scholarly journals Chronic parathyroid hormone excess in vivo increases resting levels of cytosolic calcium in brain synaptosomes: studies in the presence and absence of chronic renal failure.

1991 ◽  
Vol 1 (10) ◽  
pp. 1162-1168
Author(s):  
M Smogorzewski ◽  
P Koureta ◽  
G Z Fadda ◽  
A F Perna ◽  
S G Massry
Keyword(s):  
Renal Failure ◽  
Parathyroid Hormone ◽  
Chronic Renal Failure ◽  
Chronic Administration ◽  
Cytosolic Calcium ◽  
Phospholipid Metabolism ◽  
Brain Synaptosomes ◽  
Presence And Absence

It has been suggested that excess parathyroid hormone (PTH) in chronic renal failure (CRF) or chronic administration of PTH to normal rats caused derangements in norepinephrine and phospholipid metabolism of brain synaptosomes, because of an increase in their resting levels of cytosolic calcium which may induce a decrease in synaptosomal content of ATP. In the study presented here, the resting levels of cytosolic calcium in brain synaptosomes were measured in six groups of rats including: (1) normal rats; (2) rats with CRF of 21-days duration; (3) normocalcemic parathyroidectomized rats with CRF of 21-days duration; (4) rats with CRF of 21-days duration treated with verapamil from day 1 of CRF; (5) normal rats treated with verapamil for 21 days; and (6) normal rats treated with PTH for 21 days. Resting levels of cytosolic calcium of brain synaptosomes of CRF rats (437 +/- 18.0 nM) and normal rats treated with PTH (428 +/- 5.6 nM) were significantly (P less than 0.01) higher than those of normal rats (345 +/- 9.0 nM), normal rats treated with verapamil (354 +/- 8.7 nM), CRF rats treated with verapamil (361 +/- 12.9 nM), or CRF-parathyroidectomized rats (363 +/- 8.2 nM). There were no significant differences between the values of the last three groups of rats.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Effect of chronic renal failure on Ca2+ ATPase of brain synaptosomes.

1991 ◽  
Vol 2 (6) ◽  
pp. 1115-1121 ◽  
Author(s):  
S M Hajjar ◽  
M Smogorzewski ◽  
M A Zayed ◽  
G Z Fadda ◽  
S G Massry
Keyword(s):  
Renal Failure ◽  
Parathyroid Hormone ◽  
Chronic Renal Failure ◽  
Atpase Activity ◽  
Secondary Hyperparathyroidism ◽  
Cytosolic Calcium ◽  
Calcium Entry ◽  
Blood Levels ◽  
Brain Synaptosomes ◽  
Calcium Extrusion

Chronic renal failure (CRF) is associated with a sustained rise in the concentration of cytosolic calcium [( Ca2+]i) of brain synaptosomes. This was attributed to secondary hyperparathyroidism where the excess blood levels of parathyroid hormone (PTH) augment calcium entry into synaptosomes. However, for such an effect of PTH to cause a sustained rise in [Ca2+]i, calcium extrusion out of synaptosomes should be impaired. The study presented here examined the effect of CRF with and without (CRF-PTX) excess PTH and the treatment of CRF rats with verapamil (V) on the Vmax and Km for calcium of synaptosomal Ca2+ ATPase, an enzyme that plays an important role in pumping calcium out of the synaptosomes. The Vmax of synaptosomal Ca2+ ATPase in CRF rats was significantly (P less than 0.01) lower than that of normal, CRF-PTX, CRF-V, and normal-V rats. However, the values in CRF-V were still below normal (P less than 0.05). There were no significant differences in the Km for calcium of synaptosomal Ca2+ ATPase among the five groups of animals. [Ca2+]i was significantly (P less than 0.01) higher in synaptosomes of CRF rats than in normal, CRF-PTX, CRF-V, and normal-V animals, and the values among the latter four groups were not different. The data demonstrate that the activity of synaptosomal Ca2+ ATPase is reduced in CRF rats, and this derangement is related to the excess PTH. This derangement in Ca2+ ATPase activity plays an important role in the genesis of the sustained elevation of synaptosomal [Ca2+]i in CRF.

Effect of chronic renal failure and parathyroid hormone on phospholipid content of brain synaptosomes

1989 ◽  
Vol 256 (4) ◽  
pp. F705-F710
Author(s):  
A. Islam ◽  
M. Smogorzewski ◽  
S. G. Massry
Keyword(s):  
Central Nervous System ◽  
Renal Failure ◽  
Nervous System ◽  
Parathyroid Hormone ◽  
Chronic Renal Failure ◽  
Cholesterol Content ◽  
Phospholipid Content ◽  
Intact Pth ◽  
Central Nervous System Dysfunction ◽  
Brain Synaptosomes

The effects of 21 days of chronic renal failure (CRF) with and without excess parathyroid hormone (PTH) and those of 21 days administration of intact PTH on phospholipids and cholesterol contents of rat brain synaptosomes were examined. CRF and PTH treatment were associated with a significant (P less than 0.01-0.02) reduction in the synaptosomal contents of total phospholipids, phosphatidylinositol (PI), phosphatidylserine (PS), and phosphatidylethanolamine (PE). Parathyroidectomy (PTX) prior to the induction of CRF prevented the decrements in the synaptosomal contents of total phospholipids, PI, PS, and PE. The synaptosomal contents of these phospholipids in CRF-PTX rats were not different from those in normal rats despite CRF. There were no significant changes in the cholesterol content of the synaptosomes in the various experimental groups of animals. The data show that CRF affects synaptosomal metabolism of total phospholipids, PI, PS, and PE, and these derangements are due to the state of secondary hyperparathyroidism of renal failure. The decrements in the content of PI, PS, and PE could be, at least in part, responsible for the previously reported abnormalities in the neurotransmitter functions of brain synaptosomes in CRF and could underlie some of the abnormalities in central nervous system dysfunction in uremia.

Increased Inward Passive Permeability in Vitro to Sodium in Uraemic Erythrocytes

1996 ◽  
Vol 90 (1) ◽  
pp. 3-8 ◽  
Author(s):  
Dalila B. Corry ◽  
Charma C. Ellis ◽  
Michael L. Tuck
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Cytosolic Calcium ◽  
Na Efflux ◽  
The Mean ◽  
86Rb Influx ◽  
Cell Defect ◽  
External K

1. We have reported a normal sodium (Na) pump, but decreased loop-diuretic-sensitive Na efflux in erythrocytes from patients with chronic renal failure on haemodialysis, suggesting a different mode of co-transport in uraemia. 2. The present work extends these findings and examines in vitro simultaneous unidirectional and radiolabelled Na and K fluxes through the Na/K/Cl co-transport and the Na/K pump in washed erythrocytes from seven subjects with chronic renal failure and seven controls. Erythrocyte cytosolic calcium was also examined. 3. Ouabain-sensitive 86Rb influx was similar in patients and controls (1.76 ± 0.19 versus 1.72 ± 0.13 mmol h−1 litre−1 of erythrocytes) as was ouabain-sensitive 22Na efflux (3.62 ± 0.36 versus 4.04 ± 0.39 mmol h−1 litre−1 of erythrocytes). 4. Bumetanide-sensitive 86Rb and 22Na influx and 22Na efflux were measured at three concentrations (4, 8 and 12 mmol/l) of external K. In chronic renal failure, mean bumetanide-sensitive 22Na efflux was decreased at all external K concentrations compared with controls, and at physiological concentrations (4 mmol/l) external K was lower than controls (0.14 ± 0.01 versus 0.38 ± 0.05 mmol h−1 litre−1 of erythrocytes, P < 0.01). Mean bumetanide-sensitive 86Rb influx was also reduced in chronic renal failure at all external K concentrations, and at 4 mmol/l external K was lower than controls (0.13 ± 0.04 versus 0.34 ± 0.04 mmol h−1 litre−1 of erythrocytes, P < 0.01). Conversely, bumetanide-sensitive 22Na influx was markedly increased at all external K levels in chronic renal failure, and at 4 mmol/l external K values were elevated compared with controls (0.64 ± 0.18 versus 0.34 ± 0.04 mmol h−1 litre−1 of erythrocytes, P < 0.001). The mean cytosolic calcium concentration was higher in erythrocytes in chronic renal failure than controls (134.4 ± 8.6 versus 63.7 ± 5.8 nmol/l, P < 0.001). 5. Thus, in washed erythrocytes incubated in artificial media there is a markedly increased ouabain-insensitive Na influx in subjects with chronic renal failure which might be explained in part by the higher levels of cytosolic calcium. In vivo, this cell defect combined with suppression of the Na/K pump could lead to intracellular Na accumulation and play a role in uraemic complications.

Mechanisms of impaired insulin secretion after chronic excess of parathyroid hormone

1990 ◽  
Vol 259 (2) ◽  
pp. F210-F216 ◽  
Author(s):  
A. F. Perna ◽  
G. Z. Fadda ◽  
X. J. Zhou ◽  
S. G. Massry
Keyword(s):  
Renal Failure ◽  
Renal Function ◽  
Insulin Secretion ◽  
Parathyroid Hormone ◽  
Chronic Renal Failure ◽  
Direct Evidence ◽  
Chronic Administration ◽  
Atp Content ◽  
Impaired Insulin ◽  
Inhibit Insulin Secretion

Excess parathyroid hormone (PTH) in presence or absence of chronic renal failure impairs insulin release from pancreatic islets. This abnormality has been attributed to PTH-induced accumulation of Ca in the cytosol of the islets. Direct evidence for the latter phenomenon is lacking. This study examined the effect of chronic administration of PTH to rats with normal renal function on resting cytosolic Ca of the islets and evaluated the mechanisms through which a rise in resting cytosolic Ca may inhibit insulin secretion. After 42 days of PTH administration, glucose-induced insulin secretion was impaired, and this defect was corrected by the use of D-glyceraldehyde as secretagogue for insulin. Resting cytosolic Ca of islets from PTH-treated rats was markedly increased compared with that of islets from normal animals (288 +/- 27.1 vs. 135 +/- 3.7 nM, P less than 0.01), and their content of ATP in the presence of both 2.8 and 16.7 mM D-glucose was reduced (2.8 mM D-glucose, 4.6 +/- 0.17 vs. 6.0 +/- 0.42 pmol/islet, P less than 0.01; and 16.7 mM D-glucose, 6.9 +/- 0.25 vs. 11.1 +/- 0.95 pmol/islet, P less than 0.01). D-Glyceraldehyde increased ATP content in islets of PTH-treated rats from 4.6 +/- 0.17 to 8.8 +/- 0.71 pmol/islet. Glucose uptake by the islets, their insulin content, and both the Vmax and the apparent Km for fructose 6-phosphate of phosphofructokinase 1 (EC 2.7.1.11) in PTH-treated rats were not different from normal. The two major cellular derangements in the islets of PTH-treated rats were a reduction in ATP content and a rise in resting cytosolic Ca.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal leucine-induced insulin secretion in chronic renal failure

1994 ◽  
Vol 267 (5) ◽  
pp. F853-F860 ◽  
Author(s):  
H. Y. Oh ◽  
G. Z. Fadda ◽  
M. Smogorzewski ◽  
H. H. Liou ◽  
S. G. Massry
Keyword(s):  
Amino Acids ◽  
Renal Failure ◽  
Insulin Secretion ◽  
Parathyroid Hormone ◽  
Chronic Renal Failure ◽  
Pancreatic Islets ◽  
Reaction Rate ◽  
Cytosolic Calcium ◽  
Atp Content ◽  
Cellular Processes

Chronic renal failure (CRF) is associated with a sundry of abnormalities in pancreatic islets including a rise in their cytosolic calcium, reduced ATP content, and impaired glucose-induced insulin secretion. The latter is also stimulated by amino acids (such as leucine), and the cellular processes involved in leucine-induced insulin secretion are different from those responsible for glucose-induced insulin release. The present study examined whether leucine-induced insulin secretion is also impaired in CRF and investigated the cellular derangements for such a potential abnormality. The results showed that leucine-induced insulin secretion is markedly reduced by islets from CRF animals, and this defect was prevented by parathyroidectomy (PTX) of the CRF animals or by their treatment with verapamil, an agent that blocks the action of parathyroid hormone (PTH) on the pancreatic islets. Both leucine uptake and alpha-ketoisocaproic acid-induced insulin secretion by islets from CRF rats are normal; however, both the activation of glutamate dehydrogenase (GLDH) by leucine or by 2-aminobicyclo-[2-2-1]-haptene and the utilization of alpha-ketoglutarate are impaired, and the maximal reaction rate (Vmax) of glutaminase is reduced. These derangements are corrected by PTX of CRF rats or by their treatment with verapamil. The data demonstrate that 1) CRF is associated with impaired leucine-induced insulin secretion, 2) this defect is due to the state of secondary hyperparathyroidism of CRF, and 3) the cellular derangements responsible for this defect involve abnormalities in the metabolism of leucine and derangements in the leucine-GLDH-alpha-ketoglutarate-glutaminase pathway of the islets.

Evidence for an Increased Generation of Prostacyclin in the Microvasculature and an Impairment of the Platelet α-Granule Release in Chronic Renal Failure

1988 ◽  
Vol 60 (02) ◽  
pp. 205-208 ◽  
Author(s):  
Paul A Kyrle ◽  
Felix Stockenhuber ◽  
Brigitte Brenner ◽  
Heinz Gössinger ◽  
Christian Korninger ◽  
...  
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Blood Clotting ◽  
Normal Subjects ◽  
Chronic Uraemia ◽  
Wall Interaction ◽  
End Stage ◽  
Granule Release

SummaryThe formation of prostacyclin (PGI2) and thromboxane A2 and the release of beta-thromboglobulin (beta-TG) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the micro vasculature made to determine bleeding time, was studied in patients with end-stage chronic renal failure undergoing regular haemodialysis and in normal subjects. In the uraemic patients, levels of 6-keto-prostaglandin F1α (6-keto-PGF1α) were 1.3-fold to 6.3-fold higher than the corresponding values in the control subjects indicating an increased PGI2 formation in chronic uraemia. Formation of thromboxane B2 (TxB2) at the site of plug formation in vivo and during whole blood clotting in vitro was similar in the uraemic subjects and in the normals excluding a major defect in platelet prostaglandin metabolism in chronic renal failure. Significantly smaller amounts of beta-TG were found in blood obtained from the site of vascular injury as well as after in vitro blood clotting in patients with chronic renal failure indicating an impairment of the a-granule release in chronic uraemia. We therefore conclude that the haemorrhagic diathesis commonly seen in patients with chronic renal failure is - at least partially - due to an acquired defect of the platelet a-granule release and an increased generation of PGI2 in the micro vasculature.

scholarly journals Role of parathyroid hormone in the glucose intolerance of chronic renal failure.

1985 ◽  
Vol 75 (3) ◽  
pp. 1037-1044 ◽  
Author(s):  
M Akmal ◽  
S G Massry ◽  
D A Goldstein ◽  
P Fanti ◽  
A Weisz ◽  
...  
Keyword(s):  
Renal Failure ◽  
Parathyroid Hormone ◽  
Chronic Renal Failure ◽  
Glucose Intolerance

scholarly journals Parathyroid hormone secretion in chronic renal failure

1996 ◽  
Vol 50 (5) ◽  
pp. 1700-1705 ◽  
Author(s):  
Jesper C. Madsen ◽  
Anne Q. Rasmussen ◽  
Søren D. Ladefoged ◽  
Peter Schwarz
Keyword(s):  
Renal Failure ◽  
Parathyroid Hormone ◽  
Chronic Renal Failure ◽  
Hormone Secretion

Parathyroid hormone metabolism and its potential as a uremic toxin

1980 ◽  
Vol 239 (1) ◽  
pp. F1-F12 ◽  
Author(s):  
E. Slatopolsky ◽  
K. Martin ◽  
K. Hruska
Keyword(s):  
Renal Failure ◽  
Parathyroid Hormone ◽  
Chronic Renal Failure ◽  
Biological Effects ◽  
Uremic Toxin ◽  
Terminal Portion ◽  
Single Chain ◽  
Biochemical Alterations ◽  
Amino Terminal ◽  
Carboxy Terminal

Secondary hyperparathyroidism is a universal complication of chronic renal failure. It has been proposed that the markedly elevated levels of immunoreactive parathyroid hormone (i-PTH) in uremia may represent a “uremic toxin” responsible for many of the abnormalities of the uremic state. Plasma i-PTH consists of a mixture of intact hormone, a single-chain polypeptide of 84 amino acids, and smaller molecular weight hormonal fragments from both the carboxy- and amino-terminal portion of the PTH molecule. The hormonal fragments arise from metabolism of intact PTH by peripheral organs as well as from secretion of fragments from the parathyroid glands. The structural requirements for the known biological actions of PTH reside in the amino-terminal portion of the PTH molecule. Carboxy-terminal fragments, biologically inactive at least in terms of adenylate cyclase activation, hypercalcemia, or phosphaturia, depend on the kidney for their removal from plasma, and thus accumulate in the circulation in chronic renal failure. It is unknown at the present time if other biological effects of these carboxy-terminal fragments may contribute to some of the biochemical alterations observed in uremia. The most significant consequence of increased PTH levels in uremia is the development of bone disease characterized by osteitis fibrosa. In addition, it would appear that PTH plays an important role in some of the abnormal electroencephalographic patterns observed in uremia. This may be due to a potential role of PTH in increasing calcium content of brain. Parathyroid hormone also has been implicated as a pathogenetic factor in many other alterations present in uremia, i.e., peripheral neuropathy, carbohydrate intolerance, hyperlipidemia, and other alterations. Unfortunately, outstanding clinical research is lacking in this field and conclusive experimental data are practically nonexistent. Further studies are necessary if one is to accept the concept of PTH being a significant “uremic toxin.”

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