肠结扎穿孔(CLP)制作大鼠脓毒症模型。两组术后即刻皮下注射生理盐水5 ml。各组均于术后3、6、12、24、48 h时点,留取肺泡灌洗液检测MIP-1α。结果 CLP术后3 h肺泡灌洗液MIP-1α即开始升高,明显高于A组(P<0.05),且逐步升高,到术后12 h达峰值,随后逐渐下降,但在48 h时点仍然显著高于A组(P<0.05)。结论脓毒症致急性肺损伤后MIP-1α水平明显升高,其升高可能是脓毒症导致急性肺损伤的原因之一,在脓毒症导致急性肺损伤发生发展中具有重要作用。     

Aminoguanidine protects against intracranial hypertension and cerebral ischemic injury in experimental heatstroke

The aim of the present study was to ascertain whether aminoguanidine attenuated intracranial hypertension and cerebral ischemic injury in experimental heatstroke. Urethane-anesthetized rats were exposed to heat stress (ambient temperature of 43 degrees C) to induce heatstroke. Control rats were exposed to 24 degrees C. Mean arterial pressure, cerebral perfusion pressure, and cerebral blood flow after the onset of heatstroke were all significantly lower than in control rats. However, colonic temperature, intracranial pressure, heart rate, cerebral inducible nitric oxide synthase (iNOS)-dependent NO, and neuronal damage score were greater after the onset of heatstroke. Aminoguanidine (30 micromol/kg, i.v.; 30 min before the start of heat exposure) pretreatment significantly attenuated the heatstroke-induced hyperthermia, arterial hypotension, intracranial hypertension, cerebral ischemia and neuronal damage, and increased iNOS-dependent NO formation in the brain. The extracellular concentrations of ischemic (e.g., glutamate and lactate/pyruvate ratio) and damage (e.g., glycerol) markers in the hypothalamus were also increased after the onset of heatstroke. Aminoguanidine pretreatment significantly attenuated the increase in hypothalamic ischemia and damage markers associated with heatstroke. Delaying onset of aminoguanidine administration (i.e., 0 or 30 min after the start of heat exposure) reduced the preventive efficiency on heatstroke-induced hyperthermia, arterial hypotension, intracranial hypertension, cerebral ischemia, and increased iNOS-dependent NO formation in brain. These results suggest that aminoguanidine protects against heatstroke-induced intracranial hypertension and cerebral ischemic injury by inhibition of cerebral iNOS-dependent NO production.     

Selective inhibition of inducible nitric oxide synthase attenuates renal ischemia and damage in experimental heatstroke

The aim of the present study was to determine whether the possible occurrence of renal ischemia and damage during heatstroke can be suppressed by prior administration of L-N6-(1-iminoethyl) lysine (L-NIL), a selective inducible nitric oxide synthase (iNOS) inhibitor. Urethane-anesthetized rats were exposed to heat stress (43 degrees C) to induce heatstroke. Control rats were exposed to 24 degrees C. Mean arterial pressure and renal blood flow after the onset of heatstroke both were significantly lower in vehicle-treated heatstroke rats than in normothermic controls. However, both the body temperature and renal damage scores were greater in vehicle-treated heatstroke rats compared with normothermic controls. Plasma nitric oxide (NO), creatinine, and blood urea nitrogen (BUN), as well as the renal immunoreactivity of iNOS and peroxynitrite all were significantly higher in vehicle-treated heatstroke rats compared with their normothermic controls. Pretreatment with L-NIL (3 mg/kg, administered intravenously and immediately at the onset of heat stress) significantly attenuated heatstroke-induced hyperthermia, arterial hypotension, renal ischemia and damage, increased renal levels of immunoreactivity of iNOS and peroxynitrite, and increased plasma levels of NO, creatinine, and BUN. Accordingly, pretreatment with L-NIL significantly improved survival during heatstroke. The results suggest that selective inhibition of iNOS-dependent NO and peroxynitrite formation protects against renal ischemia and damage during heatstroke by reducing hyperthermia and arterial hypotension.     

Mu-opioid receptor blockade protects against circulatory shock and cerebral ischemia during heatstroke

Naltrexone, a nonselective antagonist of opioid receptors, is found to be beneficial in protecting against heatstroke. Further investigation using selective mu, delta, and kappa opioid receptor antagonists are needed to prove the involvement of specific receptors in heatstroke. Rats under sodium pentobarbital anesthesia were exposed to high ambient temperature of 43 degrees C to induce heatstroke. Control rats were exposed to 24 degrees C. In rats treated with normal saline 20 minutes before heat stress, the values for survival time were found to be 89-101 minutes. Intravenous administration of CTAP (a selective mu-opioid receptor antagonist; 50-200 microg/kg), but not nor-binaltorphimine (20-200 microg/kg; a kappa-opioid receptor antagonist) or ICI-174864 (50-500 microg/kg; a delta-opioid receptor antagonist), significantly increased the survival time to new values of 180-212 minutes. In vehicle-treated rats after heatstroke onset, the values for core temperature, intracranial pressure, and the extracellular markers for ischemia (eg, glutamate and lactate/pyruvate ratio) or damage (eg, glycerol) and neuronal damage scores in striatum were significantly higher than those of normothermic controls. In contrast, the values for mean arterial pressure, cerebral perfusion pressure, cerebral blood flow, and brain partial pressure of O2 were significantly lower than those of normothermic controls. The heatstroke-induced hyperthermia, arterial hypotension, intracranial hypertension, cerebral hypoperfusion and hypoxia, and increased levels of cellular ischemia and damage markers in striatum were all significantly attenuated by prior administration of CTAP. The data indicate that prior antagonism of mu-opioid receptors protects against circulatory shock and cerebral ischemia during heatstroke.     

Prior antagonism of endothelin-1A receptors alleviates circulatory shock and cerebral ischemia during rat heatstroke

In this study, we investigated the acute hemodynamic effects of an infusion of the endothelin-1 (ET-1)-A-selective receptor antagonists BQ-610 and BQ-123 in heatstroke rats with circulatory shock and cerebral ischemia. Heatstroke was induced by putting the anesthetized adult Sprague-Dawley rats into an ambient temperature of 42 degrees C. The moment in which the mean arterial pressure dropped irreversibly from the peak for an extent of 25 mmHg was taken as the onset of heatstroke. The interval between initiation of heat exposure and heatstroke onset was found to be about 80 min for rats treated with vehicle solution. When the animals were exposed to 42 degrees C for 80 min, hyperthermia, arterial hypotension, decrement of cardiac output (due to decreased stroke volume and decreased total peripheral resistance), increment of plasma ET-1 and tumor necrosis factor-alpha, and increment of cerebral ischemia and injury markers were manifested. Prior antagonism of ET-1 A receptors with BQ-610 (0.5 mg/kg, i.v.) or BQ-123 (1 mg/kg, i.v.), but not ET-1B receptors with BQ-788 (0.5 mg/kg, i.v.), 60 min before the initiation of heat exposure, appreciably alleviated hyperthermia, arterial hypotension, decreased cardiac output, increment of tumor necrosis factor-alpha, and increment of cerebral ischemia (e.g., glutamate and lactate/pyruvate ratio) and injury (e.g., glycerol) markers exhibited during heatstroke. The data indicates that ET-1A receptor antagonism may maintain appropriate levels of mean arterial pressure and cerebral circulation during heatstroke by reducing production of tumor necrosis factor-alpha.     

Flutamide, an androgen receptor antagonist, improves heatstroke outcomes in mice

Flutamide has been used as an adjunct for decreasing the mortality from subsequent sepsis. Heatstroke resembles septic shock in many aspects. We hypothesized that heat-induced multiple organ dysfunction syndromes and lethality could be reduced by flutamide therapy. In heatstroke groups, mice were exposed to whole body heating (41.2°C, for 1h) in a controlled-environment chamber. The heat-stressed mice were returned to normal room temperature (24°C) after whole body heating. Mice still alive on day 4 of WBH treatment were considered survivors. Physiological and biochemical parameters were monitored for 2.5h post-WBH. Heatstroke mice were subcutaneously treated with flutamide (12.5-50mg/kg body weight in 0.05 ml) or vehicle solution (0.05 ml/kg body weight) once daily for 3 consecutive days post-WBH. We evaluated the effect of flutamide in heatstroke mice and showed that flutamide significantly (i) attenuated hypothermia, (ii) reduced the number of apoptotic cells in the hypothalamus, the spleen, the liver, and the kidney, (iii) attenuated the plasma index of toxic oxidizing radicals (e.g., nitric oxide metabolites and hydroxyl radicals), (iv) diminished the plasma index of the organ injury index (e.g., lactate dehydrogenase), (v) attenuated plasma systemic inflammation response molecules (e.g., tumor necrosis factor-α and interleukin-6), (vi) reduced the index of infiltration of polymorphonuclear neutrophils in the lung (e.g., myeloperoxidase activity), and (vii) allowed three times the fractional survival compared with vehicle. Thus, flutamide appears to be a novel agent for the treatment of mice with heatstroke or patients in the early stage of heatstroke.     

Altered oral absorption of alcohol by combined aqueous extracts of four herbal plants in rats

This study examined the effect of combined aqueous extracts (BHR) of Ginko biloba, Mentha arvensis var. piperascens, Citrus unshiu, and Pueraria lobata var. chinensis on oral absorption of alcohol in rats. The rats were pretreated with BHR, placebo solution identical to BHR without the herbal extract, and isotonic saline. Alcohol was administered orally at 1- and 3-g/kg doses and the absorption profiles were compared. After oral administration of 1-g/kg doses, mean area under the curve (AUC) and C(max) values were significantly reduced in BHR-treated rats (16.1 +/- 10.0 and 0.3 +/- 0.1 mg/ml, respectively) as compared with saline-treated (37.9 +/- 14.4 and 0.7 +/- 0.7 mg/ml, respectively) and placebo solution-treated (63.0 +/- 46.4 and 0.7 +/- 0.4 mg/ml, respectively) rats. Similarly, after administration of 3-g/kg doses, mean AUC and C(max) values in BHR-treated rats (188.1 +/- 119.7 mg(.)min/ml and 1.0 +/- 0.4 mg/ml) were significantly reduced over those in saline-treated rats (571.4 +/- 512.4 mg(.)min/ml and 1.8 +/- 0.9 mg/ml, respectively). The relative oral bioavailability of alcohol calculated as the ratio of AUC(BHR)/AUC(Saline) was 42.5% and 32.9% at 1- and 3-g/kg doses, respectively. The reduced serum alcohol levels as well as the reduced AUC and C(max) after pretreatment with BHR appear to be a result of a reduced systemic absorption not due to an increased metabolic clearance.     

Impairment of neurogenic inflammatory and anti-inflammatory responses in diabetic rats

The effect was studied of a primary (preconditioning) neurogenic inflammatory challenge induced by electrical stimulation of the peripheral stump of the sciatic nerve (20 V, 0.5 ms, 5 Hz, for 5 min) on neurogenic oedema (5 min later) induced by stimulation of the contralateral sciatic nerve. Plasma extravasation due to the second stimulation was decreased by 52.7+/-3.1% (P<0.01) in normal animals and by 29.7+/-2.2 and 18.1+/-1.5% with 50 mg/kg streptozotocin pretreatment i.v. 4 and 8 weeks previously, respectively. Subsequently, bilateral sciatic nerve stimulation increased baseline plasma somatostatin levels from 6.4+/-0.3, 11. 7+/-1.4, and 16.8+/-3.8 to 28.3+/-2.9 (P<0.01), 17.9+/-3.7, and 25. 1+/-1.7 pmol/l in normal, and 4- and 8-week diabetic animals, respectively. We conclude that experimental diabetes impairs the capability of a preconditioning neurogenic inflammatory episode to elicit a systemic anti-inflammatory effect. This is accompanied by a deficiency in elevation of the plasma somatostatin level in response to nerve stimulation, although the baseline plasma somatostatin level increases proportionally to the duration of experimental diabetes.     

Human umbilical cord blood-derived CD34+ cells can be used as a prophylactic agent for experimental heatstroke

We attempted to assess the prophylactic effect of human umbilical cord blood-derived CD34(+) cells in experimental heatstroke. Anesthetized rats, 1 day before heat stress, were divided into 2 major groups and given CD34(-) cells (defined by 1 x 10(6) human cord blood lymphocytes and monocytes that contained <0.2% CD34(+) cells) or CD34(+) cells (defined by 1 x 10(6) human cord blood lymphocytes and monocytes that contained >95% CD34(+) cells). They were exposed to ambient temperature of 43 degrees C for 70 min to induce heatstroke. When the CD34(-) cells-treated or untreated rats underwent heat stress, their survival time values were found to be 20-24 min. Pretreatment with CD34(+) cells significantly increased survival time (123-351 min). As compared with normothermic controls, all CD34(-) cells-treated heatstroke animals displayed hypotension, hepatic and renal failure, hypercoagulable state, activated inflammation, and cerebral ischemia and injury. However, these heatstroke reactions all were significantly suppressed by CD34(+) cells pretreatment. In addition, the levels of interleukin-10 in plasma and glial cell line-derived neurotrophic factors in brain were all significantly increased after CD34(+) cell administration during heatstroke. Our data indicate that human umbilical cord-derived CD34(+) cells can be used as a prophylactic agent for experimental heatstroke.     

阿的平预防中暑的研究

本研究旨在观察预先给予阿的平对大鼠中暑模型的保护作用，同时采用体外培养的神经元热损伤模型探讨阿的平的作用机制。清醒大鼠分别灌胃给予阿的平4.5，9.0和18 mg·kg^-1，1 h后进入(41.0±0.5) ℃的水循环热仓，持续观察动物直肠温度直至死亡，直肠温度和动物存活时间分析表明,预先给予阿的平能够延缓热环境中大鼠的体温快速增加，推迟动物死亡。在细胞水平，原代培养的大鼠纹状体神经元在43.0 ℃培养条件1 h造成细胞热损伤模型，阿的平处理组预先在培养上清液中加入20 μmol·L^-1阿的平，1 h后接受热环境处理。采用荧光分光光度法测定细胞膜流动性，细胞裂解后采用［³H］标记花生四烯酸作为底物测定细胞内磷脂酶A₂活性，采用气相色谱-质谱联用的方法测定细胞内活性脂肪酸的水平。结果表明热环境导致纹状体神经元细胞膜流动性下降，细胞内磷脂酶A₂活性升高，细胞内花生四烯酸浓度升高，而阿的平稳定细胞膜、抑制细胞内磷脂酶A₂活性以及减少花生四烯酸及其代谢产物的释放，可能部分解释阿的平延缓中暑和对抗热环境损伤的机制。     

Alterations in the thermic response to chlorpromazine in rats exposed prenatally to central nervous system depressants

The thermic response to acute administration of chlorpromazine (5 mg/kg, i.p.) was assessed in rats exposed prenatally to haloperidol (0.1 mg/kg), phenobarbital (10 mg/kg), nitrazepam (2 mg/kg), propylene glycol (1 ml/kg) or saline, once daily from days 1-21 or 15-21 of gestation. The response in all animals was tested only once. The administration of chlorpromazine to 8- or 13-week-old male and female rats treated with saline (1-21 d) induced marked hypothermia for a 6-hr period of observation. Male and female rats treated with haloperidol (1-21 d) showed a delayed hyperthermic response to chlorpromazine at 8 weeks of age; the males showed an increase in rectal temperature at 3 hr and the females from 3 to 6 hr. Thirteen-week-old males but not females treated with haloperidol (1-21 d) showed a hyperthermic response to chlorpromazine during the first 2 hr. Eight-week-old male and female rats treated with phenobarbital (1-21 d) showed hypothermia, whereas 13-week-old male rats of another group treated with phenobarbital (1-21 d) showed significant hyperthermia after the administration of the chlorpromazine. The hypothermic response of the rats treated with nitrazepam (1-21 d) to chlorpromazine was similar to that in the vehicle (propylene glycol)-treated controls. The male rats treated with phenobarbital (15-21 d) responded to chlorpromazine with significant hyperthermia from 30 min to 1 hr. There was no alteration in thermic response to chlorpromazine in rats born to mothers treated with one tenth of the dose of phenobarbital, haloperidol or nitrazepam.(ABSTRACT TRUNCATED AT 250 WORDS)     

The lipoxin A4 agonist BML-111 attenuates acute hepatic dysfunction induced by cecal ligation and puncture in rats

Sepsis is a systemic inflammatory response associating severe infection leading to multi-organ failure, such as hepatic dysfunction. This study investigates the possible hepatoprotective effect of the lipoxin A₄ agonist (BML-111) in cecal ligation and puncture (CLP) model in rats. Pretreatment with BML-111 (1 mg/kg, i.p., 1 h before CLP) protected against CLP-induced mortality after 24 h. BML-111 prevented marked inflammatory cells in liver tissues and decreased elevation in serum hepatic biomarkers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), gamma-glutamyl transferase (γ-GT)] induced by CLP. Additionally, BML-111 attenuated elevated serum level of interleukin-6 (IL-6) and downregulated hepatic IL-6 mRNA expression. Meanwhile, BML-111 further increased serum IL-10 and upregulated hepatic IL-10 mRNA expression, while it downregulated hepatic mRNA expression of nuclear factor inhibitory protein kappa-B alpha (NFκBia), toll-like receptor-4 (TLR-4), and 5-lipooxygenase (5-LOX). Moreover, BML-111 prevented NF-κB/p65 nuclear translocation and activation. In conclusion, BML-111 attenuated CLP-induced acute hepatic dysfunction through its anti-inflammatory effect by decreasing NF-κB activity, TLR-4, and 5-LOX expression with subsequent decrease in pro-inflammatory IL-6 and elevation in anti-inflammatory IL-10.

     

参麦注射液预处理对大鼠心肌缺血-再灌注损伤中胰岛素抵抗的影响

目的探讨参麦注射液(SM)对胰岛素(Ins)抵抗是否有改善作用。方法 SD雄性大鼠24只随机均分为两组:A组每天腹腔注射SM 10ml/kg,连续3d;B组注射等量生理盐水。末次给药后30min采用冠脉结扎15min后再松开45min的办法制备大鼠心肌缺血-再灌注(I-R)损伤模型。放射免疫法检测血糖(Glu)、Ins和C肽的浓度,ELISA法检测血浆抵抗素和游离脂肪酸(FFA)含量。结果 A组血浆Glu[(3.64±0.53)mmol/L vs.(4.29±0.62)mmol/L]、Ins[(31.68±0.21)μU/ml vs.(39.17±0.69)μU/ml]、C肽[(9.26±1.87)ng/ml vs.(13.05±2.56)ng/ml]的浓度以及血浆FFA[(326.40±35.63)μmol/L vs.(429.30±29.64)μmol/L]和抵抗素[(13.29±1.16)ng/mlvs.(16.32±1.52)ng/ml](P<0.05)的含量均明显低于B组(P<0.05)。结论 SM预处理能减轻大鼠心肌I-R损伤过程中的Ins抵抗,对心肌产生一定的保护作用。