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Biomedical subjects

H Fleisch

Publications and source records attributed to H Fleisch.

At least 145 records · Page 8Linked to original sources
PubMed1981

Increase in fatty acid oxidation in calvaria cells cultured with diphosphonates.

1. Cultured calvaria cells oxidized palmitate and octanoate to CO2 and water-soluble products. 2. When these cells were treated for 6 days with 0.025 and 0.25 mM-dichloromethanediphosphonate, oxidation of palmitate was increased, whereas that of octanoate was influenced less. 3. When the rate of oxidation was raised by increasing the palmitate concentration in the medium, the effect of the diphosphonate was decreased and finally disappeared. 4. 1-Hydroxyethane-1,1-diphosphonate had only minor effects. 5. The increase in palmitate oxidation appeared 2 days after the addition of dichloromethanediphosphonate, simultaneously with a fall in lactate production. (Inhibition of glycolysis by diphosphonates has already been shown.) 6. Cycloheximide, an inhibitor of protein synthesis, did not influence the effect of dichloromethanediphosphonate on the oxidation of palmitate and the production of lactate. 7. Cells cultured with dichloromethanediphosphonate showed a faster uptake of palmitic acid than did control cells. However, this observation did not explain the increased palmitate oxidation, since uptake was much faster than oxidation, and was therefore not the rate-limiting step. 8. 2-Bromopalmitate, an inhibitor of fatty acid oxidation, did not influence the inhibition of glycolysis by the diphosphonates. This inhibition, therefore, did not result from the increased oxidation of palmitate. It is also unlikely that the increased oxidation of palmitate is connected with the inhibition of glycolysis.

Animals↗
PubMed1981

The effects of 1-hydroxyethane-1,1-diphosphonate and dichloromethanediphosphonate on collagen synthesis by rabbit articular chondrocytes and rat bone cells.

Investigations were performed to assess the effects of dichloromethanediphosphonate on the synthesis of collagen by (1) isolated rabbit articular chondrocytes, (2) isolated rat calvaria bone cells and (3) bone explants from rats treated with the diphosphonates. The studies showed that dichloromethanediphosphonate, but not 1-hydroxyethane-1,1-diphosphonate, causes articular chondrocytes to increase net collagen biosynthesis, both when measured as 3H-labelled or as non-radioactive material, in a dose-related fashion. The increment in collagen synthesis was still evident with cells that were exposed continuously to the diphosphonate in primary as well as secondary culture; however, it declined with cells in tertiary culture and was absent after the fourth subculture. The type of collagen was not affected by the diphosphonate. The synthesis of collagen by bone cells was likewise increased with dichloromethanediphosphonate. No effects were detected with 1-hydroxyethane-1,1-diphosphonate was tested. Finally, when calvaria and tibiae from diphosphonate-treated rats were cultured in vitro, the positive effect of dichloromethanediphosphonate on collagen synthesis was also evident. 1-Hydroxyethane-1,1-diphosphonate, on the other hand, decreased the incorporation of [3H]proline into the collagen of calvaria and osseous tibial shafts and showed no effect on the collagen synthesis of the cartilaginous tibial heads.

Animals↗
PubMed1981

The influence of 1-hydroxyethane-1,1-diphosphonate and dichloromethanediphosphonate on lysine hydroxylation and cross-link formation in rat bone, cartilage and skin collagen.

The effects in vivo of dichloromethanediphosphonate and 1-hydroxyethane 1,1-diphosphonate on collagen solubility, hydroxylation of lysine and proline and on the formation of collagen intermolecular cross-links were studied by using rat bone, cartilage and skin tissues. Dichloromethanediphosphonate decreased bone collagen solubility both in acetic acid and after pepsin treatment. Although none of the diphosphonates had any effect on the hydroxylation of proline, dichloromethane-diphosphonate, but not 1-hydroxyethane-1,1-diphosphonate, increased the number of hydroxylysine residues in the alpha-chains of bone, skin and cartilage collagen. The stimulatory effect was dose-dependent. The dichloromethanediphosphonate-mediated increase in hydroxylysine residues in bone and cartilage was manifested in an increase of dihydroxylysinonorleucine, the cross-link that is formed by the condensation of two hydroxylysine residues. The cross-link hydroxylysinonorleucine, a condensation product of hydroxylysine and lysine, on the other hand, was decreased. The total number of intermolecular cross-links was not changed by the diphosphonate.

Animals↗
PubMed1981

Tubular adaptation to Pi restriction in hypophysectomized rats.

The renal tubule adapts its tubular transport capacity for inorganic phosphate (Pi) in response to a reduction in the Pi supply. In order to assess whether growth hormone plays a critical role in this adaptive response we have studied the change in the tubular handling of Pi which follows Pi restriction in hypophysectomized (HPX) rats and compared it to that occurring in intact counterparts. HPX and intact rats were maintained either on a 1.2 g/100 g phosphorus diet or fed a 0.2 g/100 g phosphorus diet for 3, 6 or 12 days. HPX rats received ACTH and thyroxine in doses which normalize their low glomerular filtration rate (GFR). Then the maximal net Pi reabsorption per volume of glomerular filtrate (max. TRPi/ml GFR) were determined during acute Pi infusion by clearance technique. The results indicate that HPX rats responded to Pi restriction by raising their tubular capacity to reabsorb Pi. However, the rapidity and the magnitude of the adaptive response was significantly less in HPX than in intact rats. The adaptation to Pi restriction was also observed in HPX rats after thyroparathyroidectomy. It is concluded that growth hormone and other pituitary hormones do not play a key role in the adaptive response to Pi restriction. The reduced adaptive response observed in HPX rats with intact thyroparathyroid glands could be due to the decreased Pi demand consecutive to impaired growth.

Adrenocorticotropic Hormone↗
PubMed1981

The effect of diphosphonates on periosteal and bone cells in culture.

Calvaria cells were separated into periosteal and bone cells and cultured in the presence of ethane-1-hydroxy-1,1-diphosphonate (EHDP) or dichloromethanediphosphonate (Cl2MDP). Both cell types were affected to the same degree with respect to the effect on cell number and lactate production. The action of the diphosphonates seems therefore not to be specific for one of the cell types.

Animals↗
PubMed1981

Effect of diphosphonates on the synthesis of prostaglandins in cultured calvaria cells.

The calvaria cells cultured for 6 days in the presence of dichloromethanediphosphonate (Cl2MDP) (0.025-250 microM), the synthesis of prostaglandin E2 (PGE2) was inhibited by up to 90%. Inhibition of PGE2 synthesis might be one mechanism whereby this diphosphonate inhibits bone resorption. This effect is not common to all diphosphates since 25 microM 3-amino-1-hydroxypropane-1,1-diphosphonate (AHPDP) stimulated the synthesis of PGE2.

Animals↗
PubMed1981

Diphosphonates: history and mechanisms of action.

The history of diphosphonates began with studies of inorganic pyrophosphate. This compound was found to occur in many biological fluids and inhibited the precipitation of calcium phosphates. It also slowed the transformation of amorphous calcium phosphate to its crystalline form, and inhibited crystal aggregation and dissolution. These observations suggested that it might be a compound of physiological or pathophysiological significance, perhaps in hypophosphatasia and in renal lithiasis. Diphosphonates are compounds where the P-O-P bond of pyrophosphate is replaced by a P-C-P bond. Many diphosphonates have been synthesized and tested and some relationship of their structure to the spectrum of biological effects has been observed. These analogues have similar properties to pyrophosphate, but unlike pyrophosphate they are resistant to enzymic degradation. Their experimental properties have led to their clinical development as bone scanning agents and in the treatment of disorders of ectopic mineralization and increased bone resorption.

Animals↗
PubMed1981

Effect of hydrochlorothiazide on 1,25-dihydroxyvitamin D3-induced changes in calcium metabolism in experimental hypoparathyroidism in rats.

1. Chronic administration of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] can normalize plasma calcium in human hypoparathyroidism and in thyroparathyroidectomized animals. The effect of 1,25(OH)2D3 on plasma calcium is associated with an increase in urinary calcium excretion. In an attempt to prevent this increase thyroparathyroidectomized rats receiving 1,25(OH)2D3 were also treated with hydrochlorothiazide for 9-11 days. 2. Calcium clearance studies show that hydrochlorothiazide stimulated the tubular reabsorption of calcium in thyroparathyroidectomized rats treated with 1,25(OH)2D3. 3. Calcium balance and kinetic studies indicated that hydrochlorothiazide decreased 1,25(OH)2D3-induced hypercalciuria in thyroparathyroidectomized rats. Hydrochlorothiazide did not affect the 1,25(OH)2D3-induced increase in plasma calcium. The hypocalciuric effect of hydrochlorothiazide was not associated with significant changes in calcium deposition into or release from bone. 4. In thyroparathyroidectomized rats treated with 1,25(OH)2D3 the hypocalciuric effect of hydrochlorothiazide was associated with a fall in intestinal calcium absorption. Overall, the calcium balance was unaffected. 5. Thus it appears that hydrochlorothiazide reduces the 1,25(OH)2D3-induced hypercalciuria in parathyroid hormone-deficient animals by decreasing intestinal calcium absorption. Despite the decreased absorption, hydrochlorothiazide does not reduce the 1,25(OH)2D3-induced increase in plasma calcium.

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

Plasma levels of vitamin D metabolites in diphosphonate-treated rats.

1. Protein-binding assays have been used to measure plasma 1,25-dihydroxy-vitamin D [1,25-(OH)2D] as well as 25-hydroxy-vitamin D [25-(OH)D] in rats given 10 mg of phosphorus (P) day(-1) kg(-1) as ethane-1-hydroxy-1,1-diphosphonate (EHDP). 2. In control animals given a normal laboratory chow plasma 25-(OH)D and 1,25-(OH)2D were about 40 nmol/l and 300 pmol/l respectively. 3. EHDP produced a decrease of plasma 1,25-(OH)2D to below 50 pmol/l in 2 days. 4. Both in control and in EHDP-treated rats plasma 1,25-(OH)2D increased when dietary calcium (Ca) was restricted to 0.1%, or dietary P to 0.2%, indicating that the well-known stimulatory effect of Ca or P deprivation was at least partially effective in EHDP-treated rats. 5. In response to an increase of the oral supply of vitamin D3 to 65 nmol/day the plasma level of 25-(OH)D rose in both control and EHDP groups. Plasma 1,25-(OH)2D was not increased above the normal value in control rats. In EHDP-treated rats, however, plasma 1,25-(OH)2D rose to a level equal to that in controls, suggesting that the effect of EHDP on plasma 1,25-(OH)2D can be overcome at high precursor concentration.

25-Hydroxyvitamin D 2↗
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↗
PubMed1981

Plasma level and renal handling of Pi: effect of overnight fasting with and without Pi supply.

Overnight fasting significantly increases plasma inorganic phosphate ([Pi]p) in rats previously fed low Pi diet (LPD), whereas it slightly decreases [Pi]p in rats previously fed high Pi diet (HPD). We assessed the role of the kidney in these differing responses by investigating the influence of overnight fasting on renal tubular capacity to reabsorb Pi by clearance technique in conscious rats. To also evaluate the effect of Pi deprivation during overnight fasting three groups of animals were studied: fed, completely fasted, and fasted with a Pi supply in the drinking water. In intact LPD and HPD rts the tubular Pi reabsorptive capacity was not different between fed and completely fasted rats. It was, however, found to be lower in fasted but Pi-supplied than in fed animals, indicating a decrease by overnight fasting with respect to all nutrients except Pi, i.e., by fasting per se. Conversely, it was higher in the animals completely fasted than in those fasted but Pi-supplied, showing an increase by overnight Pi deprivation. These two opposite effects explain the absence of any significant influence of overnight complete fasting on tubular Pi handling. The same results were obtained in thyroparathyroidectomized rats on low Pi intake. This study shows that the kidney can adapt its transport capacity for Pi according to changes in Pi supply within 12 h. It also suggests that it may react by a decrease in reabsorption to the reduction in Pi utilization that can be expected to occur during fasting per se. Furthermore, our data explain how the kidney, by adapting its tubular Pi transport to the prior dietary intake of Pi, can account for the difference in phosphatemic response to overnight fasting and consequently in the diurnal fluctuation of [Pi]p observed between LPD and HPD animals.

Animals↗