Circulatory shock最新文献

The rat/mouse T-cell hybridoma PC60 was transfected either with hTNF-R55 cDNA, hTNF-R75 cDNA, or both. Receptor-specific stimulation was achieved using agonistic monoclonal antibodies or receptor-specific muteins of hTNF. Either hTNF-R55 or hTNF-R75 could mediate the activation of NF-kappa B and the induction of GM-CSF, IL-6, and IFN-gamma. But only in cells carrying both hTNF-R55 and hTNF-R75, was TNF able to induce apoptosis. This apoptosis could be inhibited almost completely by cotransfection with human bcl-2 cDNA. Functional cooperation was observed between liganded and unliganded receptors for the induction of apoptosis. In vitro protein kinase activity was detected only in TNF-R75 immunoprecipitates from cells in which the receptor was signaling. Direct evidence was obtained for reactive oxygen intermediates of mitochondrial origin responsible for TNF-induced cytotoxicity in L929 cells.

A reversible cardiogenic shock model in pigs investigated shock-induced changes in the pharmacokinetics and tissue distribution of ampicillin-sulbactam and the efficacy of this antibiotic regimen in eliminating enteric bacterial translocation. Sixteen pigs were randomly allocated to 3 groups: group I (shock, ampicillin-sulbactam, n = 6), group II (no shock, ampicillin-sulbactam, n = 6), and group III (shock, no ampicillin-sulbactam, n = 4). Nalidixic acid-resistant E. coli (60 x 10(6) CFU) were instilled into a jejunal loop created in each pig, and bacterial cultures were taken from thoracic duct lymph, periportal, and mesenteric lymph nodes. Ampicillin-sulbactam was administered intravenously at a standard dose of 3 g. Results showed that 1) ampicillin and sulbactam concentrations generally increase during cardiogenic shock; 2) cardiogenic shock does not increase ampicillin concentrations in jejunum and liver; 3) during resuscitation, thoracic duct lymph ampicillin concentrations decrease; and 4) during and immediately after cardiogenic shock, standard doses of ampicillin-sulbactam appear efficacious in eliminating translocated bacteria.

We examined the effect of exogenous estradiol on the changes in serum steroid hormone levels induced by a nonlethal dose of Escherichia coli endotoxin in male rats and the deaths due to nonlethal and lethal doses of endotoxin. Injection of estradiol 5 min before a nonlethal dose of endotoxin changed the serum sex steroid hormone response of male rats to endotoxin. The serum estrogen concentrations of estradiol + endotoxin-treated rats decreased by 50% (P < 0.001), while those of the endotoxin-treated rats increased (2- to 5-fold). The serum androgen concentrations of estradiol + endotoxin-treated rats did not change significantly, while those of endotoxin-treated rats dropped to 30-40%, P < 0.001. Exogenous estradiol also appeared to influence the percentage of endotoxin-induced deaths in a dose-dependent manner. It reduced the number of deaths induced by nonlethal (2 mg/kg) dose of endotoxin but increased the number of deaths induced by a highly lethal dose (8 mg/kg). These results, together with the known relationships between estrogen and the immune response, suggest that estrogens affect the course of septic shock in a complex fashion and may have either protective or deleterious effect.

We have reported that an intravenous anesthetic, ketamine, has a potent suppressive effect on lipopolysaccharide (LPS)-induced TNF-alpha production in vitro [Takenaka et al., Anesthesiology 80:402-408, 1994]. The purpose of the present study was to investigate the overall effects of ketamine on hemodynamics, serum TNF-alpha level, arterial blood gases (ABGs), blood glucose level, liver function, and lethality in carrageenan (CAR)-sensitized endotoxemic models. All animals were pretreated intraperitoneally with CAR (150 mg/kg) 16 hr before LPS stimulation. The control rats were injected LPS with 0.5 mg/kg intravenously (i.v.). The ketamine-treated rats were injected with 100 mg/kg of ketamine intramuscularly 30 min before LPS (0.5 mg/kg) i.v. injection, followed by an i.v. infusion at 0, 5, or 10 mg/kg/hr. Serum TNF-alpha, ABGs, blood glucose, and hematological studies were determined at 0, 2, and 6 hr after the LPS challenge. Serum hepatocellular enzyme levels were measured at 6 hr after the injection. In CAR-sensitized rats, serum TNF-alpha activity remarkably increased in accordance with the mild decrease of mean arterial pressure (MAP) at 2 hr after LPS stimulation. In addition, severe metabolic acidosis, hypoglycemia as well as severe hepatic injury were induced at 6 hr after the LPS challenge. By contrast, ketamine treatment significantly attenuated the decrease in MAP and LPS-induced TNF-alpha activity. Ketamine also significantly improved arterial oxygen tension (PaO2), metabolic acidosis and hypoglycemia, and attenuated endotoxin-induced hepatic injury in a dose-dependent fashion. In addition, ketamine treatment significantly improved LPS-induced lethality in CAR-sensitized mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Asymmetric dimethylarginine (ADMA) represents an endogenous inhibitor of nitric oxide (NO) production. The production of ADMA has been shown to increase during cellular stress, e.g., hypoxia. Furthermore, ADMA has recently been reported to accumulate in plasma during terminal renal failure as a consequence of diminished urinary excretion. Since tissue hypoxia and oliguria are both characteristics of severe hemorrhagic shock, this study was performed in order to establish whether plasma concentrations of ADMA increase during hemorrhagic shock. Six pigs were subjected to graded hemorrhage (20% and 40% of the calculated blood volume), resulting in significant (P < 0.05) reductions in blood pressure and cardiac output (from 98 +/- 4 to 36 +/- 5 mm Hg and from 3.0 +/- 0.2 to 1.4 +/- 0.2 L/min, respectively). Plasma ADMA concentrations as determined by high-performance liquid chromatography (HPLC) increased from a pre-hemorrhage value of 3.4 +/- 0.3 microM to 3.9 +/- 0.4 microM (ns) and 5.2 +/- 0.4 microM (P < 0.05), respectively. The present study demonstrates that plasma ADMA concentrations increase significantly during hemorrhagic shock. Thus, inhibition of the arginine-nitric oxide pathway as a result of ADMA accumulation, may represent an additional physiological mechanism to maintain systemic blood pressure in response to acute hypovolemia.

Excessive coagulation is a typical response to the vascular injury occurring in gram negative sepsis. This study evaluated the pharmacological effects of the use of a recombinant Escherichia coli derived form of tissue factor pathway inhibitor (ala-TFPI) in a baboon model of septic shock. Several doses of ala-TFPI were administered either 30 or 120 min after the initiation of a lethal intravenous infusion of E. coli into baboons. Treatment at 30 min with either 2.7 or 7.4 mg/kg of ala-TFPI resulted in the same survival rates and attenuation of both the coagulation response and cellular injury, as measured by clinical chemistry. When administration of ala-TFPI was delayed for 120 min, a dose of ala-TFPI protein continued to provide a benefit to survival. Ala-TFPI reduced the drop in mean systemic arterial pressure compared to control baboons in addition to partially attenuating the coagulopathic response. Baboons given ala-TFPI also maintained lower levels of plasma interleukin-6 (IL-6) and thrombin-antithrombin. These results suggest that the site of action of the protein may involve the later stage components of the coagulation and inflammatory pathways.

Saturated Ca2+ extrusion rate through the Ca2+ pump of erythrocytes was determined by the cobalt-exposure method in normal subjects and septic patients. From 48 normal subjects, the value of Vmax of erythrocyte Ca2+ pump was 14.83 +/- 0.49 mmol/L cells/hr; from 29 sepsis patients, it was 9.49 +/- 0.59 mmol/L cels/hr, significantly (P < 0.001) lower than that from the erythrocytes of normal subjects. When the severity of sepsis was evaluated by the septic severity score (SSS), a significant correlation (P < 0.0001) was observed between the Vmax of Ca2+ pump and the patient's SSS, indicating that the inhibition of Ca2+ pump depended on the degree of the pathological development of sepsis. Since the ATP-dependent Ca2+ transport in rat liver plasma membrane is also reduced during the late stage of sepsis [Lau et al., Circ Shock 38:238-244, 1992], impairment of the activity of Ca2+ pump appears to have a general pathophysiological significance in the development of severe sepsis.

Unlabelled: Middle cerebral artery rings (MCA) were prepared from control and hemorrhagic hypotension and retransfusion-subjected (HHR) cats, with or without superoxide dismutase (SOD) treatment. Two-mm-long MCA segments were suspended in organ chambers containing Krebs-Henseleit solution (37 degrees C, gassed with 95% O2-5% CO2) for isometric force measurements. HHR was produced by bleeding to 90, 70, and 50 mmHg MAP and maintained for 15 min at each level, followed by retransfusion. HHR resulted in a marked attenuation of the acetylcholine- and ATP-induced endothelium-dependent relaxations of the MCA in vitro. Relaxations induced by the nitric oxide (NO) donor SIN-1 remained unaltered. In vitro treatment of the vessels with SOD (150 U/ml), facilitated the acetylcholine-induced relaxations both in the control arteries and in the vessels after HHR. In the vessel rings from cats that received in vivo SOD (10 mg/kg initial bolus, followed by 0.1-mg/kg/min infusion) during HHR, cholinergic relaxations were more pronounced than in the HHR untreated cats. The ATP-induced relaxations, however, remained attenuated after SOD treatment, except for the highest dose (10(-5) M) that was applied.

Conclusion: Superoxide release attenuates the endothelium-dependent relaxation by acetylcholine both in control arteries and after HHR in vitro. The protective effect of in vivo SOD treatment on cerebrovascular endothelium-dependent reactivity in cats suggests that superoxide free radicals contribute to the development of the endothelium dysfunction in MCA rings after HHR.

Natural resistance to infection with intracellular parasites is controlled by a dominant gene on mouse chromosome 1, called Bcg. Bcg affects the capacity of macrophages to destroy ingested intracellular parasites early during infection. Reactive nitrogen intermediates (RNI) have been implicated in the interferon-gamma (IFN-gamma)-induced antimicrobial action of macrophages against a wide variety of pathogens. To determine whether Bcg (Nramp) is involved in the production of RNI, these studies have taken advantage of the recent cloning of the Bcg candidate gene, designated Nramp. The expression of Bcg has been down-regulated in the B10R (Bcgr) macrophage cell line using a ribozyme hybrid to site-specifically cleave the Nramp mRNA. Following activation with IFN-gamma, the secretory activity [nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha)] and surface marker expression (la antigen) of these Bcg(Nramp) ribozyme-transfected macrophages were markedly lower than in activated control mock-transfected macrophages (B10R-CTL). However, there was no difference in NO production of B10R-Bcg(Nramp)Rb and B10R-CTL macrophages if the treatment with IFN-gamma occurred in the presence of lipopolysaccharide (LPS). These studies support the hypothesis that the Bcg(Nramp) gene is involved in the regulation of early signaling that occurs in macrophages activated with IFN-gamma. Furthermore, it seems that IFN-gamma, but not LPS-induced activation is affected by the inhibition of Bcg(Nramp) gene expression. Definitive evidence will be provided by transfection experiments that will show whether the Bcgr allele of Bcg(Nramp) can restore NO production of the Bcgs macrophage.

Endotoxemia was induced by intravenous infusion of Escherichia coli endotoxin in 18 anesthetized pigs in a dose of 36 micrograms/kg/hr. Nine pigs were pretreated with BB-882, a novel platelet-activating factor (PAF) antagonist, 33 mg/kg/hr, starting 30 min before endotoxin, and nine pigs received a similar volume of vehicle. Normotension was maintained with intravenous crystalloid resuscitation. Six pigs received only BB-882 and served as controls. Endotoxemia induced an acute transient 300% increase in pulmonary vascular resistance, identical in both groups. The initial increase was followed by a second, more gradual, rise in resistance, which was significantly attenuated by BB-882 (P < 0.01, repeated measurements ANOVA). Endotoxin-induced arterial deoxygenation and fall in lung/thorax compliance was not significantly altered by BB-882. Hematocrit was less in endotoxic pigs receiving BB-882 (P < 0.02). There were no significant changes compared to baseline in the control group. The results indicate that PAF is a minor determinant of early pulmonary dysfunction in nonhypotensive porcine endotoxemia.