Search PubMed⌕ Search

Biomedical subjects

M Walser

Publications and source records attributed to M Walser.

At least 55 records · Page 3Linked to original sources
PubMed1990

Utilization for protein synthesis of leucine and valine compared with their keto analogues.

Fasting rats were given [3H]leucine plus [14C]2-ketoisocaproate or [3H]valine plus [14C]2-ketoisovalerate, plus 33 micromol of each compound. The ratio of 14C to 3H (R) in protein 6 h after injection of these isotopes is a measure of the extent to which extracellular keto acid, as compared with extracellular amino acid, serves as the source of the intracellular amino acid used for protein synthesis. R for 2-ketoisocaproate (KIC) vs leucine was 0.45 +/- 0.03 for whole body protein after oral injection and 0.83 +/- 0.02 after iv injection. R values for 2-ketoisovalerate (KIV) vs valine were similar. R, measured in the protein of various organs and in albumin, fibrin, and globin, varied more than twofold. We conclude that at least half of KIC and KIV given orally in this dosage is oxidized in splanchnic organs during first pass but that, nevertheless, these keto acids given orally serve as significant sources of the intracellular amino acids used for protein synthesis in most organs, particularly brain and heart.

Animals↗
PubMed1990

Comparison of the fates of ingested leucine and ingested 2-ketoisocaproate in rats.

We previously reported that the ratio, R, of 14C to 3H in the leucine of whole body protein, measured 6 h after ingestion of [3H]leucine and [1-14C]2-ketoisocaproate is equal to ratio of the dose of leucine to the dose of 2-ketoisocaproate (KIC) (on a leucine-free diet) required to achieve the same rate of growth. To determine whether R is dependent on the interval between injection and sampling, R was measured at intervals in purified whole body protein after oral injection of these isotopes in groups of rats; it was constant from 1 h onward for 1 wk, averaging 0.64 +/- 0.01 (means +/- SEM). Thus, the extent of incorporation into the leucine of whole body protein of ingested KIC remains close to 64% of the incorporation of ingested leucine administered as such simultaneously, from 1 h onward for at least 1 wk.

Animals↗
PubMed1990

Estimation of whole body protein synthesis from oxidation of infused [1-14C]leucine.

In rats infused with NaH14CO3, 14CO2 exhalation approached an asymptotic rate equal to 96.0 +/- 1.3 (SD) % of the infusion rate of 14C in a monoexponential manner with a half-time of 20 min. In rats infused with [1-14C]leucine, 14CO2 exhalation (/0.96) approached an asymptotic value, (1-F), of 16-25% of 14C infusion rate (mean 20.4%) in a monoexponential manner with a half-time of approximately 31 min. Whole body protein synthesis (S) was calculated from 1-F and urea N plus ammonia N excretion (C) as S = CF/(1-F). S was a uniform function of body weight in these rats, in six additional rats in which S was measured 6 h after single intravenous injection of [1-14C]leucine and also in previously reported rats given single injections. The relationship was S (mg.100 g-1.h-1) = 11-0.143 body wt (g) +/- 8.3. In six of these rats, S was also estimated from the plateau specific activity of plasma leucine or plasma 2-ketoisocaproate (KIC); the former estimate of S was significantly lower (by an average of 17%), but S was the same when specific activity of KIC was employed. These results support the validity of the expired 14CO2 technique for measuring S.

Ammonia↗
PubMed1990

Nitrogen sparing by 2-ketoisocaproate in parenterally fed rats.

In rats receiving total parenteral nutrition with or without sodium 2-ketoisocaproate (KIC; 2.48 g.kg-1.day-1), L-[1-13C]leucine and [1-14C]KIC were constantly infused for 6 h. CO2 production, 14CO2 production, 13CO2 enrichment, urinary urea nitrogen (N) plus ammonia N and total urinary N were measured. Whole body protein synthesis (S) was calculated in non-KIC-infused rats and also in unfed rats infused with [1-14C]leucine from fractional oxidation of labeled leucine (1-F), where F is fractional utilization for protein synthesis, and urea N plus ammonia N excretion (C) as S = C x F/(1-F). Addition of KIC caused a significant reduction in N excretion and a significant improvement in N balance. Fractional oxidation of labeled KIC increased, whereas fractional utilization of labeled KIC for protein synthesis decreased, but the extent of incorporation of infused KIC into newly synthesized protein (as leucine) amounted to at least 40% of the total rate of leucine incorporation into newly synthesized whole body protein. We conclude that addition of KIC spares N in parenterally fed rats and becomes a major source of leucine for protein synthesis.

Amino Acids↗
PubMed1989

Utilization for protein synthesis in individual rat organs of extracellular 2-ketoisocaproate relative to utilization of extracellular leucine.

Rats were given constant intravenous infusions of [3H]-leucine plus [1-14C]-2-ketoisocaproate (KIC). Specific activities of plasma leucine and plasma KIC reached plateaus by two to three hours. 3H specific activity of KIC was 85% +/- 2% of that in leucine. 14C specific activity of leucine was 36% +/- 2% of that in KIC. The 14C/3H ratios in leucine and KIC were constant from the earliest sampling time (one hour) at 0.65 +/- 0.03 and 2.20 +/- 0.07, respectively. In various tissues, 14C/3H in free leucine and in tissue protein were approximately equal, but in most organs these ratios were significantly greater than the ratio 14C/3H in plasma leucine. From these data we estimate that the fraction of leucine incorporated into protein in individual organs derived from extracellular KIC rather than extracellular leucine varies from zero (in liver and bone marrow) to 35% to 45% (in brain and heart), and comprises 12% in the body as a whole.

Animals↗
PubMed1989

Branched-chain-ketoacid metabolism in patients with chronic renal failure.

Branched-chain ketoacids (BCKAs) were determined in fasting plasma samples from 19 patients with chronic renal failure (CRF). Ketomethylvalerate (KMV) was significantly higher in patients receiving BCKA supplements, presumably reflecting accumulation of the R(-) isomer. Mean levels of all three BCKAs were not significantly different from normal. However, multiple-regression analysis showed that plasma ketoisocaproate was strongly correlated with glomerular filtration rate (GFR), negatively correlated with serum triglyceride concentration, and positively correlated with protein intake. KMV concentration was also correlated positively with GFR, negatively with triglyceridemia, and positively with serum total carbon dioxide. Ketoisovalerate concentration did not vary with GFR and was not predictable from the regressors used. Single oral doses of a mixture containing all three BCKAs led to the same areas under the three plasma concentration curves in patients with CRF as in normal subjects, indicating that absorption of all three BCKAs after oral administration in patients with CRF is unimpaired.

Adult↗
PubMed1989

Reciprocal creatinine slopes often give erroneous estimates of progression of chronic renal failure.

In 10 of 22 observation periods (lasting an average of 15 months) in 17 patients with moderate to severe chronic renal failure (GFR 4 to 23 ml/min), rates of progression as estimated from the linear regression on time of reciprocal plasma creatinine concentration (multiplied by average 24 hr creatinine excretion) (b2) differed significantly from rates of progression as estimated from the regression on time of urinary clearance of 99mTc-DTPA (b1), during all or part of the period of observation, b2 exceeded b1 in six cases and was less than b1 in the other four. Owing to these changes, measurements of reciprocal creatinine concentration gave erroneous impressions of the rate or existence of progression, during all or a portion of the period of observation, in nearly half of these patients. However, in the 22 studies as a group, using the entire periods of observation, b2 indicated nearly the same mean rate of progression as b1, and had the same variance. We conclude that sequential plasma or serum creatinine measurements in individual patients are often misleading as measures of progression and should, when feasible, be replaced by urinary clearances of isotopes in following patients with chronic renal failure.

Creatinine↗
PubMed1988

Effect of ketoleucine treatment on atrophy of skeletal muscle.

There is a net loss of skeletal muscle protein in muscle-wasting disorders including the muscular dystrophies and denervation atrophy. Regardless of the nature of the underlying defect, a treatment that could reduce the rate of muscle protein degradation may be of therapeutic value in these conditions. Ketoleucine (alpha-ketoisocaproic acid) has been reported to reduce the rate of protein degradation in skeletal muscle. To evaluate ketoleucine's therapeutic potential, we studied its effect on the muscle protein loss that follows denervation in rats. Maximum tolerated doses of ketoleucine were administered twice daily to rats after surgical denervation of one leg. Wet weights and noncollagen proteins of the soleus and extensor digitorum longus muscles were measured. The ketoleucine-treated animals failed to show significant decrease in muscle wasting, compared with nontreated denervated controls. Further, urinary 3-methylhistidine excretion, a putative measure of muscle breakdown, was not reduced in ketoleucine-treated animals. Our findings do not support the suggested therapeutic role for ketoleucine in muscle-wasting disease.

Animals↗
PubMed1988

Rate of whole-body protein synthesis in the rat as calculated from fractional oxidation of leucine, valine, or methionine.

In the steady state, the ratio of the rate of utilization for whole-body protein synthesis of any essential amino acid to its rate of oxidation should be the same as the ratio of the peak fraction of a dose of tracer incorporated into protein (F) to the fraction oxidized (1-F) provided that negligible tracer remains in the free amino acid pool or remains unabsorbed in the gut. The total rate of amino acid catabolism (C) can be estimated from the rate of urinary excretion of urea nitrogen (N) plus ammonia N. Hence the rate of whole-body protein synthesis (S) can be estimated as CF/(1-F). This method, which is not new, was explored as follows: (1) Radioactivity in the leucine of whole-body protein of rats after intravenous (IV) injection of labeled leucine was shown to plateau from three to nine hours. (2) The fractions of labeled leucine, valine, and methionine remaining in the gut six hours after enteral injection were 1.2 +/- 0.4% (SD), 1.2 +/- 0.4%, and 7.1 +/- 2.9%, respectively; thus, enterally administered methionine cannot be used for this purpose. (3) Oxidation of [1-14C]-labeled leucine or valine, measured from 14CO2 excretion, was found to be the same whether these isotopes were given IV or enterally. (4) Negligible radioactivity remained in the free leucine of plasma within one hour after injection of labeled leucine.(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithms↗
PubMed1988

Creatinine measurements often yielded false estimates of progression in chronic renal failure.

In 9 of 22 observation periods (lasting an average of 15 months) in 17 patients with moderate to severe chronic renal failure (GFR 4 to 23 ml/min), rates of progression as estimated from the linear regression on time of 24-hour creatinine clearance (b1) differed significantly from rates of progression as estimated from the regression on time of urinary clearance of 99mTc-DTPA (b2), during all or part of the period of observation. b1 exceeded b2 in four cases and was less than b2 in the other five. Thus there were gradual changes in the fractional tubular secretion of creatinine in individual patients, in both directions. Owing to these changes, measurements of creatinine clearance gave erroneous impressions of the rate or existence of progression during all or a portion of the period of observation in nearly half of these patients. In the 22 studies as a group, using the entire periods of observation, b1 indicated significantly more rapid progression (by 0.18 +/- 0.06 ml/min/month, P less than 0.01) than did b2, and had a significantly greater variance. Measurements of progression based on the rate of change of reciprocal plasma creatinine (multiplied by an average rate of urinary creatinine excretion in each study) were equally misleading, even though less variable. We conclude that sequential creatinine measurements are often misleading as measures of progression and should, when feasible, be replaced by urinary clearance of isotopes in following patients with chronic renal failure.

Creatinine↗
PubMed1988

Progression of chronic renal failure is related to glucocorticoid production.

Progression of chronic renal failure during 35 treatment periods in 27 patients was measured as the rate of change of bimonthly radioisotope GFR for an average of 15 months. Treatments were comprised of: (1) mild protein restriction; (2) more severe protein and phosphorus restriction plus essential amino acids; or (3) the same diet plus ketoacids. Progression was significantly (P less than 0.025) correlated with urinary 17-hydroxycorticosteroid excretion in all three treatment groups; overall r was 0.78 (P less than 0.0001). Multiple regression analysis showed that the following factors were not additional significant determinants of progression: urea N excretion, phosphate excretion, protein excretion, serum calcium times phosphorus product, serum alkaline phosphatase, serum uric acid, serum triglycerides, serum cholesterol, etiology, mean arterial pressure, or enalapril treatment. However, when urinary 17-hydroxycorticosteroid excretion was factored by GFR (with which it was correlated), additional significant regressors appeared: serum triglycerides and polycystic kidney disease, which tended to be associated with more rapid progression, and ketoacid treatment, which tended to be associated with slower progression. Mean 17-hydroxycorticosteroid excretion differed significantly between the three treatment groups, in the order (1) greater than (2) greater than (3) (though not when factored by GFR). Changing from essential amino acids to ketoacids (or vice versa) without change in diet was associated with lower 17-hydroxycorticosteroid excretion on ketoacids (but not when factored by GFR).(ABSTRACT TRUNCATED AT 250 WORDS)

17-Hydroxycorticosteroids↗
PubMed1988

Utilization for protein synthesis of 2-ketoisocaproate relative to utilization of leucine, as estimated from exhalation of labelled CO2.

1. We have previously shown that the ratio (RWBP) of incorporation of label from 2-ketoisocaproate (KIC) into the leucine of whole-body protein to the simultaneous incorporation of label from leucine itself into protein is a measure of the nutritional efficiency of KIC as a substitute for leucine. 2. In order to determine whether RWBP can be estimated indirectly from measurement of labelled CO2 excretion, rats were injected orally or intravenously with [4,5-3H]leucine and either [1-14C]leucine or [1-14C]KIC. Expired CO2 was collected for 6 h. 3. The results show that 9-14% of KIC underwent first-pass oxidation after oral administration. When isotopes were given intravenously, the mean rate of excretion of 14CO2 from KIC, after 20 min, remained 1.8 times the mean rate of excretion of 14CO2 from leucine. 4. Mean RWBP, measured in whole-body protein in rats given isotopes orally or intravenously along with small or large doses of carriers, was the same as mean RWBP estimated from mean cumulative CO2 excretion. 5. We conclude (1) that nutritional efficiency of KIC relative to leucine can be estimated from measurement of labelled CO2 excretion, and (2) that the relative inefficiency of KIC as a substitute for leucine in the rat is attributable to first-pass oxidation of 9-14% (when given orally) and 80% greater susceptibility to systemic oxidation than leucine.

Animals↗
PubMed1988

Radioisotopic measurement of glomerular filtration rate in severe chronic renal failure.

In order to determine the best method for routine measurement of glomerular filtration rate (GFR) in severe renal failure, we compared simultaneously the urinary clearances of [99mTc] diethylenetriaminepentaacetic acid (DTPA) (UD), [125I]iothalamate (UI), 24-hr creatinine clearance (UC) and plasma clearance of [99mTc]DTPA (PD), based on three plasma samples. In 60 studies in 22 patients with serum creatinine values of 2 to 8 mg/dl, UD and UI were almost identical: UD = 0.358 +/- 0.976 UI +/- 0.87 ml/min, r = 0.990. However, PD overestimated UD by a large and variable extent: PD = 11.3 +/- 0.843 UD +/- 5.5 ml/min, r = 0.694, and was inconsistent in sequential measurements in individual patients. UC also overestimated urinary isotope clearance: UC = 4.2 + 0.95 UI +/- 3.9 ml/min, r = 0.865. Sequential measurements of GFR in five patients with severe but stable renal failure (mean GFR 5.9 ml/min) showed an average standard deviation of only 0.83 ml/min. Thus both UD and UI appear to be reliable and precise measures of GFR in severe renal failure.

Female↗
PubMed1987

Measurement of branched-chain ketoacids in plasma by high-performance liquid chromatography.

Branched-chain ketoacids were isolated from plasma or serum samples by acidification, passage through a cationic exchange resin, ether extraction, and extraction of the ether layer with phosphate buffer. The recovery of 2-[1-14C]ketoisocaproate taken through these procedures averaged 95 +/- 3%. Branched-chain ketoacids were measured by high-performance liquid chromatography using a single mobile phase (sodium phosphate:acetonitrile). In normal human subjects, mean +/- SD fasting levels of 2-ketoisocaproate, 2-keto-3-methylvalerate, and 2-ketoisovalerate were 29 +/- 8, 18 +/- 4, and 12 +/- 3 microM, respectively. In normal rats, slightly different results were found: 24 +/- 10, 19 +/- 7 and 17 +/- 6 microM, respectively. In both species, levels of each ketoacid expressed as fractions of total branched-chain ketoacids were much less variable.

Animals↗
PubMed1987

Progression of chronic renal failure in patients given ketoacids following amino acids.

Twelve patients with chronic renal failure who exhibited a progressive decline in 24-hour creatinine clearance, despite being given for 2 to 10 months a diet containing 0.3 g per kg ideal weight of protein and 7 to 9 g mg per kg ideal weight of phosphorus, supplemented with vitamins, CaCO3, and 10 g per day of essential amino acids, were changed to a supplement containing predominantly ketoacids. In six patients whose serum creatinine was 7.5 mg/dl or greater at changeover, progression continued unabated. In six patients with serum creatinine levels at changeover of 6.6 to 7.4 mg/dl, one was non-compliant with the diet and progressed to dialysis. In the other five, progression, measured as the rate of change of a bimonthly radioisotope clearance, has been undetectable during the ensuing one to two years. There has been no change in urea appearance, blood pressure, phosphaturia or proteinuria. Nutrition has been maintained. Thus this ketoacid supplemented regimen apparently halted the progression of moderately-severe chronic renal failure for at least a year in a small group of patients in whom restriction of protein and phosphate intake without ketoacids failed to halt progression. In more severe renal failure, no effect on progression was seen.

Adult↗
PubMed1987

Progression of chronic renal failure in patients given keto acids following amino acids.

Twelve patients with chronic renal failure who exhibited a progressive decline in 24-h creatinine clearance despite being given, for 2-10 months, a diet containing 0.3 g of protein/kg ideal weight and 7-9 mg of phosphorus/kg ideal weight supplemented with vitamins, CaCO3, and 10 g per day of essential amino acids, were changed to a supplement containing predominantly keto acids. In 6 patients whose serum creatinine levels were 7.5 mg/dl or greater at changeover, progression continued unabated. In 6 patients with serum creatinine levels at changeover of 6.5-7.4 mg/dl, one was non-compliant with the diet and progressed to dialysis. In the other 5, progression, measured as the rate of change of a bimonthly radioisotope clearance, has been undetectable during the ensuing 1-2 years.

Amino Acids, Essential↗