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Biomedical subjects

R E Kuttner

Publications and source records attributed to R E Kuttner.

At least 19 recordsLinked to original sources
PubMed1987

Effect of aging on hepatic carbohydrate metabolism in septic rats.

Aged individuals have diminished resistance to severe sepsis and septic shock. Past work with animals suggested that an important determinant of survival was the ability of the liver to supply glucose. In this study, young adult (3 to 4 months) and old (24 months) Fischer 344 rats were fasted and subjected to cecal incisions producing a rapidly lethal peritonitis. We then determined gluconeogenic intermediates in the liver. In the old rats with peritonitis, hexosemonophosphates (HMP) increased 50% relative to control liver, whereas in the young animals with peritonitis, the substrate decreased 50%. The accumulation of HMP in the old rat liver cells indicates a failure to dephosphorylate glucose-6-phosphate (G6P). This increase in HMP is associated with a decline in hepatic glucose-6-phosphatase (G6Pase), the final enzyme in the gluconeogenic pathway, and is reflected in a significant reduction in serum glucose in old Fischer 344 rats when compared to young Fischer rats.

Aging↗
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 Forty per cent of intravascular blood was withdrawn and liver was sampled by freeze-clamp at 0, 0.25, 1.0, 3.0, and 4.0-5.0 hours.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

A molecular hypothesis on parallel memory function with relevance to senile dementias.

The hypothesis is presented that closely associated memories can be coded and decoded in a parallel manner analogous to genetic deoxyribonucleic acid (DNA) forming two or more different proteins from a single polynucleotide strand. Iconic, aural, and lexical stimuli could be imprinted and recovered from the same storage molecule. The described process which involved the decoding of the same neuronal DNA macromolecule two or more times but from slightly shifted reading frames has the advantage of promoting fidelity of coding and decoding. The suggested mechanism also explains why it is possible for some mnemonic elements to survive during aphasia and senile dementias, while closely linked synonymous engrams are lost.

Aphasia↗
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

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

Is child abuse a human instinct?

The modern concept of instinct maintains that certain physical signs or events trigger the release of appropriate behavioural responses. According to Konrad Lorenz and other ethological theorists, the features and proportions of the infant body and face convey a sense of cuteness which releases a protective human instinct. Members of the Lorenz-Tinbergen school may also regard violent crime or war as manifestations of aggressive drives. A survey of medical and sociological literature shows that the rate of abuse and neglect of infants and children is higher than violent crimes against adults, which reveals a contradiction in basic premises.

Adolescent↗
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↗
PubMed1981

Apparent normality and feigned sociopathy.

Attention is called to conscious episodes of mild sociopathy by technically normal individuals who are experiencing identification difficulties with their groups or substructures. These deliberately engineered episodes appear to represent distress signals to gain more attention and involvement from counsellors. The cases described involved behavioral hypochondria rather than mental or physical symptoms. Feigned sociopathy could be a surface manifestation of more serious psychological or social problems.

Antisocial Personality Disorder↗
PubMed1981

Glucocorticoid effect on glycolytic intermediates in septic rat heart.

Glycolytic intermediates in rat liver show similar changes in both endotoxic and peritonitis shock models suggesting a common etiology. To determine if this parallelism exists for other organs, adult rat hearts were analyzed 5 hours after E. coli endotoxin injection (2 mg/100 gm rat weight) or after sepsis produced by cecal incision. Tissue obtained by freeze-clamp biopsy was deproteinized and the metabolites were enzymatically assayed. Glucocorticoids were injected IV: 1 mg dexamethasone sodium phosphate (DMS) and 3 mg methylprednisolone sodium succinate (MPS) per 100 gm rat weight at time of operation. Glucose-6-phosphate (G6P) and fructose-6-phosphate (F6P) in septic hearts (N = 10) declined 36% and 37% from sham-operated control values (N = 11) of 640 nmole and 136 nmole per gm wet tissue. This finding is consistent with accelerated glycolysis. No changes of other metabolites indicative of severe hypoxic conditions were noted. A 2.5-fold increase in lactate was observed. This may reflect a shift to anaerobiosis in peripheral muscle and greater extraction by heart. Confirming earlier endotoxin rat heart data, glucocorticoids did not prevent decreases in G6P and F6P in septic hearts which declined 37% and 36% below sham controls (N = 10 for pooled glucocorticoid data). Hexose monophosphates in sham animals treated with GC alone were also found to be lowered. Glucocorticoids were synergistic with endotoxin in lowering beta-hydroxybutyrate in heart samples. It is concluded that endotoxin and sepsis produce identical responses on myocardial carbohydrate metabolites and that glucocorticoids do not counter these effects, which reflects the lack of gluconeogenic potential in this organ.

Animals↗
PubMed1981

Glucocorticoid action on rat hepatic glycolytic intermediates during experimental peritonitis.

Previous work demonstrated that glucose-6-phosphate (G6P) and fructose-6-phosphate (F6P) levels declined early in endotoxemic and septic livers. Since glucocorticoids are known to support hepatic gluconeogenesis in endotoxemia, these agents were tested in a peritonitis model produced by cecal incision in fasted adult male rats. Dexamethasone sodium phosphate (DMS) and methylprednisolone sodium succinate (MPS) were given in doses of 1 mg and 3 mg, respectively, per 100 gm rat weight at time of incision. Freeze-clamp biopsy samples obtained at 5 hr were enzymatically assayed. G6P and F6P in sepsis (N = 12) decreased 50% and 36%, respectively, below sham-operated control values (N = 15) of 236 and 61 nmole/gm wet tissue. The decrease with DMS was 20% and 16% and with MPS was 22% and 23%, showing partial restoration to normal levels. Phosphoenolpyruvate (PEP) did not decline in the moderate, non-terminal stage of peritonitis when compared to the control value (N = 19) of 209 nmole/gm. Treatment with glucocorticoids raised PEP to supernormal levels: DMS (N = 19) a 63% elevation, MPS (N = 12) a 51% elevation above controls in peritonitis rats. The glucocorticoid effect was similar in both rapid endotoxic and the slow peritonitis shock models. It is concluded that hexose monophosphate (HMP) increase is secondary to the support of PEP synthesis with glucocorticoid treatment. Changes in sham-operated control rat livers treated with glucocorticoids did not reach statistical significance.

Animals↗
PubMed1980

The effect of endotoxin on plasma alpha-aminoisobutyric acid.

The i.v. injection of bacterial endotoxin into dogs was found to cause a rapid increase in plasma levels of infused alpha-aminoisobutyric acid. The findings suggest that nonmetabolic factors (tissue uptake, fluid shifts) influence amino acid distribution during endotoxemia.

Aminoisobutyric Acids↗
PubMed1980

Glycolytic intermediates in rat heart after endotoxin treatment.

Glycolytic intermediates were determined in rat hearts five hours after an LD50 Escherichia coli endotoxin injection and glucose-6-phosphate (G6P) and fructose-6-phosphate (F6P) were decreased by 40% to 45% relative to control hearts. Levels of other intermediates which alter in severe hypoxia were unchanged. Adenosine triphosphate (ATP) and diphosphate (ADP) remained constant while glycogen was almost 50% depleted. A 30% fall in beta-hydroxybutyrate indicated that fatty acid utilization was decreased. The data were consistent with accelerated glycolysis. Pretreatment with the positive inotropic cardiac glycoside, ouabain, failed to maintain glycolytic intermediates in endotoxified heart at control levels. An identical fall in hexose monophosphates previously observed in rat livers may indicate that endotoxin has a similar action on enzymes regulating carbohydrate metabolism in different organs.

Animals↗
PubMed1980

Endotoxin role in peritonitis septic shock in rats.

We attempted to clarify the role of endotoxin in septic shock by supporting the concept that endotoxin produces hemodynamic and metabolic alterations in a peritonitis septic shock model (PSM). In the control group I, each rat was sham-operated. In group II, each rat was etherized, subjected to laparotomy, and the appendix was resected, leaving a rent at the base of the cecum for stool to enter the peritoneum. In group III, each rat was injected intraperitoneally with a 4 ml suspension of its own feces containing equal amounts of bacteria as measured by colony count. In all groups, blood pressure, plasma glucose and lactate, as well as endotoxin, were measured hourly via polyethylene catheters in the right femoral arteries. In parallel studies, liver glycolytic intermediates were measured at five hours via freeze-clamp biopsies and compared with measurements determined in an endotoxic shock model in rats (ESM). The results showed similar glucoeogenic inhibitions in both PSM and ESM, the liver anti-gluconeogenic effect in PSM probably being produced by endotoxin.

Animals↗