Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020437 (hypercalcemia)
10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reduced concentrating and diluting capacity of the kidney in acute and chronic hypercalcemia may partly be due to inhibition of transcellular sodium reabsorption (RNa) in the thick ascending limb of Henle's loop. To examine this hypothesis, local heat production and RNa were measured during normo- and hypercalcemia at comparable glomerular filtration rate (GFR) in volume expanded, anesthetized dogs. Changes in proximal RNa which might occur during CaCl2 infusion, were minimized by infusing acetazolamide (75 mg/kg body wt iv). When ultrafiltrable calcium was increased from 1.12 +/- 0.09 to 2.95 +/- 0.10 mmol/l, cortical heat production was unchanged, whereas outer medullary heat production fell by 32 +/- 4%. RNa was reduced by 32 +/- 6%. Bicarbonate reabsorption did not change but calcium reabsorption and potassium excretion increased significantly. The potassium content of cortex and outer medulla increased during hypercalcemia, whereas ouabain, an inhibitor of Na+, K+-ATPase reduces the potassium content. We conclude that hypercalcemia does not inhibit transcellular RNa in the diluting segment by a direct effect on the Na+, K+-ATPase or the mitochondria, but by interfering with the coupled NaCl transport across the luminal cell membrane.
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PMID:Inhibition of transcellular NaCl reabsorption in dog kidneys during hypercalcemia. 609 15

Infusions of ovine prolactin for 10 days induced hypercalcemia in unfed American eels, Anguilla rostrata LeSueur, that tentatively was related to stimulation of branchial Ca2+-uptake mechanisms. Analysis of ATPase activities in the plasma membranes of the branchial epithelium in prolactin treated eels showed a specific stimulation of high-affinity Ca2+-ATPase. The results of this study form further evidence that the high-affinity Ca2+-ATPase activity represents the Ca2+-pump of the branchial epithelium.
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PMID:Ca2+-dependent phosphatase and Ca2+-dependent ATPase activities in plasma membranes of eel gill epithelium--III. Stimulation of branchial high-affinity Ca2+-ATPase activity during prolactin-induced hypercalcemia in American eels. 609

The pathogenesis of acute pancreatitis is poorly understood, despite well-recognised precipitating factors. Current evidence suggests that the earliest abnormalities of acute pancreatitis arise within acinar cells, but the key intracellular trigger has yet to be identified. Within the pancreas, physiological concentrations of secretagogues bind to G-protein-linked cell-surface receptors on acinar cells, evoking short, oscillatory spikes of acinar cytosolic-free ionised calcium ([Ca2+]i), an ubiquitous intracellular messenger. Specific effects within acinar cells include initiation of enzyme release through the phosphorylation cascades of stimulus-secretion coupling. Low resting levels of [Ca2+]i are restored by Ca(2+)-ATPase, which pumps calcium into the endoplasmic reticulum and out of the cell. If high concentrations of [Ca2+]i persist, toxicity results, intracellular signalling is disrupted, and cell damage occurs. Sustained elevations in acinar [Ca2+]i result from exposure to high concentrations of secretagogues, high doses of which also induce acute pancreatitis. Similarly, sustained elevations of [Ca2+]i may result from ductal hypertension, alcohol, hypoxia, hypercalcaemia, hyperlipidaemia, viral infection, and various drugs--all factors known to precipitate acute pancreatitis. We suggest that these factors precipitate acute pancreatitis by causing either excessive release of acinar [Ca2+]i, or damage to the integrity of mechanisms that restore low resting levels of [Ca2+]i, and that the consequent calcium toxicity is the key trigger in the pathogenesis of acute pancreatitis.
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PMID:Is an elevated concentration of acinar cytosolic free ionised calcium the trigger for acute pancreatitis? 747 53

Homologous recombinant tilapia prolactin-188 (PRL-I) and tilapia prolactin-177 (PRL-II) were tested for calcitropic activity in tilapia, Oreochromis mossambicus. Injection of PRL-I and PRL-II (4 injections, 12.5 pmol/g, over an 8-day period) induced hypercalcemia that resulted from an enhanced calcium influx via the gills and a decreased calcium efflux. Both PRLs increased the density of the Ca(2+)-transporting Ca(2+)-adenosinetriphosphatase in a plasma membrane preparation of the branchial epithelium. Dose-response studies (doses tested: 0.75-12.5 pmol/g) demonstrated that PRL-I was roughly twofold more potent than PRL-II in inducing hypercalcemia, in enhancing basal levels of cortisol, and in stimulating opercular ionocyte density. PRL-I and PRL-II were equipotent in stimulating the dermal mucocyte frequency. We conclude that in this species PRL-I and PRL-II have calcitropic effects, and that PRL-I is more potent than PRL-II in this respect. We postulate that PRL has corticotrophic activity in this fish.
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PMID:Calcitropic effects of recombinant prolactins in Oreochromis mossambicus. 818 75

This study examined the potential roles of the plasma membrane Ca2+-ATPase (PMCA) at the blood-CSF and blood-brain barriers in brain Ca2+ homeostasis and blood-brain barrier Na+/K+-ATPase subunits in brain K+ homeostasis. During dietary-induced hypo- and hypercalcemia (0.59+/-0.06 and 1.58+/-0.12 mM [Ca2+]) there was no significant change in choroid plexus PMCA (Western Blots) compared to normocalcemic rats (plasma [Ca2+]: 1.06+/-0.11 mM). In contrast, PMCA in cerebral microvessels isolated from hypocalcemic rats was 150% greater than that in controls (p<0.001). Comparison of the alpha3 subunit of Na+/K+-ATPase from cerebral microvessels isolated from hypo-, normo- and hyperkalemic rats (2.3+/-0.1, 3.9+/-0.1 and 7. 2+/-0.6 mM [K+]) showed a 75% reduction in the amount of this isoform during hyperkalemia. None of the other Na+/K+-ATPase isoforms varied with plasma [K+]. These results suggest that both PMCA and the alpha3 subunit of Na+/K+-ATPase at the blood-brain barrier play a role in maintaining a constant brain microenvironment during fluctuations in plasma composition.
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PMID:Blood-brain barrier mechanisms involved in brain calcium and potassium homeostasis. 987 35

A potent and selective inhibitor of the osteoclastic V-H(+)-ATPase, (2Z,4E)-5-(5,6-dichloro-2-indolyl)-2-methoxy-N-(1,2,2,6, 6-pentamethylpiperidin-4-yl)-2,4-pentadienamide (SB 242784), was evaluated in two animal models of bone resorption. SB 242784 completely prevented retinoid-induced hypercalcemia in thyroparathyroidectomized (TPTX) rats when administered orally at 10 mg/kg. SB 242784 was highly efficacious in the prevention of ovariectomy-induced bone loss in the rat when administered orally for 6 months at 10 mg/kg/d and was partially effective at 5 mg/kg/d. Its activity was demonstrated by measurement of bone mineral density (BMD), biochemical markers of bone resorption, and histomorphometry. SB 242784 was at least as effective in preventing bone loss as an optimal dose of estrogen. There were no adverse effects of compound administration and no effects on kidney function or urinary acidity. Selectivity of the inhibitor was further studied using an in situ cytochemical assay for bafilomycin-sensitive V-H(+)-ATPase using sections of osteoclastoma and numerous other tissues. SB 242784 inhibited the osteoclast enzyme at 1,000-fold lower concentrations than enzymes in any of the other tissues evaluated. SB 242784 demonstrates the utility of selective inhibition of the osteoclast V-H(+)-ATPase as a novel approach to the prevention of bone loss in humans.
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PMID:A selective inhibitor of the osteoclastic V-H(+)-ATPase prevents bone loss in both thyroparathyroidectomized and ovariectomized rats. 1090 31

Chronic hypercalcemia (HC) is accompanied by urinary concentration defects, and functional studies indicate defects in the thick ascending limb (TAL). We hypothesize that dysregulation of renal sodium transporters may play an important role in this. Vitamin D-induced HC in rats resulted in polyuria, natriuresis, and phosphaturia. Immunoblotting revealed a marked reduction in the abundance of rat type 1 bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1) in inner stripe of the outer medullary (ISOM; 36 +/- 5%) and whole kidney (51 +/- 11%) in HC. Consistent with this finding, immunocytochemistry and immunoelectron microscopy demonstrated reduced BSC-1 labeling of the apical plasma membrane. Immunoblotting and immunohistochemical labeling of the K channel Kir 1.1 (ROMK) was also reduced in HC. In contrast, there were no reductions in the expression of Na/H exchanger (NHE)3 and Na,K-ATPase in ISOM. The abundance of the proximal tubule type II Na-P(i) cotransporter (NaPi-2) (but not Na,K-ATPase and NHE3) was significantly reduced (25 +/- 4%), consistent with a dramatic increase in urinary phosphate excretion. In conclusion, 1) the reduced abundance of BSC-1 and ROMK in TAL is likely to play a major role in the urinary concentration defects associated with HC and 2) the reduced abundance of NaPi-2 is likely to play a role in the increased urinary phosphate excretion.
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PMID:Reduced expression of Na-K-2Cl cotransporter in medullary TAL in vitamin D-induced hypercalcemia in rats. 1173 10

Gallium nitrate has been shown to be an effective treatment for patients with cancer-related hypercalcemia. Clinical studies have also suggested the drug may have considerably broader use in other diseases associated with accelerated bone loss including multiple myeloma, bone metastases, Paget's disease, and osteoporosis. The actions of gallium nitrate on bone are quite distinct from those of bisphosphonates. Preclinical studies show that gallium preferentially accumulates in trace amounts in metabolically active regions of bone. When present, gallium favorably alters the mineral properties to enhance hydroxyapatite crystallization and reduce mineral solubility. The drug also acts on the cellular components of bone to reduce bone resorption by decreasing acid secretion by osteoclasts. This effect appears to be mediated by inhibition of the ATPase-dependent proton pump of the osteoclast's ruffled membrane. Gallium does not inhibit the development or recruitment of osteoclasts to bone tissue, unlike many bisphosphonates that may induce osteoclast apoptosis. Together, these pharmacologic actions may yield a skeletal system with increased calcium and phosphate content and improved biomechanical strength. Gallium nitrate has potent antiresorptive effects on bone that can be achieved at considerably lower doses than are currently used for cancer-related hypercalcemia. Parenteral and oral formulations of gallium appear to have high activity in bone resorptive disorders, and thus development should be vigorously pursued in these diseases.
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PMID:The effects of gallium nitrate on bone resorption. 1277 54

The purpose of this study was to evaluate whether the natriuresis and polyuria seen in parathyroid hormone (PTH)-induced hypercalcemia are associated with dysregulation of renal Na transporters. Rats were infused with three different doses of human PTH [PTH (1-34); 7.5, 10, and 15 microg.kg(-1).day(-1) s.c.] or vehicle for 48 h using osmotic minipumps. The rats treated with PTH developed significant hypercalcemia (plasma total calcium levels: 2.71 +/- 0.03, 2.77 +/- 0.02, and 3.42 +/- 0.06 mmol/l, respectively, P < 0.05 compared with corresponding controls). The rats with severe hypercalcemia induced by high-dose PTH developed a decreased glomerular filtration rate (GFR), increased urine output, reduced urinary osmolality, increased urinary Na excretion, and fractional excretion of Na. This was associated with downregulation (calculated as a fraction of control levels) of whole kidney expression of type 2 Na-P(i) cotransporter (NaPi-2; 16 +/- 6%), type 3 Na/H exchanger (NHE3; 42 +/- 7%), Na-K-ATPase (55 +/- 2%), and bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1; 25 +/- 4%). In contrast, an upregulation of the Ca(2+)-sensing receptor (CaR) was observed. Rats treated with moderate-dose PTH exhibited unchanged GFR but decreased urinary concentration. The whole kidney expression of NHE3 (52 +/- 8%) and NaPi-2 (26 +/- 5%) was persistently decreased, whereas BSC-1 and Na-K-ATPase protein levels were not altered. CaR expression was also increased. Moreover, rats treated with low-dose PTH showed very mild hypercalcemia but unchanged GFR, normal urinary concentration, and unchanged expression of Na transporters and CaR. In conclusion, the reduced expression of major renal Na transporters is likely to play a role in the increased urinary Na excretion and decreased urinary concentration in rats with PTH-induced hypercalcemia. Moreover, the increase in the CaR in the thick ascending limb (TAL) may indicate a potential role of the CaR in inhibiting Na transport in the TAL.
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PMID:Reduced expression of renal Na+ transporters in rats with PTH-induced hypercalcemia. 1462 99

There is considerable evidence that osteoclasts are involved in the pathogenesis of juxta-articular bone destruction in rheumatoid arthritis. Vacuolar ATPases (V-ATPases), which are highly expressed in the ruffled border membrane of osteoclasts, play a central role in the process of bone resorption, and V-ATPase inhibitors are effective in preventing bone destruction in several animal models of lytic bone diseases. Here, we evaluated for the first time the effects of V-ATPase inhibition in rats with adjuvant-induced arthritis (AIA) using FR177995, a novel V-ATPase inhibitor. FR177995 completely inhibited H(+) transport driven by V-ATPase, but exerted no effect on the H(+) transport activities of F- and P-ATPase, indicating that FR177995 is a specific inhibitor of V-ATPase. FR177995 acted directly on osteoclastic bone resorption and equally inhibited in vitro bone resorption stimulated by IL-1, IL-6 or PTH. In addition, FR177995 dose-dependently reduced retinoic acid-induced hypercalcemia in thyroparathyroidectomized-ovariectomized rats. When FR177995 was administered to AIA rats once a day, the loss of femoral bone mineral density was significantly improved. Moreover, indicators of cartilage damage (arthritis score and glycosaminoglycan content in the femoral condyles) and inflammation parameters (paw swelling volume, erythrocyte sedimentation rate and plasma sialic acid level) were found to be unexpectedly ameliorated. These results strongly suggest that V-ATPase may be an interesting drug target in the treatment of rheumatoid arthritis.
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PMID:FR177995, a novel vacuolar ATPase inhibitor, exerts not only an inhibitory effect on bone destruction but also anti-immunoinflammatory effects in adjuvant-induced arthritic rats. 1715 74


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