Adrenergic blockade attenuates endotoxin-induced hepatic glucose uptake

The purpose of the present study was to elucidate the role of catecholamines in mediating the endotoxin-induced increase in glucose uptake of individual tissues. In vivo glucose utilization by selected tissues, assessed by the 2-deoxyglucose (2dGlc) tracer technique, was determined 3 hr following the i.v. injection of Escherichia coli lipopolysaccharide (LPS; 100 micrograms/100 g bw) or saline. Catecholamine action was inhibited by the combined administration of alpha and beta receptor antagonists, phentolamine and propranolol. Adrenergic antagonists alone did not change plasma glucose levels or the glucose metabolic rate (Rg) of the investigated tissues; however, adrenergic blockage resulted in mild hypoglycemia in endotoxemic animals. LPS administration increased in vivo Rg by the liver (571%), lung (229%), spleen (210%), intestine (76%), skin (82%), fat (181%), gastrocnemius muscle (70%), and kidney (61%). There was a significant elevation in the glucose metabolic clearance rate (MCR) by these tissues as well. LPS did not increase Rg by brain and testis. Adrenergic blockade completely prevented the LPS-induced Rg increase in the liver and partially inhibited the elevation in other tissues. The LPS-induced increase in the MCR in spleen, lung, intestine, skin, fat, muscle, and kidney was not altered by adrenergic blockade, indicating that the attenuated Rg in these tissues was the consequence of the decreased plasma glucose concentration observed under this condition. However, in the liver, adrenergic antagonists markedly inhibited the LPS-induced increase in both Rg and MCR. Thus our data indicate that the glucose metabolic response to LPS is partially mediated by catecholamines through the accompanying changes in plasma glucose concentration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dopexamine attenuates endotoxin-induced microcirculatory changes in rat mesentery: role of beta2 adrenoceptors

OBJECTIVE: To investigate the influence of dopexamine on endotoxin-induced leukocyte adherence and on vascular permeability in postcapillary venules of rat mesentery. DESIGN: Randomized, controlled trial. SETTING: Experimental laboratory. SUBJECTS: Twenty-seven male Wistar rats, weighing 250 to 350 g. INTERVENTIONS: Rats received one of three treatments: a) infusion of Escherichia coli endotoxin without dopexamine pretreatment; b) infusion of endotoxin with dopexamine pretreatment; or c) infusion of endotoxin after pretreatment with dopexamine and ICI 118,551, a selective beta2-receptor antagonist. MEASUREMENTS AND MAIN RESULTS: Leukocyte adherence, red blood cell velocity, and vessel diameters in postcapillary venules were evaluated using in vivo videomicroscopy. Vascular permeability was determined by measuring the extravasation of fluorescence-labeled albumin. Venular wall shear rate was calculated from red cell velocity and vessel diameter. Dopexamine attenuated both the increase in leukocyte adherence and vascular permeability during endotoxemia. The attenuating effect on leukocyte adherence could not be antagonized by the beta2-adrenoceptor antagonist. However, the attenuating effect on vascular permeability was antagonized by ICI 118,551. Dopexamine prevented a decrease in venular wall shear rate during endotoxemia. This effect was not influenced by ICI 118,551. CONCLUSIONS: Dopexamine attenuates endotoxin-induced microcirculatory disturbances in rat mesentery. The attenuating effect on vascular permeability is a beta2-adrenoceptor-mediated process, whereas the beta2-adrenoceptor actions of dopexamine play no significant role in attenuating leukocyte adherence.     

Green tea polyphenols block endotoxin-induced tumor necrosis factor-production and lethality in a murine model

The effects of arginine on cell proliferation and subsequent T helper (Th) 1 and Th 2 cytokine synthesis by murine Peyer's patch (PP) Th cells in vitro and the influence of arginine on the induction of antigen-specific mucosal and systemic immune responses in vivo were examined. When the PP T cells were stimulated with the anti-alpha beta T cell receptor (TCR) antibody in the presence of different concentrations of arginine, a higher proliferative response was observed in the culture with an optimal concentration of arginine compared with that with a minimum amount of this amino acid. The concentration of cytokines in the supernatant, the number of cytokine-producing cells and the cytokine-specific mRNA expression of PP T cells were also increased in a dose-dependent fashion. Furthermore, when mice fed on an arginine-supplemented liquid diet were orally immunized with tetanus toxoid plus cholera toxin as a mucosal adjuvant, a higher level of antigen-specific fecal IgA was observed when compared with the response in mice fed on an arginine-free diet. Taken together, these results suggest that arginine enhanced antigen-specific mucosal immune response resulting from the supporting activation of cell proliferation and subsequent cytokine synthesis of PP Th cells.     

Endothelin mediation of insulin and glucose-induced changes in vascular contractility

Although the prevalence of hypertension in diabetic patients is high and many factors participate, hyperinsulinemia cannot be discarded as a contributing factor. Insulin could act directly on smooth muscle altering intracellular calcium levels that mediate contraction and glucose transport or could induce the secretion of endothelin by the endothelial cells lining the vessels. The aim of the present report was to study the effect of different glucose and insulin concentrations on rat vascular smooth-muscle contractile characteristics and to determine whether insulin effects are mediated by endothelin. Femoral arteries obtained from Wistar rats were placed in an in vitro chamber and superfused with different glucose and/or insulin solutions. The contractile response to KCl 80 mmol/L, measured by the force generated, showed a significant decrease with high extracellular glucose concentrations (11 mmol/L). Insulin caused a dose-dependent increase in arterial contraction induced by KCl. This increase was significant when arteries were stimulated with 80 mmol/L KCl in the presence of 5.5 mmol/L glucose, but when 40 mmol/L KCl was used, an increase was observed with both 5.5 and 11 mmol/L glucose. The insulin-induced contraction was significantly reduced in the presence of hyperimmune anti-endothelin serum and in the presence of endothelin receptor ET(A) and ET(B) antagonists PD 151,242 and BQ-788, respectively. These results suggest that hyperinsulinemia and hyperglycemia may contribute to hypertension in diabetes and that responses to insulin are mediated partially by endothelin, thus explaining why non-insulin-dependent diabetes mellitus patients show an increase in arterial pressure before the onset of nephropathy.     

Early hemodynamic changes at the microcirculatory level and effects of mannitol following focal cryogenic injury

Changes in cerebral blood flow due to infusion of hyperosmolar solutions are of considerable importance in states of raised intracranial pressure. The present study was aimed to evaluate the effects of mannitol on the cerebral microcirculation, in a model of vasogenic brain edema. A right fronto-parietal craniotomy was performed in 30 adult Sprague-Dawley rats. Vasogenic edema was produced by placing dry-ice over the dura for 1 min. The cortical blood flow was monitored for 120 min using a laser-Doppler flowmeter (Perimed, Stockholm, Sweden), and graphics were recorded using a personal computer. Animals were randomly divided into three groups: group 1 (control group) received no mannitol; group 2 was treated with a bolus injection of 20% mannitol (1 mg kg-1); group 3 received the same dose over a 30 min infusion. Mean blood pressure, temperature, and respiratory rate were continuously monitored. At the end of the procedure, an intravenous injection of Evan's blue 2% was given. Results were compared by using repeated measures of analysis of variance and a two-sample t-test at each time. After the production of a cryogenic injury, we found a marked decrease in the cerebral blood flow, whereas mannitol partially reversed that effect. There was not significant difference between groups 2 and 3; however, there was a significant difference between mannitol and control groups after 15 min. During the early phase of vasogenic edema, early use of mannitol did not increase the blood flow, but stabilized it, preventing further decrease. Laser-Doppler flowmetry is a valuable method for continuous estimation of hemodynamic changes in the cerebral microcirculation.     

Obstructive jaundice in rats results in exaggerated hepatic production of tumor necrosis factor-alpha and systemic and tissue tumor necrosis factor-alpha levels after endotoxin

BACKGROUND: Obstructive jaundice (OJ) predisposes patients to postoperative sepsis. We determined whether OJ led to an increased endotoxin stimulated tumor necrosis factor-alpha (TNF-alpha) production by macrophage-rich organs and whether a lack of intraluminal gut bile contributed to this increased sensitivity. METHODS: Rats underwent laparotomy and common bile duct ligation and division (CBDL) or sham operation after they were given low-dose endotoxin or saline solution (NS). TNF-alpha levels in plasma, perfusate from the isolated perfused rat liver, and tissue from lung, spleen, and liver were measured 90 minutes later. An additional group underwent creation of a choledochal-vesical fistula and endotoxin administration. RESULTS: The plasma TNF-alpha, liver perfusate TNF-alpha, and the tissue TNF-alpha levels in liver, lung, and spleen were significantly elevated in the CBDL + endotoxin (CBDL + ETX) group compared with the SHAM + ETX and CBDL + NS groups (p < 0.05). The choledochal-vesical fistula group after endotoxin had plasma TNF-alpha levels only 27% that of the CBDL + ETX group (p < 0.05). CONCLUSIONS: OJ sensitizes macrophage-rich organs to produce larger amounts of TNF-alpha in response to endotoxin. This sensitization is not solely due to decreased intraluminal gut bile.     

Mirex-induced hepatic changes in chickens, Japanese quail, and rats

Mirex was fed in the diet to chickens at 0 to 160 ppm for 12 and 16 weeks, to Japanese quail at 0 to 80 ppm for 12 weeks, and to rats at 0 to 100 ppm for 2 and 4 weeks. Mirex did not affect the concentration of protein or cytochrome P450 in hepatic microsomes of chickens or Japanese quail, nor did it affect hydroxylation of aniline or demethylation of aminopyrine. However, structural changes were apparent in livers of chickens fed mirex at 10 ppm and above and included regions of necrosis and nonspecific cellular aberrations and alterations of sinusoids and bile canaliculi. Mirex caused liver enlargement in rats and increased microsomal protein and cytochrome P450 but did not affect hydroxylation of aniline or demethylation of aminopyrine. Hepatic structural changes in rats that were associated with mirex included proliferation of smooth endoplasmic reticulum and degeneration of some bile canaliculi.     

The effect of zardaverine, an inhibitor of phosphodiesterase isoenzymes III and IV, on endotoxin-induced airway changes in rats

Zardaverine is a novel phosphodiesterase III/IV inhibitor, developed as a potential therapeutic agent for asthma. In this study we evaluated the effect of zardaverine in an in vivo animal model of airway inflammation and hyperresponsiveness. Endotoxin exposure in rats causes a transient increase in airway responsiveness and a neutrophilic inflammation of the bronchi, which are both at least partly mediated through the secondary release of tumour necrosis factor alpha (TNF alpha). Groups of 10 animals each were pretreated with placebo or zardaverine (1, 10, 30 mumol/kg) i.p., 30 min prior to exposure to aerosolized endotoxin (LPS) or saline. Ninety minutes later, airway responsiveness to 5-HT was assessed and bronchoalveolar lavage (BAL) performed. Zardaverine did not influence baseline lung resistance (RL), but inhibited dose dependently the 5-HT induced increase in RL in control animals. In placebo pretreated animals LPS exposure caused a significant decrease in PC50RL5-HT (provocative concentration of 5-HT causing a 50% increase in RL), compared to the saline exposed control group (1.1 +/- 0.1 vs 2.7 +/- 0.4 micrograms/kg) (P < 0.01). This decrease in PC50RL5-HT was significantly inhibited by zardaverine 30 mumol/kg (5.4 +/- 1.8 vs 1.1 +/- 0.1 micrograms/kg) (P < 0.05). Compared to placebo pre-treated, LPS exposed animals, zardaverine 30 mumol/kg also significantly inhibited to LPS induced neutrophil increase (193.0 +/- 50.0 vs 915.6 +/- 181.3 x 10(3)) (P < 0.01), increase in elastase activity (23 +/- 11 vs 54 +/- 9 nmol substrate/h/ml) (P < 0.05) and TNF alpha release in BAL fluid (93.1 +/- 19.5 vs 229.5 +/- 24.8 U/ml BAL fluid) (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Prostacyclin analogue (OP-2507) attenuates hepatic microcirculatory derangement, energy depletion, and lipid peroxidation in a rat model of reperfusion injury

Between 1985 and 1994, 1223 patients with malleolar fractures of the ankle were treated by open reduction and internal fixation with absorbable pins and screws, of whom 74 (6.1%) had an obvious inflammatory foreign-body reaction to the implants. Of these 74, ten later developed moderate to severe osteoarthritis of the ankle despite no evidence of incongruity of the articular surface. The implants used in these patients were made from polyglycolide, polylactide or glycolide-lactide copolymer. The joint damage seemed to be due to polymeric debris entering the articular cavity through an osteolytic extension of an implant track. The ten patients had a long clinical course which included a vigorous local foreign-body reaction, synovial irritation and subsequent degeneration. At a follow-up of three to nine years, ankle arthrodesis had been necessary in two patients and is being considered for another two. The incidence of these changes in the whole series was 0.8%, which is not high, but awareness of this possible late complication is essential.     

Selective autonomic blockade of conditioned and unconditioned cardiovascular changes in rhesus monkeys (Macaca mulatta).

Examined changes in heart rate and systolic and diastolic blood pressures in 8 rhesus monkeys during 6 sessions of differential classical conditioning. The conditioned stimuli consisted of tones differing in frequency, and the unconditioned stimuli consisted of tail shock. Both the CRs and UCRs consisted of increases in heart rate and in systolic and diastolic pressures, but blood pressure CRs sometimes occurred in the absence of heart rate CRs. In Exp II, graded doses of the selective blocking agents propranolol, phentolamine, and atropine methylnitrate were systemically administered to 4 of the Ss prior to additional conditioning sessions. Results suggest that the CRs and UCRs were mediated by both sympathetic and parasympathetic influences. (15 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of tumour necrosis factor-alpha on proliferation, activation and protein synthesis of rat hepatic stellate cells

BACKGROUND/AIMS: Hepatic stellate cells represent the principal matrix-synthesising cells of damaged liver and are targets of a number of cytokines currently under investigation. The study analyses the effects of tumour necrosis factor-alpha and interferon-gamma on proliferation, "activation" and protein synthesis of hepatic stellate cells. METHODS: Primary cultures of hepatic stellate cells were exposed to tumour necrosis factor-alpha and interferon-gamma. Cell proliferation was studied by 3H-thymidine and bromo-deoxy-uridine incorporation. Protein synthesis was analysed using immunoprecipitation, Western- and Northern blotting techniques. RESULTS: Proliferation of hepatic stellate cells was reduced by tumor necrosis factor-alpha and interferon-gamma, while "activation" of hepatic stellate cells as assessed by expression of smooth muscle alpha-actin and of TGF-beta/activin type I receptor was induced by tumour necrosis factor-alpha but downregulated by interferon-gamma. Tumour necrosis factor-alpha increased the synthesis of distinct extracellular matrix proteins, particularly of fibronectin and tenascin, but decreased collagen type III expression. In contrast, interferon-gamma reduced the synthesis of all connective tissue proteins tested. Among the protease inhibitors, interferon-gamma induced C1-esterase inhibitor synthesis, while tumour necrosis factor-alpha stimulated plasminogen activator inhibitor type 1 production. CONCLUSIONS: Tumour necrosis factor-alpha and interferon-gamma decrease proliferation of hepatic stellate cells, while "activation" of hepatic stellate cells and synthesis of proteins involved in matrix metabolism are regulated in a differential, cytokine-specific manner, suggesting that both cytokines play an important role in liver repair.     

Inhibition of Corynebacterium parvum-primed and lipopolysaccharide-induced hepatic necrosis in rats by selective depletion of neutrophils using a monoclonal antibody

The use of hospital ethics committees or infant care review committees has been recommended for difficult decision making. In a survey of military and civilian neonatologists, ethics committees had been established in 27 of their 28 hospitals and fewer than 50% had infant care review committees. Despite the frequently of potential cases for committee review, they were seldom consulted. Inquiry into the educational background of respondents revealed that at least 62% of neonatologists had received ethics education during their professional careers. Most made difficult decisions in conjunction with parents or used a multidisciplinary patient care conference. The use of these conferences antedated any federal regulations. Sixty-seven percent indicated that the Baby Doe regulations had affected neither their thinking about ethical issues nor their practice. In 13 different hypothetical cases in delivery room, intensive care nursery, and long-term care settings, the provision of comfort care, limited care, or withdrawal of support was noted by a sizable percentage of neonatologists; exceptions included meningomyelocele and trisomy 21. The need for ethics committee input in decision making for neonates is questionable.     

Age-related changes in hepatic and splenic insulin receptors and serum insulin and glucose levels in inbred mice

A 62-year-old man and 26-year-old man with re-expansion pulmonary edema (RPE) after thoracic drainage as a treatment for pneumothorax are presented. Blood cell counting and biochemical serum analysis were performed throughout their treatment in both patients, and biochemical sputum analysis was in one patient. The results showed transient marked leukocytosis just after RPE. Total protein and albumin concentrations of sputum approximated to those of serum. The above results suggested that RPE is based on pulmonary microvascular injury, which may introduce leukocytosis.     

Age- and gender-related changes in the hepatic metabolism of 2-methylpropene and relationship to epoxide metabolizing enzymes

The effect of age and gender on the in vitro biotransformation of 2-methylpropene, an alkene metabolized to 2-methyl-1,2-epoxypropane, was studied. The epoxide concentration and the epoxide metabolizing enzymatic activities were investigated in male and female Brown Norway rats of different ages. Liver tissue of senescent rats was exposed to smaller 2-methyl-1,2-epoxypropane concentrations than that of young animals, although changes during ageing were rather modest. With advancing age a feminization of male glutathione S-transferase and cytosolic epoxide hydrolase activities was found, as well as a significant decline of the female microsomal epoxide hydrolase activity and an increase of the cytochrome P-450 content in the oldest female rats.