Distribution of respiratory muscle and organ blood flow during endotoxic shock in dogs

Respiratory muscle blood flow and organ blood flow during endotoxic shock were studied in spontaneously breathing dogs (SB, n = 6) and mechanically ventilated dogs (MV, n = 5) with radiolabeled microspheres. Shock was produced by a 5-min intravenous injection of Escherichia coli endotoxin (0.55:B5, Difco, 10 mg/kg) suspended in saline. Mean arterial blood pressure and cardiac output in the SB group dropped to 59 and 45% of control values, respectively. There was a similar reduction in arterial blood pressure and cardiac output in the MV group. Total respiratory muscle blood flow in the SB group increased significantly from the control value of 51 +/- 4 ml/min (mean +/- SE) to 101 +/- 22 ml/min at 60 min of shock. In the MV group, respiratory muscle perfusion fell from control values of 43 +/- 12 ml/min to 25 +/- 3 ml/min at 60 min of shock. In the SB group, 8.8% of the cardiac output was received by the respiratory muscle during shock in comparison with 1.9% in the MV group. In both groups of dogs, blood flow to most organs was compromised during shock; however, blood flow to the brain, gut, and skeletal muscles was higher in the MV group than in the SB group. Thus by mechanical ventilation a fraction of the cardiac output used by the working respiratory muscles can be made available for perfusion of other organs during endotoxic shock.     

Liver iron depletion and toxicity of the iron chelator Deferiprone (L, CP20) in the guinea pig

The use of the iron chelator deferiprone (L, CP20, 1,2-dimethyl-3-hydroxypyrid-4-one) for the treatment of diseases of iron overload and other disorders is problematic and requires further evaluation. In this study the efficacy, toxicity and mechanism of action of orally administered L were investigated in the guinea pig using the carbonyl iron model of iron overload. In an acute trial, depletion of liver non-heme iron in drug-treated guinea pigs (normal iron status) was maximal (approximately 50% of control) after a single oral dose of L1 of 200 mg kg, suggesting a limited chelatable pool in normal tissue. There was no apparent toxicity up to 600 mg kg. In each of two sub-acute trials, normal and iron-loaded animals were fed L (300 mg kg day) or placebo for six days. Final mortalities were 12/20 (L) and 0/20 (placebo). Symptoms included weakness, weight loss and eye discharge. Iron-loaded as well as normal guinea pigs were affected, indicating that at this drug level iron loading was not protective. In a chronic trial guinea pigs received L (50 mg kg day) or placebo for six days per week over eight months. Liver non-heme iron was reduced in animals iron-loaded prior to the trial. The increase in a wave latency (electroretinogram), the foci of hepatic, myocardial and musculo-skeletal necrosis, and the decrease in white blood cells in the drug-treated/normal diet group even at the low dose of 50 mg kg day suggests that L may be unsuitable for the treatment of diseases which do not involve Fe overload. However, the low level of pathology in animals treated with iron prior to the trial suggests that even a small degree of iron overload (two-fold after eight months) is protective at this drug level. We conclude that the relationship between drug dose and iron status is critical in avoiding toxicity and must be monitored rigorously as cellular iron is depleted.     

Sequential release of eicosanoids during endotoxin-induced shock in anesthetized pigs

The release of eicosanoids during endotoxin shock was investigated in anesthetized pigs receiving 5 micrograms/kg Escherichia coli lipopolysaccharide (LPS) over 60 min into the superior mesenteric artery. TXB2, 6-keto PGF1 alpha and LTB4 concentrations in blood obtained from the superior mesenteric vein (SMV), right ventricle (RV) and aorta, during LPS infusion and an additional period of 2 h, were assessed along with hemodynamic variables, blood gases and pH and laboratory parameters. Half of the animals died within 30 min after termination of LPS infusion (non-survivors, n = 8), while the other half survived the experimental period of 3 h, though in a shock state (survivors, n = 9). The non-surviving pigs demonstrated progressively reduced cardiac output, hypotension and hypoperfusion in all organs. The surviving pigs demonstrated also a reduced cardiac output, which however was compensated by an elevated systemic vascular resistance resulting in a maintenance of arterial blood pressure. After exhausting this compensation the flow to non-vital organs increased and consequently arterial blood pressure was reduced resulting in hypoperfusion. In survivors a marked, though, transient increase was measured in concentrations of TXB2 and 6-keto PGF1 alpha level. A significant increase was measured in plasma concentration of LTB4 in SMV without any elevation in RV and aorta. LTB4 production started when prostanoid release had decreased. In contrast to survivors, no changes could be observed in eicosanoid release for non-survivors. A correlation was observed between systemic vascular resistance and TXB2 to 6-keto PGF1 alpha ratio.(ABSTRACT TRUNCATED AT 250 WORDS)     

卡巴胆碱改善犬50%TBSA烧伤胃内补液时氧动力学指标

目的:研究卡巴胆碱(CAR)对50%TBSA烧伤休克期胃内补液时氧动力学指标的影响。方法:成年雄性Beagle犬12只,先期无菌手术行颈动、静脉置管和肠造口术,24h后用凝固汽油燃烧法造成50%体表面积Ⅲ度烧伤。随机分为2组(n=6):胃内补液组和胃内补液+CAR组。伤后第一个24h从胃内分别输注葡萄糖-电解质溶液(GES)和含CAR的GES液(20μg/kgCAR溶于GES);伤后24h起实施静脉延迟补液,补液量和速率均根据Park-land公式确定。测定动物非麻醉状态下的平均动脉压(MAP)、肠粘膜血流量(IMBF)和血乳酸(LAC)含量,通过血气分析测定动、静脉氧分压和血氧含量、计算氧供量(DO2)、氧耗量(VO2)和氧摄取(Oext),并统计动物72h死亡数。结果:两组犬MAP和IMBF伤后均显著降低,LAC显著升高;伤后72hMAP回升至0h水平,但IMBF和LAC仍低于或高于0h水平。伤后2h胃内补液+CAR组MAP显著高于胃内补液组(P0.01),但之后两组MAP水平无统计学差别。胃内补液/CAR组IMBF伤后高于胃内补液组,伤后8h起LAC也显著低于胃内补液组(P0.05或P0.01)。伤后两组犬DO、VO2和Oext水平较伤前均显著降低(P0.01),伤后72hDO2恢复至0h水平,但VO2和Oext仍显著低于0h。胃内补液/CAR组DO2、VO2和Oext水平伤后8h起始终高于胃内补液组(P0.05或P0.01)。伤后72h胃内补液组死亡数为3/6,胃内补液/CAR为2/6。结论:50%TBSA烧伤胃内补液时加入卡巴胆碱能显著改善氧动力学指标,降低高乳酸血症,提高口服液体复苏的疗效。     

Hospitalized dogs recovery from naturally occurring heatstroke; does serum heat shock protein 72 can provide prognostic biomarker?

Heatstroke is a serious illness in dogs characterized by core temperatures above 41 °C with central nervous system dysfunction. Experimental heatstroke models have tried to correlate biomarker levels with the severity of the syndrome. Serum heat shock protein (eHSP70) levels were recently evaluated as a biomarker of heat tolerance and acclimation, their role as a marker of heatstroke is inconclusive. Here, we monitored eHSP70 levels in correlation with systemic biomarkers in 30 naturally occurring canine heatstroke cases. Thirty dogs diagnosed with environmental (33 %) or exertional (66 %) heatstroke admitted to hospital (0–14 h post-injury) were tested for biomarkers of organ damage and coagulation parameters. eHSP70 levels were measured upon admission and 4, 12, and 24 h later (T1, T2, and T3, respectively). No differences were found between exertional and environmental heatstroke cases. The eHSP profile demonstrated an inverted bell shape, with the lowest levels at the 12 h time point. A positive correlation between eHSP70, lactate, and aPPT was also noted at T2 in all the dogs in the study. Twenty-four h after presentation, eHSP70 levels returned to those measured upon admission, this change was only significant in the survivors. The obtained results suggest that eHSP72 level profile may be predictive of survival.     

TNF but not IL-1 in dogs causes lethal lung injury and multiple organ dysfunction similar to human sepsis.

We compared the early and late pulmonary effects of human recombinant tumor necrosis factor (TNF) and interleukin 1 (IL-1) challenges in awake dogs with chronic tracheostomies. Serial blood gas analysis, bronchoalveolar lavage (BAL) with cell and protein analysis, intravascular catheter hemodynamics, and radionuclide left ventricular ejection fractions (LVEF) were determined before and after infusion of TNF (60 micrograms/kg body wt, n = 8), IL-1 (1,000 micrograms/kg body wt, n = 6), or heat-inactivated IL-1 (n = 6, controls). Controls given heat-inactivated IL-1 had no changes (P = NS) in any pulmonary parameter throughout the study. Animals given IL-1 had a transient increase (P less than 0.05) in BAL neutrophil concentration 1 day after infusion but no other changes (P = NS) in pulmonary function throughout the study. Animals given TNF had early (0-4 h) decreases (P less than 0.05) in arterial PO2, increases (P less than 0.05) in physiological shunt fraction and alveolar-to-arterial PO2 gradient, and a high mortality rate (50%). In TNF animals, volume challenges at 4 h were associated (P less than 0.05) with death and noncardiogenic pulmonary edema. In TNF survivors, hypoxemia persisted for 2-3 days and was associated with increases (P less than 0.05) in alveolar protein and neutrophil concentration on days 1 and 3, respectively, which in survivors returned to near normal over 6-21 days. Animals challenged with TNF and not IL-1 had reversible depression of LVEF similar in time course to abnormalities in arterial PO2. In this study, TNF (but not IL-1) challenges were lethal and produced acute pulmonary dysfunction sustained over days (reversible in survivors) that was similar to that seen in human septic shock. The ability of TNF to induce pulmonary injury similar to bacterial shock suggests that TNF is a key mediator of sepsis-induced lung injury. Furthermore, because TNF challenge induced both sustained pulmonary and cardiac injury, TNF may be a common pathway for the multiple organ dysfunction that occurs during septic shock.     

Induction of acquired thermotolerance in Tetrahymena thermophila: effects of protein synthesis inhibitors.

When Tetrahymena thermophila cells growing at 30 degrees C are shifted to either 40 or 43 degrees C, the kinetics and extent of induction of heat shock mRNAs in both cases are virtually indistinguishable. However, the cells shifted to 40 degrees C show a typical induction of heat shock protein (HSP) synthesis and survive indefinitely (100% after 24 h), whereas those at 43 degrees C show an abortive synthesis of HSPs and die (less than 0.01% survivors) within 1 h. Cells treated at 30 degrees C with the drugs cycloheximide or emetine, at concentrations which are initially inhibitory to protein synthesis and cell growth but from which cells can eventually recover and resume growth, are after this recovery able to survive a direct shift from 30 to 43 degrees C (ca. 70% survival after 1 h). This induction of thermotolerance by these drugs is as efficient in providing thermoprotection to cells as is a prior sublethal heat treatment which elicits the synthesis of HSPs. However, during the period when drug-treated cells recover their protein synthesis ability and simultaneously acquire the ability to subsequently survive a shift to 43 degrees C, none of the major HSPs are synthesized. The ability to survive a 1-h, 43 degrees C heat treatment, therefore, does not absolutely require the prior synthesis of HSPs. But, as extended survival at 43 degrees Celsius depends absolutely on the ability of cells to continually synthesize HSPs, it appears that a prior heat shock as well as the recovery from protein synthesis inhibition elicits a change in the protein synthetic machinery which allows the translation of HSP mRNAs at what would otherwise be a nonpermissive temperature for protein synthesis.     

Cardiac depression and cellular injury in hemorrhagic shock and reinfusion: Role of free radicals

We investigated the effects of hemorrhagic shock and reinfusion on the cardiac function and contractility, plasma CK and CK-MB activity and lactate concentration, oxyradical-producing activity of polymorphonuclear leukocytes (PMNL-CL), cardiac chemiluminescence (LV-CL), antioxidant enzyme activity [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-P_X)] and malondialdehyde (MDA) concentration in anesthetized dogs to determine the role of oxyradicals in cardiac depression and cellular injury in hemorrhagic shock and reinfusion. The dogs were assigned into three groups: I (sham), 4 h duration; II (S + R), 2 h of shock followed by reinfusion for 2 h; III (SOD + S + R), as II but pretreated with PEG-SOD. Hemorrhagic shock was produced by withdrawal of blood to maintain the mean arterial pressure at 50 ± 5 mm Hg. Cardiac function and contractility were depressed during hemorrhagic shock. Plasma CK, CK-MB and lactate increased during shock. Following reinfusion after 2 h of shock hemodynamic parameters and plasma lactate tended to return towards control values. Plasma CK and CK-MB, PMNL-CL and cardiac MDA, total-, Mn- and CuZn-SOD activity increased while LV-CL decreased. In spite of the increase in the antioxidant reserve, there was oxidative damage. Pretreatment with SOD attenuated the deleterious effects of shock and reinfusion on the cardiovascular function, plasma CK, and CK-MB, PMNL-CL, cardiac MDA, SOD, and LV-CL. Protection was incomplete for cardiovascular function and plasma CK and CK-MB. These results suggest that oxyradicals may partly be involved in the deterioration of cardiovascular function and cellular injury during hemorrhagic shock and reinfusion.     

The physiological changes of cumulative hemorrhagic shock in conscious rats

Summary Hemorrhagic shock is a common cause of death in emergency rooms. Current animal models of hemorrhage encounter a major problem that the volume and the rate of blood loss cannot be controlled. In addition, the use of anesthesia obscures physiological responses. Our experiments were designed to establish an animal model based on the clinical situation for studying hemorrhagic shock. Hemorrhagic shock was induced by withdrawing blood from a femoral arterial catheter. The blood volume withdrawn was 40% of the total blood volume for group 1 and 30% for group 2 and 3. Group 3 was anesthetized with sodium pentobarbital (25 mg/kg, i.v.) at the beginning of blood withdrawal. Our data showed that the survival rate was 87.5% at 48 h in the conscious group and 0% at 9 h in anesthetic group after hemorrhage. The levels of mean arterial pressure, heart rate, white blood count, TNF-, IL1-, CPK, and LDH after blood withdrawal in the anesthetic group were generally lower than those in conscious groups. These results indicated that anesthetics significantly affected the physiology of experimental animals. The conscious, unrestrained and cumulative volume-controlled hemorrhagic shock model was a good experimental model to investigate the physical phenomenon without anesthetic interfernce.     

Effect of sulfatide on acute lung injury during endotoxemia in rats

Experimental studies have shown that intrapulmonary leukocyte sequestration and activation is implicated in the pathogenesis of acute lung injury during endotoxemia. Selectins are involved in the adhesion of leukocyte to the endothelium. Sulfatide is recognized by P selectin and blocks this adhesion molecule. We studied the effects of sulfatide on endotoxin-induced lung damage in rats. Endotoxin shock was produced in male rats by a single intravenous (i.v.) injection of 20 mg/kg of Salmonella enteritidis lipopolysaccharide (LPS). LPS administration reduced survival rate (0%, 72 h after endotoxin challenge) decreased mean arterial blood pressure (MAP), produced leukopenia (Controls = 11,234+/-231 cells/mL, LPS = 4,567+/-123 cells/mL) and increased lung myeloperoxidase activity (MPO; a marker of leukocyte accumulation) in the lung (Controls = 0.35+/-0.1 U/g/tissue; LPS = 10+/-1.2 U/g/tissue). Furthermore LPS administration markedly impaired the concentration-response curves for acetylcholine and sodium nitroprusside in isolated pulmonary arterial rings. There was also an increased staining for P-selectin in the pulmonary arteries. Sulfatide treatment (10 mg/kg, 30 min. after LPS challenge), significantly protected against LPS-induced lethality (90% survival rate and 70% survival rate 24 h and 72 h after LPS injection), reduced LPS induced hypotension, reverted leukopenia (8,895+/-234 cells/ml) and lowered lung MPO activity (1.7+/-0.9 U/g/tissue). Furthermore sulfatide restored to control values the LPS-induced impairment in arterial pulmonary vasorelaxation and reduced P-selectin immunostaining. Our data indicate that sulfatide attenuates LPS-induced lung injury and protects against endotoxin shock.     

Systemic responses to prolonged hemorrhagic hypotension

Studies are needed to provide a rigorous examination of the relevance of monitored variables during prolonged hemorrhagic hypotension (HH). This study was designed to investigate the parameters that describe biochemical and O2 transport patterns in animals subjected to HH. Systemic parameters that could differentiate survivors from nonsurvivors were identified. An aortic flow probe was implanted in rats (n = 21) for continuous measurement of cardiac output. Experiments were performed 6-9 days after surgery. Rats were bled to a mean arterial pressure of 40 mmHg and kept at that level using Ringer-lactate solution. Arterial and venous blood pressures, gases, acid-base status, glucose, lactate, electrolytes, hemoglobin, O2 saturation, heart and respiratory rates, total peripheral resistance, and O2 delivery and consumption were measured before hemorrhage, soon after 40 mmHg was reached, and 0.5, 1, 2, 3, and 4 h later. Fifty-three percent of rats survived > or =3 h (survivors); others were considered nonsurvivors. Nonsurvivors showed a significantly greater degree of metabolic acidosis than survivors. Arterial PO2, respiratory rate, O2 saturation, O2 content, glucose, and pH were significantly higher in survivors. The rate of Ringer-lactate infusion, arterial K+, and PCO2 were lower in survivors. Arterial K+ and respiratory rate were the only parameters significantly different between survivors and nonsurvivors at all time points during HH. Arterial levels of K+ showed the clearest distinction between survivors and nonsurvivors and may explain the sudden death experienced by animals during HH. The data suggest that early respiratory and metabolic compensations are essential for survival of prolonged HH.     

Hemodynamic changes before and after short and prolonged periods of hypothermia in dogs

Dogs were cooled to 30 °C and either rewarmed immediately or after being kept at 30 °C for 6 hr. The acid-base balance was determined and hemodynamic data were collected. At the beginning of the rewarming period the arterial blood pressure and the left ventricular work output were increased after short hypothermia, but not after prolonged hypothermia. The survivors of prolonged hypothermia had had a higher arterial blood pressure and left ventricular work output before cooling began than did nonsurvivors. An additional load on the cardiovascular system (A-V shunt) was incompatible with survival. The so-called rewarming shock, therefore, appears to be cardiogenic, and the treatment of the victims of accidents causing hypothermia due to exposure should be directed against cardiogenic shock.     

Effects of hyperbaric oxygen in circulatory shock induced by splanchnic artery occlusion and reperfusion in rats

We studied the effects of hyperbaric oxygen in a severe model of circulatory shock induced by occlusion and reperfusion of major splanchnic arteries (splanchnic artery occlusion (SAO) shock). Pentobarbital-anesthetized rats subjected to total occlusion of the superior mesenteric and the celiac arteries for 40 min developed a severe shock state, resulting in a uniformly fatal outcome after release of the occlusion. Exposure to hyperbaric oxygen at 2 ATA (atmosphere absolute) (1 ATA = 0.1 MPa) was initiated immediately after reperfusion. SAO shock rats exposed to hyperbaric oxygen maintained mean arterial blood pressure at significantly higher values throughout the postreperfusion period compared with untreated SAO shock rats (p less than 0.01), with final mean arterial blood pressures of 88 +/- 9 and 51 +/- 4 mmHg, respectively. Treatment with hyperbaric oxygen attenuated the increase in plasma activities of the lysosomal hydrolase cathepsin D (p less than 0.05), and diminished the increase of hematocrit (p less than 0.01 from untreated shock rats). Splanchnic occlusion shock rats treated with hyperbaric oxygen also exhibited a significantly higher survival rate than the untreated shock group (77 vs. 0%, respectively; p less than 0.01). Our results suggest that the beneficial effects of exposure to hyperbaric oxygen immediately after reperfusion of the splanchnic region outweigh its possible deleterious effect.     

沙漠干热环境创伤失血性休克猪模型的氧代谢特点

目的:探讨沙漠干热环境创伤失血性休克猪的氧代谢特点。方法:选择长白仔猪40头,随机分为四组:常温假手术组(NS)、常温创伤失血性休克组(NTHS)、干热假手术组(DS)、干热创伤失血性休克组(DTHS),分别置于相应的环境暴露3小时后,进行麻醉,动静脉置管,NTHS组和DTHS组分别自剖腹术后,行左下叶1/4肝脏切除及脾切除术后,再快速放血至平均动脉压(MAP)降至45±5mmHg;NS组和DS组仅行腹中线剖腹术。持续检测计算动脉、混合静脉氧饱和度、氧含量及氧输送(DO_2)、氧耗(VO_2)、氧摄取率(O_2ER)和动脉血乳酸(Lac)。结果:整个病程中,各组动脉氧饱和度均无显著变化。DTHS组混合静脉氧饱和度和氧含量均较相同时间点的其他各组低,DO_2、VO_2、O_2ER均显著高于常温环境组(P0.05)。模型成功后,NTHS组和DTHS组DO_2均经历"下降-代偿-稳定"的过程,但DTHS组短暂稳定后立即呈进行性快速下降至到动物死亡。在实验过程中,DTHS组各时间点氧摄取率(O_2ER)均高于相同时间点的其他组,差异具有统计学意义(P0.05)。NTHS组和DTHS组氧O_2ER均在休克后0 h出现明显变化,而动脉血乳酸(Lac)在休克后1.5 h才出现明显变化,但DTHS组动脉Lac增高较NTHS组升高更加明显(P0.05),且进展迅速。结论:(1)沙漠干热环境创伤失血性休克较高的氧代谢,是机体代偿能力弱、病程变化快的重要原因之一;(2)VO_2、O_2ER等直接氧代谢指标可作为早期评估监测机体氧代谢的敏感指标;(3)血Lac浓度可能是反映干热环境创伤失血性休克严重程度的重要指标。     

Preservation of neurological functions by nitric oxide synthase inhibitors in conscious rats following delayed hemorrhagic shock

Excessive production of nitric oxide (NO) as result of inducible nitric oxide synthase (iNOS) induction has been implicated in the pathophysiology of hemorrhagic shock. Our aim was to study the effects of NOS inhibitors, aminoguanidine (AG) and NG-nitro-L-arginine methyl ester (L-NAME), on survival rate, mean arterial blood pressure (MABP), temporal evolution of infarct volume, nitric oxide (NO) production and neurological deficit in a model of delayed hemorrhagic shock (DHS) in conscious rats. Our results showed that the NOS inhibitors significantly improved survival rate, MABP, and attenuated brain NO overproduction 24, 48 h and 72 h after DHS. AG reduced brain infarct volume and improved the neurological performance evaluated by the rotameric and grip strength tests while L-NAME did not show protective effect in rats following DHS. These findings suggest that NO formation via iNOS activation may contribute to organ damage and that the selective iNOS inhibitor, AG, may be of interest as a therapeutic agent for neurological recovery following DHS.     

Heat shock protein (hsp70) expression and thermal tolerance in sublethally heat-shocked eastern oysters Crassostrea virginica infected with the parasite Perkinsus marinus

To investigate whether sublethal heat shock protects Perkinsus marinus (Dermo)-infected oysters Crassostrea virginica from lethal heat stress, and the effects of P. marinus infection on sublethal heat shock response, oysters were first experimentally challenged with P. marinus. Then, when infections in oysters progressed to moderate levels (parasite burden = 10(4) to 10(5) cells g(-1) wet tissue weight), oysters were treated with a sublethal heat shock at 40 degrees C for 1 h (heat shock + Dermo challenge). Other treatment groups included heat-shocked, unchallenged (non-P. marinus challenged) oysters and non-heat-shocked, P. marinus-challenged and -unchallenged oysters. Thermal tolerance was compared among these treatments by administering a lethal heat treatment at 44 degrees C for 1 h, 7 d after sublethal heat shock. Sublethal heat shock enhanced survival to lethal heat treatment in both P. marinus-challenged and -unchallenged oysters. Although levels of hsp70 isoforms (hsp69 and hsp72) did not vary significantly by heat shock or infection with P. marinus, responses due to these treatments were apparent when comparing hsp70 levels within infected and uninfected oysters. Infection enhanced expression of hsp69, regardless of whether oysters were heat shocked or not. In uninfected oysters, hsp72 increased due to heat shock 2 and 7 d post heat shock. Overall, this study demonstrates that heat shock can improve survival in oysters, even in oysters infected with P. marinus. Expression of hsp70 varied among isoforms after sublethal and lethal heat shocks and in infected and uninfected oysters. The heat shock response was not negatively affected by P. marinus infection.     

Temporal changes in free iron levels after brain ischemia Relevance to the timing of iron chelation therapy in stroke

Whereas iron chelators have been proposed as therapeutic agents in stroke, changes in free iron levels have never been explored after focal brain ischemia. Therefore, free and total iron levels in cortical tissue and free iron levels in plasma were measured before and after (1, 4 and 24h) photothrombotic occlusion of cortical vessels in rats. Brain ferritin expression and localization were also investigated before and after (24, 72 and 192 h) occlusion. The results showed that free iron remained below detectable levels in plasma and that the lesion exhibited high levels of free and total iron. As compared to contralateral values, free iron levels in ischemic core and penumbra increased (+50%) at 1h and returned to control values at 4h post-occlusion. In contrast, the increase in total iron levels (+20-30%) was long-lasting, but confined to the ischemic core. A time-dependent increase in the expression of both chains of ferritin was detected in regions that previously exhibited free iron accumulation. Finally, ischemic damage was reduced by the liposoluble iron chelator 2,2'-dipyridyl (20 mg/kg, i.p.) when injected 15 min or 1 h post-occlusion, yet not later (4 h). In conclusion, our results show that focal brain ischemia results in an early and transient elevation in free iron levels in the ischemic tissue and suggest that free iron excess does not originate in blood. They also highlight the importance of starting iron chelation therapy as soon as possible after stroke.     

Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis

Septic shock is a life-threatening condition that results from exposure to bacterial endotoxin. It is manifested by cardiovascular collapse and mediated by the release of cytokines such as tumor necrosis factor. Some of these cytokines cause the release of vasoactive substances. In the present study, administration of 40 microgram/kg of bacterial endotoxin to dogs caused a 33% decrease in peripheral vascular resistance and a 54% fall in mean arterial blood pressure within 30 to 90 minutes. Vascular resistance and systemic arterial pressure returned to normal within 1.5 minutes after intravenous administration of NG-methyl-L-arginine (20 mg/kg), a potent and selective inhibitor of nitric oxide synthesis. L-Arginine reversed the effect of L-NMA and restored the endotoxin-induced hypotension. Although NG-methyl-L-arginine injection increased blood pressure in control dogs, the hypertensive effect was much greater in endotoxemic dogs (24.8 +/- 2.7 mmHg vs 47.8 +/- 6.8 mmHg, p = 0.01, n = 4). NG-Methyl-L-arginine caused only a modest increase in blood pressure in dogs made hypotensive by continuous intravenous infusion of nitroglycerin (17.1 +/- 5.0 mm Hg, n = 3). These findings suggest that nitric oxide overproduction is an important contributor to endotoxic shock. Moreover, our findings demonstrate for the first time, the utility of nitric oxide synthesis inhibitors in endotoxic shock and suggest that such inhibitors may be of therapeutic value in the treatment of septic shock.     

Post-operative analgesia following thoracotomy in the dog: an evaluation of the effects of bupivacaine intercostal nerve block and nalbuphine on respiratory function.

Pain following thoracotomy reduces pulmonary ventilation in man and a similar effect is believed to occur in animals. The effects of two analgesic regimens on arterial blood gas parameters were studied in dogs following thoracotomy. Post-Operative analgesia was provided with intermittent nalbuphine, either alone or in combination with an intercostal nerve block using bupivacaine. Arterial blood gas analysis was carried out at 4, 8 and 16 h post-operatively, both before the administration of nalbuphine and again 30 min later. Animals which received nalbuphine alone had a significant rise in arterial oxygenation following administration of this analgesic. This effect was not observed at 4 and 8 h post-operatively in dogs which had an intercostal block with bupivacaine, but was seen at 16 h post-operatively when it could be anticipated that the effects of bupivacaine would have waned. These results suggest that intercostal block with bupivacaine can provide analgesia for over 8 h, and that the duration of action of nalbuphine in controlling post-operative pain in the dog is probably less than 4 h.     

Systemic effect of chitin after intravenous administration to dogs

The systemic effect of chitin and chitin oligomer after intravenous administration was investigated in dogs by determining the chemiluminescence (CL) response and the white blood cell count (WBC). Chitin oligomer (2mg/kg) and physiological saline (5ml) did not have a systemic effect. However, in the dogs injected with chitin, WBC decreased significantly from 1 to 4 h after injection and then increased gradually to 1.4 times the pre-injection level at 72 h, while CL was significantly increased 1–2 h after injection.