Biomedical subjects

B W Warner

Publications and source records attributed to B W Warner.

At least 91 records · Page 5Linked to original sources

PubMed1990

Reduced amino acid transport in skeletal muscle caused by a circulating factor during endotoxemia.

The present study was designed to determine whether reduced amino acid uptake in skeletal muscle during endotoxemia is due to associated hypotension or is caused by a factor present in plasma. Three series of experiments were performed. In the first series of experiments, mean arterial pressure (MAP), heart rate, and amino acid uptake in incubated soleus muscles were measured after intravenous injection of endotoxin (1 mg/kg) in male Sprague-Dawley rats (40 to 60 g). Amino acid transport was measured by determining intracellular uptake of [3H]-alpha-amino-isobutyric acid (AIB) during 2 hours of incubation. In the second series of experiments, hypotension was induced by bleeding and muscle amino acid uptake was measured. In the third series of experiments, whole plasma or a low molecular weight fraction (less than 10,000 d) of plasma from endotoxin-injected rats was added in vitro to incubated muscles and amino acid uptake was determined. One hour after injection of endotoxin, MAP was reduced from 80 +/- 2 mmHg to 54 +/- 4 mmHg (p less than 0.05). AIB uptake was reduced by 20% (p less than 0.05) 2 hours after endotoxin injection. When MAP was maintained at 50 mmHg for 1 hour by bleeding, no changes in muscle AIB uptake were noted. When plasma obtained from rats 2 hours after endotoxin injection was added to incubated soleus muscles, AIB uptake was reduced by 22%. This effect was duplicated by a fraction of endotoxic plasma containing substances with a molecular weight less than 10,000 d. The present results suggest that reduced muscle amino acid uptake during endotoxemia is not due to associated hypotension, but may be caused by a circulating factor(s) with a molecular weight less than 10,000 d.

Amino Acids↗

PubMed1989

Transduodenal sphincteroplasty and transampullary septotomy for primary sphincter of Oddi dysfunction.

We examined 29 patients without stone disease or pancreatic ductal ectasia who underwent transduodenal sphincteroplasty and transampullary septotomy for symptoms of biliary colic or pancreatitis. The combination of biliary symptoms and a fibrotic ampulla of Vater portends a favorable surgical outcome in virtually all such patients. Patients with pancreatitis did worse overall, perhaps due to the existence of unappreciated subclinical parenchymal disease not related to sphincter dysfunction. Although endoscopic retrograde cholangiography was sensitive in demonstrating abnormalities of the pancreaticobiliary system, its specificity as a predictor of good results was poor. It seems prudent to temper one's enthusiasm for sphincteroplasty in the patient with pancreatitis, whereas patients with biliary symptoms, the postcholecystectomy syndrome, or both will usually benefit significantly from this procedure.

Adult↗

PubMed1989

Protein synthesis in liver following infusion of the catabolic hormones corticosterone, epinephrine, and glucagon in rats.

The mediator(s) and mechanism(s) of acute-phase protein synthesis in the liver following injury and sepsis are not fully known. Elevated plasma levels of the catabolic hormones cortisol, glucagon, and epinephrine have been reported in trauma and sepsis. In previous reports, when these hormones were infused simultaneously (triple hormone infusion), several, but not all, of the metabolic alterations characteristic of sepsis occurred. In the current investigation, the effect of triple hormone infusion on hepatic protein synthesis was studied. Rats were infused intravenously during 16 hours with a solution containing corticosterone (4.2 mg/kg/h), glucagon (2.5 micrograms/kg/h), and epinephrine (6 micrograms/kg/h). Control animals were infused with a corresponding volume of vehicle. Total hepatic protein synthesis in vivo was measured with a flooding dose technique using [14C]-leucine. The synthesis of total secretory proteins and of the individual proteins albumin, complement component C3, and alpha 1-acid glycoprotein was measured in isolated, perfused liver using [3H]-leucine and a recirculating technique. Urinary excretion of nitrogen and plasma concentration of glucose were higher and plasma total amino acid concentration was lower in hormone-infused than in control rats. Total hepatic protein synthesis in vivo, expressed as the proportion of the protein pool that was replaced each day, was increased from 39% +/- 2% per day to 48% +/- 3% per day (P less than .05) by hormone infusion, but synthesis of secretory proteins in perfused liver was not significantly altered. The results suggest that although total hepatic protein synthesis may be increased by catabolic hormones, other mediator(s) are probably responsible for the stimulation of acute-phase protein synthesis in sepsis.

Acute-Phase Proteins↗

PubMed1989

Mediastinal hemorrhage during extracorporeal membrane oxygenation.

A case of mediastinal hemorrhage along with hemorrhage into a pneumatocele while on extracorporeal membrane oxygenation (ECMO) is presented. Computerized tomography of the chest was utilized to support the diagnosis. Barotrauma to the lungs best explains the inciting event that allowed the hemorrhage to occur once the patient was heparinized for ECMO. This complication serves to point out the importance of commencing early ECMO support before widespread pulmonary and mediastinal barotrauma develops.

Barotrauma↗

PubMed1989

Hemodynamic and metabolic alterations during experimental sepsis in young and adult rats.

Cecal ligation and puncture (CLP) has been extensively used as a model of sepsis in adult rats. It is not known if the response to sepsis is similar in young and adult rats. This investigation was done to compare hemodynamic and metabolic alterations in young (four to six weeks of age, 60 to 90 grams) and adult (12 to 14 weeks of age, 270 to 340 grams) rats after CLP. In one series of experiments, survival rate was determined for 96 hours, and in other experiments, mean arterial blood pressure (MAP), heart rate (HR), white blood cell count, hematocrit, platelets, plasma glucose, lactate, amino acids, blood urea nitrogen (BUN), blood and peritoneal cultures and resting energy expenditure (REE) were determined eight and 16 hours after CLP. Levels of glycogen in liver and muscle were determined 16 hours after CLP. Mortality rate was similar in young and adult rats. MAP was stable throughout the course of sepsis, with no significant differences between the two groups of rats. HR was higher in young rats at all times studied. The adult rats became hyperglycemic after CLP while the young were hypoglycemic eight hours after CLP but normalized at 16 hours. Plasma lactate and BUN were similar in the two groups of rats, and no alterations were seen during sepsis. Both young and adult rats became hypoaminoacidemic after CLP. The phenylalanine to tyrosine ratio increased in a similar manner during sepsis in both experimental groups. REE was higher in young than in adult rats, but no significant changes were observed during the course of sepsis in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed1988

Evidence that cathepsin B contributes to skeletal muscle protein breakdown during sepsis.

The mechanisms of accelerated skeletal muscle protein degradation during sepsis have not been fully elucidated. Activity of the lysosomal protease cathepsin B is increased in skeletal muscle during various catabolic states other than sepsis. In the present study the protein degradation rate and cathepsin B activity were determined in extensor digitorum longus and soleus muscles from nonseptic and septic rats. The protein degradation rate during incubation in vitro with or without the cathepsin B inhibitor leupeptin was also determined. Both protein degradation and cathepsin B activity were increased in muscles from septic rats. Incubation with leupeptin reduced, but did not normalize, the protein degradation rate in both extensor digitorum longus and soleus muscles from septic animals. These studies suggest that increased cathepsin B activity contributes to the accelerated muscle proteolysis seen during sepsis and that proteases other than cathepsin B are also involved.

Animals↗

PubMed1988

Protein synthesis and degradation in skeletal muscle from septic rats. Response to leucine and alpha-ketoisocaproic acid.

It has been suggested that leucine and alpha-ketoisocaproic acid (KIA) stimulate protein synthesis and reduce protein breakdown and may be useful in the treatment of muscle catabolism during sepsis. However, whether leucine and KIA regulate protein turnover in septic skeletal muscle is not known. In this study, intact muscles from untreated normal rats or from rats subjected to cecal ligation and puncture were incubated in the presence of leucine or KIA. In normal muscle, leucine stimulated protein synthesis and reduced protein degradation, while KIA decreased protein breakdown. In septic muscle, protein synthesis was also stimulated by leucine, but only at a concentration higher than that needed to affect protein synthesis in normal muscle. Protein breakdown in septic muscle was unaffected by leucine and KIA even at an extracellular concentration as high as 5 mmol/L. Since other experiments showed that the intracellular concentration of leucine was not different in incubated normal and septic muscles, these results suggest that sepsis induces changes in skeletal muscle protein turnover that are resistant to the effects of leucine.

Animals↗

PubMed1988

Current concepts of protein turnover and amino acid transport in liver and skeletal muscle during sepsis.

The metabolic response to trauma and sepsis is characterized by a negative nitrogen balance, accelerated muscle proteolysis, increased ureagenesis, and stimulated acute-phase protein synthesis in liver. Inhibited uptake of amino acids and accelerated protein breakdown in muscle increase the flux of amino acids from the periphery to the liver. Concomitantly, hepatic uptake of amino acids is stimulated and protein synthesis and gluconeogenesis in the liver are enhanced. These events are important to the survival of patients with sepsis. Stimulated ureagenesis resulting in nitrogen loss from the body is another important aspect of hepatic nitrogen metabolism following trauma and sepsis. The mediator(s) initiating metabolic changes is not yet exactly defined, although regulatory protein(s) released from stimulated macrophages (particularly interleukin 1 and tumor necrosis factor) may play a major role in altered amino acid and protein metabolism in muscle and liver during sepsis. However, these factors alone are probably not responsible for the metabolic disturbances, since the catabolic hormones cortisol, glucagon, and the catecholamines can simulate the metabolic pattern observed in sepsis. Other possible mediators include prostaglandins and thyroid hormones. It is possible that the interaction between different types of mediators is necessary for the full manifestation of host responses to severe injury and sepsis.

Amino Acids↗

PubMed1988

Effects of indomethacin and leupeptin on muscle cathepsin B activity and protein degradation during sepsis.

The roles of prostaglandins and lysosomal proteases in accelerated skeletal muscle proteolysis during sepsis are not yet fully understood. In this study rats received intraperitoneal injections of the prostaglandin synthesis inhibitor indomethacin (IND, 5.0 mg/kg), the lysosomal cathepsin B inhibitor leupeptin (LEU, 2.5 mg/kg), or normal saline 2 hr before cecal ligation and puncture (a model of intraabdominal sepsis) or sham-operation. The injections were repeated every 6 hr for a total of four doses. Sixteen hours after operation, intact extensor digitorum longus (EDL) muscles were harvested and cathepsin B activity was measured in one muscle. The contralateral muscle was incubated in oxygenated Krebs-Henseleit bicarbonate buffer containing glucose (10 mM) and cycloheximide (0.5 mM), and protein degradation rate was determined as the release of tyrosine into the incubation medium. Both muscle cathepsin B activity and protein degradation rate were higher in septic than in sham-operated rats. Treatment with IND or LEU significantly reduced the elevated cathepsin B activity in septic muscles, but failed to significantly alter muscle proteolysis. In nonseptic muscle, both cathepsin B activity and protein degradation rate were unaffected by the different types of treatment. The results suggest that although prostaglandins may influence muscle lysosomal protease activity, neither prostaglandins nor the lysosomal protease cathepsin B appear to be major regulators of accelerated muscle protein breakdown during sepsis.

Animals↗

PubMed1988

Methods for studying protein synthesis and degradation in liver and skeletal muscle.

Different methods used for measuring protein turnover in liver and skeletal muscle are described, with special emphasis on technical and practical aspects and the advantages and limitations of different techniques. In the first part of the review, the concept of precursor specific radioactivity and its importance for accurate determination of protein synthesis rate is discussed. In the second part, different in vivo techniques for protein turnover measurements are reviewed, including continuous administration of tracer amino acid, flooding dose technique, indirect measurement of protein synthesis, and estimation of protein degradation in vivo. In the third part of the report, in vitro techniques are described, including measurement of protein turnover in incubated liver slices, perfused liver, isolated hepatocytes, incubated isolated muscles or muscle biopsies, and perfused rat hemicorpus. In vivo techniques are preferred when accurate absolute values of protein turnover rates are desired. In vitro techniques offer the advantage of standardized conditions, maintaining strict control of substrate and hormone concentrations, and eliminating complicating interactions with other tissues. For several in vitro techniques, a good correlation has been demonstrated between relative changes in protein turnover in vitro and in vivo in different conditions.

Animals↗

PubMed1988

The effect of sepsis in rats on skeletal muscle protein synthesis in vivo and in periphery and central core of incubated muscle preparations in vitro.

Recent studies demonstrated the development of a central, hypoxic core in incubated rat skeletal muscles. The influence of a central core on changes in protein synthesis rate, observed in incubated muscles from septic rats, is not known. In the present study, intact soleus muscles from 40 to 60-g sham-operated control rats and from septic rats (16 hours after cecal ligation and puncture) were incubated in vitro in a flaccid or stretched state. Protein synthesis rate was determined in whole muscle and in the central core and periphery of the muscle by measuring incorporation of 14C-phenylalanine into protein. Protein synthesis rate in vivo was measured with a flooding-dose technique using 3H-phenylalanine. The development of a central, hypoxic core in incubated muscles was assessed histochemically by staining the muscles for alpha-glucan phosphorylase activity. A central core with loss of alpha-glucan phosphorylase activity was noted after incubation for 30 minutes in both control and septic muscles. The protein synthesis rate was lower in the central core than in the periphery of incubated flaccid control muscles. In all other in vitro muscle preparations, however, there were no significant differences in protein synthesis rate among whole muscles, central core and periphery. Protein synthesis rate in septic muscles was reduced to a similar extent, approximately 20%, in vivo and in the different in vitro preparations, both when measured in whole muscle and in the central core or periphery.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Further evidence that accelerated muscle protein breakdown during sepsis is not mediated by prostaglandin E2.

Prostaglandin E2 (PGE2) reportedly increases protein break-down in skeletal muscle. The role of PGE2 for accelerated muscle proteolysis during sepsis, however, is controversial. In this study, the effect of the prostaglandin synthesis inhibitor indomethacin on PGE2 release and protein breakdown in skeletal muscle from nonseptic and septic rats was evaluated. Sepsis was induced in male Sprague-Dawley rats (40-60 g) by cecal ligation and puncture (CLP). After 16 hours the extensor digitorum longus (EDL) and soleus (SOL) muscles were dissected with intact tendons and incubated in an oxygenated medium, and the release of tyrosine (protein breakdown) and PGE2 into the incubation medium was determined. Paired muscles were incubated in the absence or presence of indomethacin (3 mumol/L or 6 mumol/L). In some experiments the effect of indomethacin was investigated in the presence of different concentrations of insulin (1, 10, or 100 mU/mL) since previous reports suggested an interaction between insulin and prostaglandins on protein turnover in skeletal muscle. In other experiments muscles were incubated in a flaccid or stretched state, which is known to influence the metabolic response to different substances. Protein breakdown rate was 0.210 +/- 0.013 and 0.492 +/- 0.025 mumol Tyr/g X 2 hours in EDL from nonseptic and septic rats, respectively (p less than 0.01). The corresponding values for SOL were 0.480 +/- 0.037 and 0.712 +/- 0.039 mumol Tyr/g X 2 hours (p less than 0.01). Addition of indomethacin to the incubation medium reduced PGE2 release from 29.1 +/- 3.1 to 6.8 +/- 0.7 ng/g X 2 hours in nonseptic SOL and from 50.6 +/- 10.4 to 5.6 +/- 0.7 ng/g X 2 hours in septic SOL. Protein breakdown rate in SOL and EDL from sham-operated or septic rats was unaffected by indomethacin, both when muscles were incubated in a flaccid or stretched state, and when they were incubated in the presence or absence of insulin. The present results do not suggest a role of PGE2 for accelerated muscle proteolysis in the present experimental septic model.

Animals↗

PubMed1987

Effect of insulin on amino acid uptake and protein turnover in skeletal muscle from septic rats. Evidence for insulin resistance of protein breakdown.

We investigated the effect of different concentrations of insulin (0, 10, 1 X 10(2), 1 X 10(3), 1 X 10(4), and 1 X 10(5) mU/L [0, 70, 7 X 10(2), 7 X 10(3), 7 X 10(4), and 7 X 10(5) pmol/L]) on amino acid (alpha-aminoisobutyric acid) uptake and protein synthesis and breakdown in incubated extensor digitorum longus (EDL) and soleus muscles of rats. We studied three groups: untreated, fed rats; sham-operated rats; and septic rats. Sepsis was induced by cecal ligation and puncture. The alpha-aminoisobutyric acid uptake was increased by insulin in all three groups. Protein synthesis was maximally stimulated by 30% to 40% by 1 X 10(2) mU/L (7 X 10(2) pmol/L) of insulin in all three groups. Protein degradation in soleus muscle was not affected by insulin. In EDL muscles from untreated and sham-operated rats, protein breakdown was reduced by 15% to 20% by 1 X 10(2) mU/L (7 X 10(2) pmol/L) of insulin. In contrast, protein breakdown was not inhibited by insulin in septic EDL muscle until the concentration of the hormone was increased to 1 X 10(4) mU/L (7 X 10(4) pmol/L), at which concentration the hormonal effect was less than half that in nonseptic muscle. The results suggest a postreceptor insulin resistance of protein breakdown in septic muscle, while the response to the hormone of amino acid transport and protein synthesis was not altered in sepsis.

Aminobutyrates↗

PubMed1987

Superoxide dismutase in rats with sepsis. Effect on survival rate and amino acid transport.

In a recent study, administration of the free radical scavenger superoxide dismutase (SOD) improved survival in rats with sepsis when administered two hours before induction of sepsis. The present study was designed to determine whether free radical-induced membrane damage is involved in the pathogenesis of decreased muscle amino acid uptake, noted in sepsis. Additionally, the effect on survival rate of SOD given after the onset of sepsis was studied. Sepsis was induced by cecal ligation and puncture in rats. Amino acid transport in incubated soleus muscles was studied using tritiated alpha-aminoisobutyric acid. Amino acid uptake was significantly reduced in muscle from rats with sepsis. Administration of SOD before induction of sepsis or added in vitro to incubated muscles with sepsis had no effect on alpha-aminoisobutyric acid uptake. Survival rate was not increased when SOD was given two hours after cecal ligation and puncture. The results suggest that free radical-induced membrane damage is not the mechanism of inhibited muscle amino acid transport in sepsis. Since survival was not improved by SOD administered after induction of sepsis, the role of the enzyme in the treatment of sepsis may be questioned.

Amino Acids↗

PubMed1987

Early total parenteral nutrition in acute pancreatitis: lack of beneficial effects.

To determine the effect of early aggressive parenteral support in pancreatitis, 54 patients with acute pancreatitis were randomized to receive either conventional therapy (control group) or conventional therapy plus the institution of total parenteral nutrition within 24 hours. The two groups were similar demographically. The total parenteral nutrition group had a significantly higher rate of catheter-related sepsis than did an additional group of contemporaneous patients without pancreatitis who received total parental nutrition (10.5 percent and 1.47 percent, respectively; p less than 0.01). There was no advantage to the use of early total parenteral nutrition; that is, there was no difference in the number of days to oral intake, total hospital stay, or number of complications of pancreatitis. Patients with zero or one Ranson's criterion on admission were more likely to be eating by the seventh hospital day than were those with two or more Ranson's criteria (80 percent and 54 percent, respectively; p less than 0.05). The early institution of total parenteral nutrition in patients with acute pancreatitis did not appear to improve the outcome. Its use should be limited to prolonged periods of no oral intake or treatment of a specific complication, such as a pseudocyst.

Acute Disease↗

PubMed1987

Effect of sepsis and starvation on amino acid uptake in skeletal muscle.

Sepsis and starvation are catabolic conditions often occurring simultaneously. We recently found that uptake of the nonmetabolized amino acid analog, alpha-aminoisobutyrate (AIB), was reduced in skeletal muscle during sepsis, and data were presented suggesting that this reduction was caused by a factor present in septic plasma. The purpose of the present study was to determine the effect of starvation on amino acid uptake and to investigate possible interactions between sepsis and starvation regarding effects on muscle amino acid uptake. Soleus muscles were removed intact from rats fasted for 0, 24, 48, or 72 hr. Muscles were incubated for 2 hr in Krebs-Henseleit bicarbonate buffer (pH 7.4) and glucose (5 mM) with or without 0.25 ml of septic plasma (total volume 3 ml). Muscle AIB uptake progressively decreased by approximately 50% during the first 48 hr of starvation, with no further decrease at 72 hr. Addition of septic plasma in vitro reduced AIB uptake in muscles from fed rats and from rats which had been fasted for 24 hr, but did not further reduce uptake after longer periods of starvation. The results suggest that starvation reduces amino acid uptake in skeletal muscle and that the nutritional status of muscle is an important component of the response to the factor(s) in septic plasma capable of inhibiting amino acid uptake.

Aminoisobutyric Acids↗

PubMed1987

Effect of catabolic hormone infusion on organ amino acid uptake.

Elevated plasma levels of the so-called catabolic hormones (glucocorticoid, epinephrine, glucagon) have been observed in severely injured patients, and infusion of these hormones to normal subjects has reportedly simulated several metabolic aberrations characteristic of severe trauma and sepsis. We recently reported that amino acid uptake was reduced in soleus muscle, heart, and diaphragm, and increased in the liver, of septic rats. The purpose of the present study was to investigate organ amino acid uptake in nonseptic rats infused with catabolic hormones. Central venous catheters were placed in male Sprague-Dawley rats (100-150 g) and after 24 hr hormones (glucagon 5 micrograms/kg/hr, epinephrine 6 micrograms/kg/hr, corticosterone 4.2 mg/kg/hr) or vehicle (saline, ascorbic acid 1 mg/ml, albumin 3 mg/ml) was infused for 72 hr. Animals were housed in metabolic cages and allowed food and water ad lib. One hour prior to sacrifice, alpha-[3H]aminoisobutyric acid (AIB) (2.5 microCi), a nonmetabolized amino acid analog mainly transported by system-A, was injected intravenously. Animals were killed and organs were removed, weighed, and dissolved in tissue solubilizer for measurement of radioactivity. AIB uptake was significantly elevated in all organs of catabolic hormone-infused animals studied. The results suggest that catabolic hormones may be involved in the pathogenesis of increased amino acid uptake in the liver during sepsis. Inhibited amino acid uptake in skeletal muscle during sepsis, however, is probably not primarily mediated by catabolic hormones.

Aminoisobutyric Acids↗

PubMed1987

Multiple purpose central venous access in infants less than 1,000 grams.

The use of central venous catheters in low birthweight infants has been associated with a high rate of infectious and mechanical-related complications. We reviewed our experience with multipurpose central venous catheters in infants less than 1,000 g to determine the rate of catheter-related sepsis and mechanical catheter malfunction. From October 1981 to August 1984, 20 infants (average weight 778 g) underwent placement of 22 central venous Broviac catheters. In addition to parenteral nutrition, antibiotics, aminophylline, and replacement fluids were infused. Total catheter days were 961, with an average of 44 days per catheter. Primary catheter sepsis occurred with two catheters (9%). Mechanical complications occurred with six catheters (exposed cuff, 1; catheter break, 2; catheter reposition, 1; catheter thrombosis, 1; dehiscence of cutdown site, 1). The incidence of catheter-related sepsis was acceptably low. The high incidence of mechanical catheter malfunction (6/22, 27%) resulted in minimal morbidity to the infant and could have been avoided by better operative technique, proper positioning intraoperatively, and meticulous care of the catheter post-operatively. We conclude that multipurpose long-term central venous access can be safely utilized with the Broviac catheter in infants less than 1,000 g.

Catheterization, Central Venous↗