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Biomedical subjects

B D Ross

Publications and source records attributed to B D Ross.

At least 145 records · Page 8Linked to original sources
PubMed1984

Gluconeogenesis and phosphate reabsorption in isolated lactate- or pyruvate-perfused rat kidneys.

Recent experiments suggest that cytoplasmic free NAD inhibits renal phosphate reabsorption and that gluconeogenesis, by increasing NAD concentration, inhibits phosphate reabsorption. To examine these relationships further we measured phosphate reabsorption by isolated kidneys perfused with either lactate or pyruvate. Lactate perfusion increased the ratio of the cytoplasmic redox couple (glycerol-3-phosphate/dihydroxyacetone phosphate) in snap-frozen kidneys 3-fold relative to the ratio with pyruvate perfusion (p less than 0.001). Inulin clearance and fractional phosphate reabsorption were lower with lactate than with pyruvate perfusion. Phosphate reabsorption decreased throughout the lactate perfusion but was constant for 1 h of pyruvate perfusion. Basal and norepinephrine (NE)-stimulated gluconeogenesis were lower with lactate than with pyruvate perfusion. With lactate and pyruvate perfusions, NE induced equal increases in fractional sodium reabsorption, although only with pyruvate perfusion was there increased phosphate reabsorption. In these experiments, oxidative phosphorylation, not cytoplasmic free NAD concentrations, influenced phosphate reabsorption, and NE-stimulated gluconeogenesis was associated with increased phosphate reabsorption.

Absorption↗
PubMed1983

The impact of acetazolamide on renal ammoniagenesis and gluconeogenesis.

In view of recent reports suggesting that acetazolamide (ACZ) inhibits renal ammoniagenesis and the pentose phosphate pathway, its effects on renal metabolism were investigated with rat isolated perfused kidney and isolated cortical tubules. In the isolated kidney perfused with glutamine (2 mM) and glucose (5mM), ACZ (0.1 mM) resulted in a natriuresis and bicarbonate diuresis and decreased NH3 production from 1.72 to 1.35 mumol/min/gm dry weight (p less than 0.05). NH3 production was unchanged in control perfusions in which no inhibitor was added. With kidneys from acidotic animals perfused with glutamine (2 mM) without glucose, NH3 production was unaltered by ACZ but glucose production decreased from 0.93 to 0.20 mumol/min/gm (p less than 0.01). ACZ inhibited NH3 (14.2 to 12.6 mumol/min/gm, p less than 0.01) and glucose (1.6 to 1.2 mumol/min/gm, p less than 0.05) and stimulated glutamate (2.2 to 2.9 mumol/min/gm, p less than 0.01) production by isolated tubules from normal rats incubated with 2 mM glutamine and had similar effects with acidotic animals. Glucose production from malate was also inhibited. The increase in glutamate and decrease in glucose production from glutamine, as well as malate, suggest that ACZ inhibits ammoniagenesis by altering metabolism of the glutamate carbon skeleton rather than by affecting glutamyl transferase. Finally, these results emphasize that ACZ has definite effects on renal metabolism, which must be considered in interpreting studies using it to elucidate hydrogen ion transport.

Acetazolamide↗
PubMed1982

Energy metabolism and cellular pH in normal and pathological conditions. A new look through 31phosphorus nuclear magnetic resonance.

Cellular energetics can be studied non-invasively using 31P nuclear magnetic resonance (NMR). Besides the concentration of the major phosphorus-containing metabolites, enzyme-catalysed fluxes and intracellular pH can be obtained from the NMR measurement. Metabolic acidosis in the ischaemic myocardium has been studied in the perfused rat heart. Comparison of the pH, measured from the position of the inorganic phosphate (Pi) resonance, with the pH obtained from the resonance of 2-deoxyglucose 6-phosphate (accumulated after perfusion with 2-deoxyglucose) demonstrates that cytoplasmic pH values are being obtained. The pH changes during ischaemia are quantitatively related to the glycogen leads to lactate conversion. Preperfusion with insulin enhanced the lactate production but resulted in the maintenance of ATP for a longer period during ischaemia, even though acidosis was enhanced. In acute renal acidosis, the decrease in intracellular pH is smaller than might have been expected, as demonstrated in the perfused rat kidney. The importance of acidosis in relation to renal preservation was examined in human kidneys prior to transplantation. 31P NMR studies on human forearm muscle have been done. The pH changes measured during aerobic and anaerobic exercise demonstrate the importance of glycogenolysis in providing energy for ATP production. In a patient with suspected McArdle's syndrome, 31P NMR was used to detect the lack of glycogenolysis since during both aerobic and anaerobic exercise a pH rise was observed together with the rapid breakdown of phosphocreatine.

Acidosis↗
PubMed1982

Preliminary observations on the metabolic responses to exercise in humans, using 31-phosphorus nuclear magnetic resonance.

The new non-invasive method of 31P nuclear magnetic resonance (NMR) has been applied for the first time to human muscle. The metabolic response to exercise--a fall in intracellular pH, a fall in phosphocreatine content, and an increase in inorganic phosphate (Pi) content--occurs without any change in ATP content of the exercised muscle. Abnormal spectra occur in two myopathies examined to date: in McArdle's syndrome, pH rises during exercise, in contrast to the normal fall; and, in an unusual mitochondrial myopathy, Pi content is high, relative to phosphocreatine content, and in keeping with an excessive oxygen consumption in this patient. Intracellular pH reflected, in addition, the systemic pH of the subject; the anticipated abnormalities in muscle pH have been observed in association with lactic acidosis, renal failure and hyperventilation.

Acidosis, Respiratory↗
PubMed1982

Nonoxidative glucose metabolism a prerequisite for formation of dilute urine.

To examine links between norepinephrine- (NE) stimulated sodium transport and gluconeogenesis, we perfused isolated rat kidneys with 6% albumin, containing various combinations of glucose, alanine, pyruvate. and lactate and inhibitors of gluconeogenesis (0.1 mM mercaptopicolinate, MP) or glucose metabolism (0.2-0.5 mM 2-deoxyglucose, DG). Inulin clearance, fractional potassium reabsorption, total sodium reabsorption, and free water clearance were higher in kidneys perfused with 5 mM glucose plus 2 mM alanine than in kidneys perfused with either 10 mM lactate or 5 mM pyruvate. NE, added after 40 min of perfusion, decreased fractional sodium and potassium excretion in all experiments. In lactate- and/or pyruvate-perfused kidneys NE decreased fractional water excretion with little increase in free water clearance; free water formation was lowest in kidneys perfused with DG or MP. Glucose (5 mM) reversed the inhibitory effect of MP on free water clearance. In glucose-perfused kidneys NE did not decrease fractional water excretion, whereas free water clearance increased threefold. NE stimulated glucose production from pyruvate 2.4-fold and from lactate 1.6-fold. MP inhibited gluconeogenesis both in the basal state and after NE. We conclude that the formation of dilute urine requires nonoxidative glucose metabolism to maintain low water permeability in the diluting segment and a high peritubular glucose concentration that is ensured by gluconeogenesis in adjacent proximal tubules.

Animals↗
PubMed1982

Improved function with amino acids in the isolated perfused kidney.

When isolated rat kidneys are perfused with glucose as the only substrate, there is a progressive diminution in glomerular filtration rate and fractional reabsorption of sodium. This is most marked after 1 h. Renal glutathione content rapidly falls and is less than 30% of control levels after 1 h. Renal concentrating ability is markedly impaired and structural lesions are consistently observed in cells lining the thick ascending limb of Henle's loop. Addition of 20 physiologic amino acids including cysteine to the perfusate prevents the fall in renal glutathione, prevents the anatomical damage to ascending limb cells, permits GFR and fractional sodium reabsorption to remain high and close to their initial levels for as long as 4 h, and improves renal concentrating capacity. If amino acid supplementation is limited to three precursors of glutathione--cysteine, glycine, and glutamic acid--renal glutathione content is preserved and concentrating ability is improved, but GFR and fractional sodium reabsorption are not maintained as well as with comprehensive amino acid supplements. The results suggest that amino acid deficiency and glutathione depletion may contribute to disturbances in renal structure and function.

Absorption↗
PubMed1982

Redox state of cytochrome aa3 in isolated perfused rat kidney.

Optical spectroscopy was used to evaluate mitochondrial anoxia in the isolated perfused rat kidney by determining the percentage of cytochrome aa3 in the reduced state. Despite high levels of plasma flow (greater than 20 ml . g-1 . min-1) and venous PO2 (greater than 300 mmHg), 25--40% of cytochrome aa3 appeared to be in its reduced form. Agents that alter metabolism or transport primarily in renal cortex had little or no effect on the redox state of cytochrome aa3. These included 3-mercaptopicolinate, an inhibitor of gluconeogenesis; 2-tetradecylglycidic acid, an inhibitor of fat metabolism via carnitine-fatty acyltransferase, and acetazolamide. In contrast, a decrease in medullary transport induced by the loop diuretics bumetanide or furosemide produced an increase in cytochrome aa3 oxidation consistent with a decrease in transport-related oxygen consumption in the hypoxic area. The results suggest that substantial portions of the kidney, particularly in the renal medulla, may normally operate on the brink of anoxia despite high PO2 in artery and vein.

Animals↗
PubMed1981

Glutamate metabolism in malnutrition and sepsis in man.

The metabolism of intravenous glutamate has been studied for its usefulness as a nutrient in intravenous feeding regimens. Intravenously infused monosodium L-glutamate was rapidly removed from the blood with a half-life of 10.7 and 9.1 min in healthy control and malnourished septic patients, respectively. Under the same conditions, alanine was metabolized much more slowly, with a half-life of 35 min (1). After the infusion of glutamate, blood lactate fell and glucose was increased in the control patients but not in the sick patients. Blood pyruvate, ketone bodies, glutamine, aspartate and alanine levels did not change after the infusion of glutamate in either group of patients. Increased urinary excretion of aspartate was observed in the control patients following the infusion of glutamate, but in the sick patients there was an increased excretion of glutamine. Insulin concentration in the blood rose after the infusion of glutamate in the control patients but not in the sick patients. Although the glutamate half-life life was similar in the two groups of patients, glutamate was metabolized differently in the sick. Deamination predominates over transamination. We conclude that glutamate, in the amounts provided in intravenous feeding, is safe, although its effectiveness may be less than previously thought.

Adult↗
PubMed1981

Childhood mitochondrial myopathy with ophthalmoplegia.

A 14-year-old boy with mitochondrial myopathy is described, and the findings on muscle biopsy shown. He presented with mild weakness, and severe exercise intolerance; examination showed ptosis, external ophthalmoplegia and severe muscle wasting. There was a possible family history of a similar disorder. Metabolic study demonstrated severe lactic acidosis on exercise. Oxygen consumption was measured and found abnormally high at rest and on exercise. Biochemical study of extracted muscle mitochondria showed decreased respiratory rates with NAD-linked substrates. These and other results suggest the site of the defect to be in the electron transport chain. The possible significance of abnormally high oxygen consumption in the presence of such a defect is discussed.

Adolescent↗
PubMed1981

Selective distal nephron damage during isolated kidney perfusion.

The morphologic characteristics of the isolated perfused rat kidney were examined by light and electron microscopy. Following perfusion for 90 min, the cortex appeared normal except for the development of spaces in glomerular mesangial regions and ultrastructural abnormalities in very few proximal tubular cells. In the medulla, descending limbs of the loops of Henle and Collecting tubules appeared normal. During perfusion, however, even under optimal conditions, consistent and reproducible changes rapidly developed in cells of the thick ascending limb of Henle's loop, more specifically, in cells of the straight portion of the distal tubule in the inner stripe of the outer medulla. The changes became progressively more severe as perfusion continued and ranged from swelling of mitochondria at 15 min to complete cellular disruption by 90 min. Horseradish peroxidase added to the perfusion medium was found in and between damaged cells and in the interstitial tissue adjacent to affected areas. The pathogenesis of these selective medullary distal tubular abnormalities may relate to the specialized functional activity of this segment of the nephron. Such abnormalities may contribute to the specific functional defects of the preparation.

Animals↗
PubMed1981

The role of intrarenal pH in regulation of ammoniagenesis: [31P]NMR studies of the isolated perfused rat kidney.

1. [31P]NMR spectra were obtained from a functioning isolated perfused rat kidney with the aim of determining intrarenal pH in acute acidosis. 2. Signals from intracellular inorganic phosphate could be observed in the absence of phosphate in the perfusion medium. Under these conditions renal ATP and inorganic phosphate content fell by 30% but total adenine nucleotide and phosphorylation potential ATP/ADP x Pi were unchanged compared with kidneys perfused with phosphate-containing medium. In addition, G.F.R., Na+ reabsorption and ammonia formation from glutamine remained normal. Ammonia production increased 93%, urine pH fell to 5.8 +/- 0.1 and kidney 2-oxoglutarate content fell by 80% upon acidification of the perfusion medium from pH 7.4 to pH 6.9, findings identical with those obtained in controls (Ross & Tannen, 1979). 3. [31P]NMR spectra of the isolated perfused rat kidney showed a pattern of adenine nucleotides and a small concentration of phosphocreatine, Intra-renal pH was measured from the resonance position of intracellular inorganic phosphate and in perfusions with pH 7.4 buffer was 7.19 +/- 0.10 (n = 11). 4. Acidification of the perfusion medium to pH 7.0 resulted in 0.3 pH unit fall in intrarenal pH. This fall in total intrarenal pH is insufficient to explain the fall in 2-oxoglutarate concentration observed if the glutamate-dehydrogenase-equilibrium model is invoked. 5. The line-width of the NMR signal is compatible either with heterogeneity of intra-renal pH or the existence of a pH gradient between cytosol and mitochondria, or both.

Acidosis↗