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Biomedical subjects

M Walser

Publications and source records attributed to M Walser.

At least 109 records · Page 6Linked to original sources
PubMed1980

Failure of the normal ureagenic response to amino acids in organic acid-loaded rats. Proposed mechanism for the hyperammonemia of propionic and methylmalonic acidemia.

Propionic and methylmalonic acidemia are both known to be associated with hyperammonemia. Rats injected with 10 or 20 mmol/kg of propionate or 20 mmol/kg of methylmalonate, along with 1.5 g/kg of a mixture of amino acids, developed severe hyperammonemia, whereas rats administered the same dosages of acetate did not. In vitro, neither propionyl nor methylmalonyl CoA affected the activity of carbamyl phosphate synthetase I, ornithine transcarbamylase, nor the activation constant (K(A)) of carbamyl phosphate synthetase I for N-acetyl glutamate. Furthermore, rats injected with propionate showed no alteration of liver amino acid concentrations, which could explain impaired ureagenesis. Animals injected with methylmalonate showed an increase in both citrulline and aspartate, suggesting that argininosuccinic acid synthetase may also have been inhibited. Liver ATP levels were unchanged. Citrullinogenesis, measured in intact mitochondria from livers of injected animals, was reduced 20-25% by 20 mmol/kg of propionate or methylmalonate (compared with acetate). This effect was attributable to an impairment in the normal rise of liver N-acetyl glutamate content after amino acid injection. Thus, carbamyl phosphate synthetase I activation was reduced. Liver levels of acetyl CoA and free CoA were reduced. Levels of unidentified acyl CoA derivatives rose, presumably reflecting the accumulation of propionyl and methylmalonyl CoA. Thus, the principal mechanism for hyperammonemia induced by these acids is depletion of liver N-acetyl glutamate, which is in turn attributable to depletion of acetyl CoA and/or competitive inhibition by propionyl and methylmalonyl CoA of N-acetyl glutamate synthetase. Injection of methylmalonate may also have an additional inhibitory effect on argininosuccinic acid synthetase.

Acyl Coenzyme A↗
PubMed1980

Plasma alpha-ketoglutarate in urea cycle enzymopathies and its role as a harbinger of hyperammonemic coma.

Metabolic observations during early stages of hyperammonemia in two infants with ornithine transcarbamylase deficiency suggest that plasma alpha-ketoglutarate concentration ([alpha-KG]) becomes subnormal before the development of hyperammonemic coma. In one case, plasma [NH4+] remained normal until 40 days of age when it rose to 58 microM. However, this hyperammonemia was preceded by a fall in plasma [alpha-KG] to 15 microM at 27 days of age. It was only after severe hyperammonemia was established at 50 days of age that coma supervened. In the second case, plasma [alpha-KG] became subnormal (14 microM) 8 days before the rise in plasma ammonium concentration [NH4+] (52 microM) and 14 days before the onset of hyperammonemic coma. In eight patients with urea cycle enzymopathies, there was a highly significant (P less than 0.01) negative linear correlation between [NH4+] and [alpha-KG]. In patients with portal-systemic encephalopathy, there was a similar relationship between [NH4+] and [alpha-KG], although the absolute [alpha-KG] levels in these patients were normal (23 +/- 4 microM) while the patients were hyperammonemic (88 +/- 25 microM).

Adolescent↗
PubMed1980

The use of ornithine salts of branched-chain ketoacids in portal-systemic encephalopathy.

In eight patients with chronic portal-systemic encephalopathy who were symptomatic despite protein restriction and lactulose, a double-blind crossover comparison was conducted of branched-chain amino acids (68 mmol/d) versus ornithine salts of branched-chain ketoacids (34 mmol/d), both mixtures being administered orally for 7 to 10 days, after control periods, during a single hospitalization. Ornithine salts of branched-chain ketoacids markedly improved electroencephalographic abnormalities and clinical grade of encephalopathy; branched-chain amino acids had significantly lesser effects, which were of borderline statistical significance. To ascertain whether ornithine or branched-chain ketoacids were responsible for the improvement observed, we administered to six patients calcium salts of branched-chain ketoacids (34 mmol/d) after control periods; only slight improvement was seen.. Four patients received a daily dose of ornithine alpha-ketoglutarate containing the same quantity of ornithine; one did not change and three deteriorated rapidly. We conclude that the combination of ornithine and branched-chain ketoacids improves chronic portal-systemic encephalopathy more than its components given separately and more than branched-chain amino acids at twice the molar dose.

Adult↗
PubMed1979

Concentration-dependence of nonelectrolyte permeability of toad bladder.

A theoretical formulation was derived for the dependence of bulk solute permeability, P, defined as net flux divided by concentration gradient, delta c, across any membrane in which solute concentration is controlling for net flux, delta J. According to this formulation, delta J is stimulated by increments in trans concentration, c2, in the range c2/c1 equals 0.0--0.1. Net flux of urea across toad bladder down concentration gradients was shown to be stimulated threefold by small increments in trans urea concentration. The theory also predicts that, in the absence of concentration gradients, tracer permeability, P, defined as tracer flux divided by tracer concentration, will be independent of c provided that P equals P, but will diminish with increasing c if P/P less than 1.P/P was not significantly different from unity for urea, and both P and P were independent of c in the absence of concentration gradients. However, P/P was significantly less than unity (0.90 and 0.85) for thiourea and mannitol, respectively. In conformity with theory, P (and also P) of these two solutes, measured as c was increased by 3--4 orders of magnitude, diminished progressively. These effects are more consistent with this formulation than with transport via a saturable carrier.

Animals↗
PubMed1979

Effects of electrochemical gradients on active sodium transport in toad urinary bladder.

To determine the concentration dependence of active sodium transport in toad urinary bladder, bidirectional fluxes of sodium were measured at three mucosal sodium concentrations (Cm) (114, 27, and 3 mM), before and after addition of sufficient ouabain to eliminate active transport. The results permit estimation of E, the electromotive force of the sodium pump, and its conductance, ga. E averaged 137 mV and was unaffected by depolarization or by reduction of Cm; ga fell by only 40%, suggesting that a Cm of 3 mM was still above the half-maximal value for the sodium pump. However, net open-circuit transport was estimated to become zero at Cm = 6 mM, owing to backflux through the shunt path, which did not vary with Cm. The flux ratio in the active path exhibited the type of abnormality first described as "single-file pore diffusion," which is attributed to relatively tight coupling between transport and metabolism.

Animals↗
PubMed1979

Use of keto acids in inborn errors of urea synthesis.

Our experience with nitrogen-free analog therapy of these disorders indicates that these compounds are adequate nutritional supplements which are non-toxic and which promote mental and somatic growth. They prevent or reduce hyperammonemia for varying periods of time in three of these disorders, but as yet have not prevented hyperammonemic coma and death in infants with complete enzyme deficiencies. Further work wi-l be necessary to determine how impending hyperammonemic coma can be detected before it becomes irreversible, as asll as to improve the therapy of hyperammonemic coma when it develops.

Amino Acid Metabolism, Inborn Errors↗
PubMed1978

Type C botulism in American Foxhounds.

Diffuse lower motor neuron dysfunction developed in a group of American Foxhounds while they were hunting. Of 19 dogs, 10 became weak and 9 became quadriplegic. Three of the quadriplegic dogs died before treatment could be instituted. The remaining quadriplegic dogs recovered after being given supportive treatment, with (4 dogs) or without (2 dogs) trivalent (types A, B, E) botulinal antitoxin. The 10 dogs that were weak recovered without treatment. A markedly decreased amplitude of evoked potentials and increased chronaxy were found by electromyographic examination of 2 of the quadriplegic dogs. A toxic substance that was neutralized by type C botulinal antitoxin in mouse inoculation tests was in the serum and feces of the most severly affected dog presented alive and in a fecal extract of another affected dog. In the one dog necropsied, neither gross nor histologic lesions were found in the central or peripheral nervous systems or in the skeletal musculature. The history, clinical signs, electromyographic findings, toxin neutralization tests in mice, and absence of histologic abnormalities in the neuromuscular system provided evidence for the diagnosis of C botulism.

Animals↗
PubMed1978

Effect of branched-chain keto-acids and dietary protein content on the activity of branched-chain amino acid transferase in rat tissues.

Rats fed branched-chain keto-acids in place of branched-chain amino acids exhibited increased specific activity of branched-chain amino acid transferase (BATase) in muscle, intestine, brain and liver as compared with controls fed sufficient diet to achieve comparable weight gain. This increase was observed whether or not methionine and phenylalanine were also replaced by their N-free analogues. Kidney BATase was unaffected. Rats fed a protein-free diet exhibited higher BATase specific activity in kidney, brain, liver and intestine than rats fed diets containing 6% casein; but little change in specific activity in these organs was seen as casein intake was progressively increased from 6% to 18%. Muscle BATase specific activity was the same between 0 and 18% dietary casein. The results show that branched-chain keto-analogues augment BATase in several tissues, including muscle. In contrast, varying casein intake from 6% to 18% had little effect, although protein-feeding augments BATase in some organs.

Amino Acids↗
PubMed1978

A proposed mechanism for reduced creatinine excretion in severe chronic renal failure.

Creatinine appearance, defined as the sum of daily creatinine excretion in urine (average over 5 days) plus accumulation in body water, measured over the same interval, was calculated in 27 patients with severe chronic renal failure (creatinine clearance less than 0.15 liter/kg/day). Creatinine appearance per kg body weight in patients with the lowest clearances decreased to values as low as one third of values predicted from age and sex. The absolute value of measured cratinine accumulation was only 11 +/- 2% of creatinine appearance and thus could not account for such deficits in appearance and therefore renal excretion. One explanation for these results is that extrarenal clearance, CM, remains constant, that is, that the quantity of creatinine degraded, M, is proportional to serum creatinine, S: CM = M/S. When the values for extrarenal clearance necessary to account for the measured deficit in creatinine appearance were calculated, they were found to be quite constant: 0.042 +/- 0.004 liter/kg/day (SEM, n=13) in males and 0.041 +/- 0.004 liter/kg/day (SEM, n=14) in females. Renal creatinine clearance in these patients, predicted from age, sex, serum creatinine, and the assumed constant value for extrarenal clearance, corresponded closely to observed clearance (r = 0.93). From these calculations, decreased creatinine appearance (and excretion) of uremic patients may be explained by a constant extrarenal clearance, indicating degradation.

Adult↗
PubMed1977

Passive sodium fluxes across toad bladder in the presence of simultaneous transepithellal gradients of concentration and potential.

Bidirectional sodium fluxes were measured across toad bladder sacs after eliminating active transport with ouabain. Transepithelial potential was clamped to 100 mV or the Nernst potential, psieq, at varying sodium concentrations, Cm, in the mucosal medium. Serosal sodium concentration, Cs, was held constant. Equations were derived for permeability, partial ionic conductance, and unidirectional fluxes as functions of Cm and Cs, based in part on the assumption that the ratio, Q, of bulk sodium permeability to tracer sodium permeability is a constant, independent of concentration and potential. The results conformed closely to these equations.

Animals↗
PubMed1977

Nitrogen sparing induced early in starvation by infusion of branched-chain ketoacids.

The alpha-ketoanalogues of the branched-chain amino acids were administered to fasting subjects to determine whether or not they promoted nitrogen sparing. Two fasting studies were carried out in each subject. During the first week of one of the two fasts 4.7 g of a mixture of the alpha-ketoanalogues of valine, leucine, and isoleucine were infused daily. No infusions were administered during the other fast, which served as a control. Urinary urea and calculated total urinary nitrogen were significantly lower during both the week of infusions and the ensuing week of fasting after the infusions were discontinued. Immediately after ketoacid infusions, plasma branched-chain amino acids, including allosioleucine, rose, while alanine and several other amino acids (but not glutamine) fell. There were no differences between the two fasts with respect to ketone bodies, free fatty acids, glucose, insulin, or glucagon concentrations. We conclude that branched-chain ketoacids spare nitrogen early in fasting and that this effect persists after they are metabolized.

Adult↗