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Biomedical subjects

W Schumer

Publications and source records attributed to W Schumer.

At least 37 records · Page 2Linked to original sources
PubMed1986

Hepatic glycolytic intermediates in fed and fasted rats after severe hemorrhage.

The responses of key liver carbohydrate intermediates to severe hemorrhage were investigated in fed and fasted young adult male rats. Forty per cent of intravascular blood was withdrawn and liver was sampled by freeze-clamp at 0, 0.25, 1.0, 3.0, and 4.0-5.0 hours. Fed rats with abundant glycogen showed a threefold increase in glucose-6-phosphate (G6P) concentration, and fasted rats showed a 75% decline in G6P immediately after hemorrhage. This significant difference in response traces to the fact that G6P is one of the first catabolites in fed liver formed by glycogenolysis but is the last intermediate of the gluconeogenic pathway in fasted animals. Phosphoenolpyruvate (PEP), the high-energy intermediate, was markedly depleted in both fed and fasted rats at zero time. In the fasted animal, however, the PEP was rapidly restored, and by 1.0 hour was threefold above normal. The ability of fasted rats to rapidly synthesize glucose from accumulated lactate is attributed to increased amount of gluconeogenic enzymes induced by fasting. In prolonged shock states, this synthetic capacity plays a protective role. Contrariwise, in brief shock states such as hemorrhage, the immediate availability of glucose from stored glycogen appears to be a more important determinant of survival. In the present experiments, fed rats were more resistant to the hemorrhage protocol.

Animals↗
PubMed1986

Cellular metabolic alterations in shock.

Circulatory shock is considered one of the most severe stimulus of the pituitary adrenal axis, therefore causing profound physiologic and metabolic sequelae. It is defined as inadequate circulating blood volume producing decreased perfusion first to nonvital tissues (skin, connective tissue, bone, and muscle), and subsequently to vital organs (brain, heart, lungs, liver, and kidney). Decreased perfusion of nonvital tissues results in anaerobic metabolism because the nonvital tissue cell mass is significantly larger than the vital tissue cell mass. As circulating blood volume decreases, catecholamines and angiotensin are secreted which increases peripheral resistance thus producing low flow in the periphery. Later, baroreceptors in the auricles and carotid and aortic bodies stimulate the vasomotor center in the medulla oblongata via the sympathetic nerves. The vasomotor center compounds sympathetic vasoconstriction further, increasing peripheral resistance.

Animals↗
PubMed1986

Endotoxin lethality is intensified by inhibited gluconeogenesis.

There are two major etiologies regarding the lethal element in the pathophysiology of endotoxemia and severe gram-negative sepsis: 1) metabolic lesions culminating in terminal hypoglycemia and 2) circulatory deficits resulting in early peripheral and late vital organ perfusion failure. Although not mutually exclusive, a direct test of the relative importance of either hypothesis is needed. The impact of inhibited gluconeogenesis on endotoxin lethality in young adult male rats (180-220 g) was investigated. Fasted rats received 20 mg/kg intravenous E. coli endotoxin (LD10) simultaneously with 500 mg/kg intraperitoneal L-tryptophan. This amino acid rapidly forms quinolinic acid, which blocks liver glucose synthesis. Endotoxin together with tryptophan caused hypoglycemic convulsions, killing 22 of 24 rats, 75% within 6 hours. In parallel studies, liver intermediates were assayed in freeze-clamped samples obtained at 5 hours from ether anesthetized rats. The high-energy intermediate phosphoenolpyruvate was 222 +/- 79 nmole/gm +/- 1 S.D. wet liver in the moderately endotoxic rats (N = 8). In the endotoxin-plus tryptophan group (N = 7), the PEP intermediate had fallen to 58 +/- 24 nmole/gm liver (P = 0.005). Liver lactate was increased 2.8-fold over the value in the endotoxin-only group, to 4390 nmole/gm wet tissue, showing the failure to utilize gluconeogenic precursors. Tryptophan given alone was not lethal. It is concluded that inhibited gluconeogenesis greatly intensifies the hepatic metabolic derangement of endotoxemia.

Animals↗
PubMed1984

Pathophysiology and treatment of septic shock.

Shock is defined as inadequate circulating blood volume producing decreased peripheral vascular perfusion and cellular metabolic derangements, first in the nonvital tissues (the gastrointestinal tract, muscle, connective tissue, and skin) and later in the vital tissues (the brain, heart, lung, liver, and kidneys). This inadequate microcirculatory perfusion is the common denominator of all types of shock. Septic shock is caused by an immunologic reaction characterized by a hyperdynamic state, which produces increased cardiac output and decreased peripheral resistance. This reaction is secondary to endotoxin-antibody-complement complexing and leukocyte lysis that results in the production of histamine, serotonin, super-radicals, lysosomal enzymes, and kinins. These substances induce a marked capillary permeability and a third space loss, leading to hypovolemia. This is the hypodynamic state of septic shock, which is characterized by decreased cardiac output and increased peripheral resistance. Diagnosis should be established in the hyperdynamic state of septic shock. Monitoring of the patient in septic shock requires continuous evaluation of the status of clinical signs, peripheral perfusion, vital organ function, and volume requirements. There are four principal and equally important objectives in the treatment of septic shock: treatment of sepsis, management of the hypovolemic state, reparation of the metabolic acid-base imbalance, and correction of the nutritional deficit. There are no priorities; all aspects of treatment must be rendered concomitantly and rapidly. It is essential that the septic and hypovolemic processes be treated concomitantly, since preventing the complexing of antigen-antibody and complement will deter vascular permeability and its consequent hypovolemia. Prompt and adequate treatment of hypovolemia prevents the development of attendant cellular metabolic derangements.(ABSTRACT TRUNCATED AT 250 WORDS)

Emergencies↗
PubMed1984

Hepatic fructose 2,6-bisphosphate in rats with peritonitis and septic shock.

The possible role of inhibited gluconeogenic enzymes in rat liver during preterminal peritonitis septic shock was investigated. There was no difference in maximal activity of the enzymes phosphofructokinase and fructose biphosphatase in septic and control, fasted rats. Rats with sepsis showed a decrease in hexose monophosphates and an increase in fructose biphosphate. There was an unexpected increase in fructose 2,6-bisphosphate despite the hyperglucagonemic state of sepsis. This suggested a dissociation in the coordination of extracellular hormonal and intracellular effector mechanisms in the control of glucose metabolism during the preterminal phase of septic shock. This dissociation may be responsible for the metabolic dyshomeostasis in septic shock.

Animals↗
PubMed1984

The mediated effect of endotoxin and lead upon hepatic metabolism.

A test was made of the possibility that gram-negative bacterial cell wall lipopolysaccharides acted directly on key glucoregulatory enzymes in rat liver cytosol to cause the characteristic hypoglycemia of severe endotoxemia. Fasted male rats were sensitized to endotoxin by the simultaneous intravenous injection of lead acetate. The minimum systemic dosage of endotoxin necessary to perturb the normal pattern of hepatic glycolytic intermediates was determined by serial testing with diminishing dosages of endotoxin. The hepatocyte concentration of endotoxin was then calculated from this minimum dosage by use of literature data on the fraction of endotoxin delivered to liver cells after a systemic intravenous injection of radiochromium labeled lipopolysaccharides. Accepting a molecular weight of 118,000 daltons for the smallest endotoxin monomer capable of evoking a physiologic response, the molar amount of endotoxin present in 1 gram of hepatocytes was readily calculated. The concentration of glucoregulatory enzymes in parenchymal cells was then estimated from other literature sources. It was found that the amount of endotoxin in the hepatocytes was insufficient to combine directly with even 1 per cent of the quantity of a single key glucoregulatory enzyme in liver parenchyma. Since a one to one stoichiometric reaction between endotoxin and enzyme could not occur in the liver cytosol, a direct interaction mechanism between agonist and biocatalyst can be ruled out. It is concluded that bacterial endotoxin must act on hepatic glucoregulation by an indirect mechanism presumably based upon the release and operation of mediators.

Animals↗
PubMed1984

Altered carbohydrate metabolism in endotoxin-tolerant rats after lead sensitization.

The lethality of endotoxin is greatly enhanced in lead-sensitized rats. Previous work showed that hepatic carbohydrate metabolism in lead-treated rats is perturbed by minute endotoxin doses [Fed Proc 41:1607, 1982]. These studies were extended to rats made tolerant to endotoxin by IV injection of lipopolysaccharide (50 micrograms/100 g body weight [BW]) 18 h before simultaneous treatment with lead acetate trihydrate (1.5 mg/100 g BW) and endotoxin (1.0 micrograms/100 g BW). Liver samples removed by freeze-clamping at 5 h from fasted young adult male rats were assayed for glycolytic intermediates. The tolerant rats generally showed smaller alterations in concentrations of metabolites than nontolerant comparison rats challenged with lead and endotoxin. However, phosphoenolpyruvate (PEP) levels were similarly elevated (80-90%) in both groups. The failure of the tolerance procedure to minimize or protect against hepatic PEP changes suggests that the enzymes forming or consuming this metabolite were particularly vulnerable to the action of an endotoxin-released mediator. The fact that some liver glycolytic intermediates remain markedly altered despite amelioration of the lethal effects of endotoxin by the tolerance procedure indicates the existence of independent mediators acting on carbohydrate metabolism in the endotoxic rats.

Animals↗
PubMed1983

Efficacy of oral and systemic antibiotic prophylaxis in colorectal operations.

A cooperative Veterans Administration study of the septic complication rate during large-bowel surgery was undertaken in two groups of patients. The first group received oral neomycin and erythromycin base plus parenteral placebo; the second, the oral antibiotics plus parenteral cephalothin sodium. During a five-year period, 1,128 patients were studied. The overall septic complication rate was 7.8% in patients receiving only oral antibiotics, and 5.7% in patients receiving both oral and parenteral antibiotics. This difference was not significant. The only significant finding was a greater incidence of fever of unknown origin in patients receiving only oral antibiotics. None of those patients were treated with additional antibiotics, and all fevers cleared spontaneously. There seems to be no discernible benefit from adding parenteral antibiotic prophylaxis when performing elective colon surgery if appropriate mechanical cleansing and oral neomycin and erythromycin therapy are employed.

Administration, Oral↗
PubMed1983

Evaluation of efficacy of cefoxitin in the prevention of abdominal trauma infections.

Recent studies showed high populations of both aerobes and anaerobes in penetrating abdominal trauma infections. Combined aminoglycoside-clindamycin therapy has resulted in infection rates of 7 to 10 per cent. However, high side-effect incidences of nephrotoxicity and ototoxicity have been attributed to the aminoglycosides. Cefoxitin is reportedly free of these side effects. In our study, 62 penetrating abdominal trauma patients requiring laparotomy were treated with cefoxitin pre- and postoperatively. The majority of the injuries, 75.8 per cent, involved small bowel and large bowel. Infections occurred in four patients of the total 62 (6.5%). Two side effects, a fever and a rash, subsided immediately after discontinuing cefoxitin; no ototoxicity or nephrotoxicity occurred. The safety and efficacy of cefoxitin alone versus aminoglycoside-clindamycin combination therapy was statistically compared in intestinal injuries only among two historical controls and our subgroup. Our infectious rate, 8.5 per cent, was comparable to 7.4 per cent and 10.4 per cent of the historical controls. We concluded that pre- and postoperative use of cefoxitin alone is as effective in the prevention of penetrating abdominal trauma infections as combined aminoglycoside-clindamycin therapy. Experience to date suggests that the use of a beta-lactam antibiotic such as cefoxitin may allow the physician to avoid the more serious side effects associated with the use of aminoglycosides in these patients.

Abdominal Injuries↗
PubMed1983

The influence of glucocorticoids on hepatic glycolytic intermediates in fed peritonitis rats.

Earlier work on fasted endotoxemic and septic rats suggested that glucocorticoid pretreatment improved survival by promoting gluconeogenesis. The possible mechanism of this therapeutic effect was investigated in fed peritonitis septic rats, which are in a predominantly glycolytic mode of metabolism. Fed adult male rats (185-255 g) received cecal incisions or sham operations under ether with or without simultaneous IV injection of dexamethasone (DMS) (1.0 mg/100 g rat). Liver was sampled by freeze-clamping at 5 h, and glycolytic intermediates were determined by UV spectrophotometry. The high-energy intermediate, phosphoenol-pyruvate (PEP), fell 57% to 76 +/- 83 nmole/g wet liver (+/- 1 SD) in the fed peritonitis group; nine of 13 rats had PEP values at least 50% below mean control concentrations. Fasted septic rats (N = 26) do not have decreased PEP levels. Glucocorticoids were protective in the fed septic rats; only five of 17 DMS-pretreated rats had PEP fall below 50% of the fed normals. A significant finding was the decline in fructose diphosphate (FDP) from 32 +/- 9 nmole in fed shams (N = 12) to 21 +/- 11 nmole/g wet liver with DMS-pretreated fed shams (N = 15). This suggests that DMS may be inhibiting the glycolytic enzyme, phosphofructokinase, and thereby enhancing gluconeogenesis by sparing hexose monophosphates. Lactate in fed sham liver was 1,869 +/- 336 nmole/g, a concentration twofold greater than in fasted liver. This difference may contribute to the increased vulnerability of fed rats to septic shock. It is concluded that glucocorticoids tend to normalize Embden-Meyerhof pathway intermediates in both fed and fasted rat livers.

Animals↗
PubMed1983

Effect of a new synthetic complement inhibitor on hepatic glycolytic intermediates in septic rats.

Peritonitis and endotoxemia produce similar derangements in carbohydrate metabolism, indicating a common mechanism of action. Endotoxin activates the complement chain by the alternate pathway with the release of chemical mediators. These mediators may be responsible for the changes occurring in hepatic metabolite pools during endotoxemia. This hypothesis was tested with FUT-175, a complement inhibitor, (2-(6-amidino)naphthyl-4-guanidinobenzoate 2HC1). Peritonitis was induced by cecal incision in fasted male rats. FUT-175 was infused in 5% dextrose at a dose of 0.1 mg/ml/h. Survival time was 12.1 +/- 2.3 h in the FUT-175 group and and 6.6 +/- 1.1 h without FUT-175. Three peritonitis groups received either 5% dextrose alone; FUT-175 2.5 mg/100 g by IP injection, or FUT-175 0.1 mg/ml/h by infusion. Liver was sampled at 5 h by freeze-clamping, and metabolites were assayed by UV spectrophotometry. Peritonitis caused 33% decrease in glucose-6-phosphate (G6P), a 2.5-fold increase in fructose diphosphate (FDP), and 3.5-fold increase in lactate. In FUT-175-injected rats, G6P was decreased by 20%, FDP increased only 50%, and lactate doubled. Phosphoenolpyruvate (PEP) levels were increased 30% above peritonitis values. The drug produced a partial normalization of liver metabolites. The data suggest that the anticomplement action prevented the release of potent mediators which otherwise cause physiological changes leading to the metabolic imbalance of septic shock.

Animals↗
PubMed1982

Effect of endotoxin and glucocorticoid pretreatment on hexose monophosphate shunt activity in rat liver.

The acceleration of glycolysis by the Embden-Meyerhof pathway (EMP) in endotoxic and septic states and its counteraction by glucocorticoids has been demonstrated by past research. Although the glycolytic contribution of the hexose monophosphate (HMP) shunt is minor, its response during endotoxemia, if similar to that of EMP, could be theoretical interest, Fasted male rats (150-260 gm) were sacrificed at 5 hr after IV injection of E coli endotoxin in dosages of 2 or 3 mg/100 gm rat weight: LD50 (Nm= 15). A second group received 1 mg dexamethasone (DMS) IV per 100 gm rat weight simultaneously with endotoxin (N = 15). Livers were homogenized in 0.25 M cold sucrose and centrifuged at 15,000 g for 20 min. Specific activity of glucose-6-phosphate dehydrogenase (G6PDH) in control livers (N = 17) was 7.1 nmoles of substrate consumed per min/mg biuret protein. Endotoxin raised G6PDH activity by 49% to 10.64 units, and the endotoxin-DMS-protected group was 6.0 units. Levels of 6-phosphogluconate (6PG) were also measured in frozen liver biopsies from similar groups of rats. Liver 6PG concentrations of control (N = 15), endotoxic (N = 15), and endotoxified-DMS-treated (N = 9) groups were 22.5, 14.3, and 17.6 nmoles/gm wet tissue, respectively. The data indicate a significant 36% acceleration in 6PG consumption during endotoxemia, which is not blocked by DMS. The cofactor, nicotinamide adenine dinucleotide phosphate (NADP), decreased significantly by 18% from the control level of 152 nmoles/gm liver (N = 9) during endotoxemia, and this fall was not corrected by DMS. In a small group (N = 6), sedoheptulose-7-phosphate declined from the control value of 76 nmoles/gm wet liver by 38% after endotoxification. It is concluded that endotoxin stimulates G6PDH, the initial enzyme of the HMP pathway, and accelerates consumption of several intermediates, Glucocorticoid prevents the enzyme activity increase but does not restore 6PC and NADP concentrations to normal levels, suggesting that different enzyme sites along the HMP shunt may have unequal responses to DMS.

Animals↗