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Biomedical subjects

R C Mühlbauer

Publications and source records attributed to R C Mühlbauer.

At least 19 recordsLinked to original sources
PubMed1995

The diurnal rhythm of bone resorption in the rat. Effect of feeding habits and pharmacological inhibitors.

Prevention of low bone mass is important to reducing the incidence of osteoporotic fractures. This paper shows that, in rats, bone mass can be increased by feeding habits per se. Using six-hourly urinary excretion of [3H]tetracycline from prelabeled rats to monitor bone resorption, we previously found a peak of bone resorption following food administration. We now demonstrate that dividing the solid and liquid intake into portions blunts this peak and leads to a decrease in 24-h bone resorption to the level observed in thyroparathyroidectomized animals. Calcium balance increases and, when such feeding schedules are imposed for 30 d, bone mass increases. Dividing the intake is not effective in thyroparathyroidectomized animals, indicating the importance of PTH and/or calcitonin. Administration of calcitonin inhibits practically only the peak of bone resorption, suggesting that it is osteoclast mediated. In contrast, treatment with a bisphosphonate reduces basal bone resorption without a specific effect on the peak, indicating a fundamentally different mechanism of action. This is also supported by the finding that their combined effects are additive. Whether bone mass in humans is also under the control of dietary habits is not known. If so, an increased meal frequency may be used to prevent osteoporosis.

Animals↗
PubMed1994

Evaluation of urinary pyridinium crosslink excretion as a marker of bone resorption in the rat.

The aim of this study was to evaluate the value of the urinary excretion of the pyridinium crosslinks, pyridinoline (Pyr) and deoxypyridinoline (D-Pyr), as markers of bone resorption in the rat. The excretion of the crosslinks was compared with that of urinary [3H]tetracycline ([3H]TC) excretion from chronically [3H]TC-prelabeled animals, a technique established to monitor bone resorption in the rat. Bone resorption was modulated by Ca restriction, infusion of PTH, thyroparathyroidectomy, and administration of different bisphosphonates. Furthermore, the urinary crosslinks were assessed in three different osteopetrotic mutations in the rat. We found a delayed response of Pyr and D-Pyr excretion to acute changes in bone resorption compared with [3H]TC excretion. This delay was 1 day after Ca restriction and longer after other treatments, such as PTH administration or bisphosphonate treatment, with which it was more than 3 weeks. In contrast, chronic states with stimulation or inhibition of bone resorption showed similar changes in excretion of the urinary crosslinks and [3H]TC, except after PTH administration. The excretion of the crosslinks was greatly reduced in osteopetrotic rats (op/op, tl/tl, and ia/ia) and increased to normal levels in tl/tl rats after stimulation of bone resorption by M-CSF administration. These results suggest that, in rats, urinary excretion of the pyridinium crosslinks reflects bone resorption in chronic but not always in acute conditions. The cause of this discrepancy is still unclear.

Amino Acids↗
PubMed1991

BM 21.0955, a potent new bisphosphonate to inhibit bone resorption.

A total of 300 new bisphosphonates were screened for their effect on bone resorption in the rat. Among these, 1-hydroxy-3-(methylpentylamino)propylidenebisphosphonate (BM 21.0955) was selected for detailed investigation. It inhibited arotinoid-stimulated bone resorption as assessed by calcemia in thyroparathyroidectomized rats at a SC dose as low as 0.001 mg P (0.016 mumol) per kg body weight per day. The compound was thus about 2, 10, 50, and 500 times more potent than risedronate, alendronate, pamidronate, and clodronate, respectively. Intravenous administration was as effective as subcutaneous, and oral administration was 100 times less effective. The effect after one administration decreased with time but was still measurable after 2 weeks. Nonstimulated bone resorption assayed by the urinary excretion of radiolabeled tetracycline from lifelong prelabeled animals was also inhibited. This effect started 3 days after a single dose and was still maximal after 7 days. Histomorphometric analysis of the tibial metaphysis in growing intact rats also showed an inhibition of bone resorption along with an increase in bone mass. The number of osteoclasts increased in animals treated with 0.01 and 0.1 mg P per kg (0.16 and 1.6 mumol/kg) body weight SC but decreased in animals given 1 mg P per kg (16.1 mumol/kg), showing that the inhibition of bone resorption was not due to an inhibition of osteoclast recruitment. No inhibition of mineralization occurred. This new bisphosphonate appears to have great potential for use in human bone disease.

Alendronate↗
PubMed1991

Sodium EDTA enhances intestinal absorption of two bisphosphonates.

Bisphosphonates are poorly absorbed when given orally and their absorption is subject to a large inter- and intraindividual variability. This poor absorbability is thought to result, at least in part, from formation of unabsorbable complexes with calcium. It was therefore investigated whether the calcium chelator EDTA could improve intestinal absorption of two bisphosphonates, 4-amino-1-hydroxybutylidene-1,1-bisphosphonate (AHBuBP), and dichloromethylenebisphosphonate (Cl2MBP). Absorption was assessed indirectly by measuring the suppression of hypercalcemia induced in thyroparathyroidectomized rats by a retinoid. The absorption of AHBuBP was in the range of 1-3%. EDTA increased absorption about tenfold at a AHBuBP dose of 0.6 mg P/kg and about twofold at lower doses, with the minimal effective dose of EDTA being 10 mg/kg. The absorption of Cl2MBP was also increased by EDTA, although to a smaller extent, the lowest effective dose being 100 mg/kg EDTA. Thus, EDTA can, in certain circumstances, increase the intestinal absorption of bisphosphonates. The mechanism might involve an increase in available bisphosphonate and a change in mucosal permeability. The amount of EDTA required is, however, too high for use clinically.

Administration, Oral↗
PubMed1991

Abnormal renal glucose handling in X-linked hypophosphataemic mice.

1. The renal handling of glucose was determined in male X-linked hypophosphataemic (Hyp/Y) mice and in control littermates (+/Y) aged 4 months. Plasma glucose concentration and urinary glucose excretion were measured before and during stepwise increase in glycaemia induced by an acute infusion of glucose. The relationship between plasma glucose concentration and urinary glucose excretion was monitored per ml of glomerular filtrate in mice fed high and low phosphate diets. 2. Hyp/Y mice fed the high phosphate diet showed a significantly higher glucosuria compared with +/Y littermates. When glycaemia was increased, Hyp/Y mice developed frank glucosuria earlier than +/Y animals. In Hyp/Y mice we could not find a threshold below which virtually no glucose was excreted in the urine, whereas this was clearly visible in +/Y mice. These differences persisted in animals fed the low phosphate diet. 3. Using the acute response to the glucoregulatory hormones, glucagon and insulin, administered exogenously, we found that the regulation of plasma glucose concentration did not differ between Hyp/Y and +/Y mice. 4. The significantly lower plasma glucose concentration observed in Hyp/Y as compared with +/Y mice decreased further during fasting. 5. We conclude that the renal reabsorptive capacity for glucose is defective in Hyp/Y mice and their low plasma glucose concentration may be explained by the renal leak. Therefore the X-linked phosphataemic mouse appears not only to be characterized by a defect in renal phosphate and calcium reabsorption but also by an altered glucose reabsorption.

Animals↗
PubMed1990

A method for continual monitoring of bone resorption in rats: evidence for a diurnal rhythm.

A method has been developed to monitor bone resorption (BR) based on the urinary excretion of [3H]tetracycline ([3H]TC) from chronically prelabeled rats. This is possible because the [3H]TC released from bone has been found to be in a form that is not or only poorly bound to apatite and thus not reincorporated into newly formed bone. When BR was increased by means of dietary calcium restriction, parathyroid hormone (PTH) infusion, or retinoid injections, urinary [3H]TC doubled. When BR was inhibited by feeding calcium supplements or administration of dichloromethylenebisphosphonate, [3H]TC excretion dropped by two-thirds. Thyroparathyroidectomy inhibited [3H]TC excretion by one-third. The results obtained with this technique are therefore similar to those obtained with other methods such as 45Ca kinetics. The effect of dietary manipulations on BR was detected within 6 h of changing diet. Furthermore, a strong diet-dependent but PTH- and calcitonin-independent diurnal rhythm in BR was found. By use of this technique, bone resorption can be assessed continuously over long periods, and the acute regulation of bone resorption can be studied for the first time.

Animals↗
PubMed1990

Inverse relation between plasma inorganic phosphate and phospholipids in mice: effect of dietary inorganic phosphate, fasting and glucagon.

We measured in mice under various conditions plasma phospholipids (PlipPl), total phosphate (PtotPl), inorganic phosphate (PiPl), and calculated other phosphate-containing material (PXPl) by subtracting (Plip + Pi)Pl from PtotPl. In mice fed low Pi diet (LPD) for 10 days, PlipPl was higher, PxPl did not change, whereas PiPl and PtotPl were lower than under high Pi diet (HPD). A highly significant inverse correlation was found between PlipPl and PiPl. The effect on PlipPl of maneuvers known to change PiPl acutely (within hours) was then investigated. In LPD mice, 6 h fasting, which increases PiPl, led to a decrease of PlipPl without significant changes of PtotPl and PxPl. The conspicuous rise in PiPl observed with glucagon treatment was associated with a decrement of PlipPl of the same magnitude as the increase in PiPl without a change of PtotPl or PxPl. Finally, injection of Pi lowered PlipPl in a dose-dependent manner within 2 h. In mice fed HPD, PlipPl decreased similarly during all acute maneuvers described under LPD, except Pi injection, where it did not decrease. In conclusion, the effects described above would suggest that the regulation of the two phosphate species may be linked and that PlipPl may possibly be involved in Pi homeostasis.

Animals↗
PubMed1988

Tumor necrosis factor alpha and interleukin-1 stimulate bone resorption in vivo as measured by urinary [3H]tetracycline excretion from prelabeled mice.

Tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) have been shown to stimulate bone resorption in vitro. We have now investigated whether these cytokines also cause a similar action when administered in vivo. This was made possible by the adaptation of a newly developed technique that enables the continual assessment of bone resorption in vivo in mice by measuring urinary excretion of 3H from [3H]tetracycline-prelabeled animals. Experiments using maneuvers known to influence bone resorption, such as a change in dietary calcium or administration of parathyroid hormone or dichloromethylenebisphosphonate, indicate that the technique is reliable and sensitive in mice. Daily intravenous administration of either recombinant human or recombinant murine TNF-alpha, as well as subcutaneous administration of recombinant human IL-1 alpha, were found to stimulate bone resorption in a dose-dependent manner. The effect was maximal within 2 days. Thus, exogenous TNF-alpha and IL-1 alpha can stimulate bone resorption in vivo, suggesting that these cytokines may also exert a systemic effect on bone.

Animals↗
PubMed1987

Effects of glucagon on renal and extrarenal handling of inorganic phosphate in mice: evidence for inorganic phosphate mobilizing activity.

Glucagon administration is known to increase urinary inorganic phosphate (Pi) excretion. We have now confirmed that this effect also occurs in mice. While, at lower glucagon doses, phosphaturia was accompanied by a decrease in plasma Pi, at the highest dose of glucagon plasma Pi was not altered in spite of a massive increase in urinary Pi. This suggested that glucagon may additionally have another effect on phosphate homeostasis, i.e. of mobilizing Pi from body stores. In order to distinguish between the renal and extrarenal effects of glucagon, the animals were fed a low-phosphate diet, a procedure known to blunt the effect of several phosphaturic agents. Under these conditions, any Pi mobilized from body stores should be reflected by an increment of plasma Pi. Glucagon phosphaturia was indeed blunted under this condition. Furthermore, plasma Pi increased spontaneously by 0.82 +/- 0.14 mmol/l (mean +/- SEM) in an experimental period of 8 h during which the mice were fasted. In mice injected with zinc-protamine-glucagon subcutaneously at 4 and 16 micrograms/g of body weight, plasma Pi increased by 1.45 +/- 0.17 and 2.38 +/- 0.14 mmol/l during 8 h, respectively. Thus, it appears that exogenous glucagon is a strong Pi-mobilizing hormone. Furthermore, during the recovery phase following insulin-induced hypoglycemia, in which glucagon is thought to play a primordial role, a similar Pi mobilization to that obtained after glucagon administration was observed. Thus, since glucagon is released during fasting to maintain the homeostasis of blood glucose, it is conceivable that the mobilization of Pi induced by fasting might also have been caused by endogenous glucagon and that this hormone might be involved in Pi homeostasis.

Animals↗
PubMed1984

Abnormal hyperphosphatemic response to fasting in X-linked hypophosphatemic mice.

It has been proposed that renal inorganic phosphate (Pi) transport adaptation is a prerequisite for the hyperphosphatemic effect of fasting in animals previously fed low Pi diet (LPD). To test the validity of this proposal we have used X-linked hypophosphatemic (HYP) mice, since these animals are unable to adapt their renal Pi transport to LPD. HYP and control mice were pair-fed either high Pi diet (HPD) or LPD for 9 days. Then the influence of 24-hour fasting on plasma and urine Pi was studied. In the HPD condition, fasting led to a decrease in plasma Pi concentration, [Pi]P1, in both control and HYP mice. In the LPD condition fasting markedly increased [Pi]P1 from 1.61 +/- 0.13 mmol/l (mean +/- SEM, n = 8) to 2.33 +/- 0.05 mmol/l (n = 8, p less than 0.001) in control mice. In sharp contrast, in HYP mice fed LPD [Pi]P1 tended to decrease from 1.17 +/- 0.10 (n = 7) to 0.91 +/- 0.12 mmol/l (n = 7). As estimated from 24-hour urinary Pi excretion the mobilization of Pi from body stores was not different in HYP as compared to control mice fed either LPD or HPD. In conclusion, the results of this study support the hypothesis that the renal Pi transport adaptation to dietary Pi restriction is indeed the prerequisite for a hyperphosphatemic response to fasting. They also suggest that the mobilization of Pi from body stores during fasting with LPD is normal in HYP mice, even after Pi restriction.

Animals↗
PubMed1982

Abnormal tubular adaptation to dietary Pi restriction in X-linked hypophosphatemic mice.

The renal handling of inorganic phosphate (Pi) is in part under the control of a powerful mechanism that is independent of parathyroid hormone and has the ability to enhance net tubular Pi reabsorption in response to a reduction in the Pi supply. The decreased renal reabsorption of Pi, the salient feature of the human disease X-linked hypophosphatemia, could be due to a loss of this adaptive capability of the tubular Pi transport system. To investigate this hypothesis, mutant hypophosphatemic (HYP) mice were used as a model of the human disease. Male HYP mice and normal littermates were subjected to high (0.75 g/100 g), low (0.25 g/100 g), or very low (0.03 g/100 g) phosphorus diets for periods varying between 1 and 20 days. Then the overall tubular Pi transport capacity was assessed by determining the maximal net Pi reabsorption per unit volume of glomerular filtrate (max TRPi/ml GF). The results indicate that the marked enhancement of max TRPi/ml GF, which is observed in normal mice after the first day of Pi restriction, is completely absent in HYP mice. In chronically thyroparathyroidectomized animals, 10 days of low phosphorus diet stimulated conspicuous max TRPi/ml GF in normal mice, whereas the same regimen did not significantly change the Pi reabsorptive capacity of HYP counterparts. The results of this study suggest that X-linked hypophosphatemia is a disease with a defect in the mechanism responsible for the adaptation of the tubular Pi transport system to Pi restriction.

Animals↗
PubMed1981

Tubular handling of phosphate along the nephron of thyroparathyroidectomized rats injected with ethane-1-hydroxy-1,1-diphosphonate.

1. Previous studies have shown that in thyroparathyroidectomized rats injection of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) at doses that inhibit bone mineral retention (0.16 mmol = 10 mg of phosphorus/kg body wt. per day subcutaneously) leads to a decrease in the net tubular reabsorption of phosphate. 2. In the present work the tubular response to EHDP (0.16 mmol/kg body wt.) injected subcutaneously for 9 days has been localized by free-flow micropuncture in thyroparathyroidectomized rats. 3. The results show tht the net tubular reabsorption of phosphate along the first portion of the (early) proximal tubule was markedly depressed in the EHDP-injected thyroparathyroidectomized rats compared with that in the pair-fed thyroparathyroidectomized control animals. In this latter group the delivery of phosphate to the distal tubule was larger than in the final urine, confirming previous reports. In the EHDP-injected thyroparathyroidectomized rats no difference in delivery of phosphate was found between the distal tubule and the final urine, suggesting that diphosphonate inhibited net reabsorption of phosphate in the terminal nephron. 4. The sites of the EHDP-induced changes in the tubular handling of phosphate were similar to those previously determined for the adaptive response to an increase in the supply of phosphate.

Animals↗
PubMed1981

Tubular handling of Pi: localization of effects of 1,25(OH)2D3 and dietary Pi in TPTX rats.

Previous clearance studies have shown that chronic administration (26 pmol/day i.p. for 7 days) of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) decreases the tubular reabsorptive capacity for inorganic phosphate (Pi) in thyroparathyroidectomized (TPTX) rats. In the present study the tubular localization of this effect was examined by free-flow micropuncture in TPTX rats. At the mentioned dosage, 1,25(OH)2D3 inhibited net Pi reabsorption in the early portion of the proximal tubule. In addition, 1,25(OH)2D3 treatment altered the difference in Pi delivery between the distal tubule and the final urine, suggesting an inhibition of net Pi reabsorption along the terminal portion of the nephron, or, alternatively, admixture of tubular fluid with higher Pi concentration from deep nephrons. Finally, in TPTX rats the tubular localization of the effect of varying the dietary Pi content was found to be quite similar to that of 1,25(OH)2D3.

Animals↗
PubMed1980

Chronic thyroparathyroidectomy and tubular handling of phosphate: increased reabsorption in late but not in early proximal tubule.

The fractional reabsorption (FR) of inorganic phosphate (Pi) along the proximal tubule depends upon both the filtered load of Pi (FLPi) and the tubular reabsorptive capacity of the Pi transporting system. To assess the actual effect of parathyroid hormone on the reabsorptive capacity only, the influence of Pi load has to be eliminated. In this study FRPi was determined by free-flow micropuncture along superficial nephrons of chronically (48 h) thyroparathyroidectomized (TPTX) and pair-fed sham-operated (SHAM) rats at identical FLPi [TPTX 3.07 +/- 0.14 (n = 26) and SHAM 3.07 +/- 0.11 (n = 26) mumol/min +/- SEM]. The micropuncture results indicate that in the ranges of tubular fluid over plasma inulin concentration [TF/P)In] 1.00-1.49 and 1.50-1.99, no difference in FRPi between TPTX and SHAM could be detected. It is only between a TF/PIn of 2.0 and 2.49 that chronic TPTX resulted in a significant increase in FRPi. Accordingly the present study indicates that chronic TPTX increases FRPi in late but not in early portions of proximal tubule. Thus in the early proximal tubule the tubular reabsorptive capacity of the Pi transporting system appears to be unaffected by chronic removal of the parathyroid glands. From this result it can be inferred that the increased plasma concentration of Pi which follows the removal of the parathyroid glands, particularly in the chronic stage, will lead to an apparently paradoxical decrease in FRPi in early proximal tubule as a mere consequence of the increased filtered load of Pi.

Absorption↗