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S G Massry

Publications and source records attributed to S G Massry.

At least 19 recordsLinked to original sources
PubMed1992

Impaired phagocytosis in chronic renal failure is mediated by secondary hyperparathyroidism.

Patients with chronic renal failure (CRF) display impaired phagocytosis by the polymorphonuclear leucocytes (PMNL), and these cells have elevated basal levels of cytosolic calcium ([Ca2+]i) and reduced ATP content. It has been suggested that these changes in PMNL metabolism and function are mediated by the state of secondary hyperparathyroidism of CRF. To examine the role of excess PTH in these derangements of PMNL, we studied [Ca2+]i, ATP and phagocytic ability of PMNL in five groups of rats including: CRF, CRF normocalcemic parathyroidectomized (CRF-PTX), CRF and normal animals treated with verapamil (CRF-V), and normal-V, respectively. The level of [Ca2+]i in the PMNL of CRF rats (149 +/- 2.7 nM) was significantly (P less than 0.01) higher and the ATP content (4.2 +/- 0.17 nmol/5 x 10(6) PMNL) significantly lower (P less than 0.01) than in normal (108 +/- 2.4 nM; 9.5 +/- 0.15 nmol/5 x 10(6) PMNL), CRF-PTX (103 +/- 2.9 nM; 9.2 +/- 0.19 nmol/5 x 10(6) PMNL), CRF-V (107 +/- 2.2 nM; 9.0 +/- 0.2 nmol/5 x 10(6) PMNL) and normal-V (106 +/- 1.8 nM; 9.2 +/- 0.2 nmol/5 x 10(6) PMNL), despite sustained elevation in blood PTH in the CRF-V group. Phagocytosis was significantly (P less than 0.01) impaired in CRF animals (5.6 +/- 0.25 micrograms oil/10(7) PMNL/min) but was normal in CRF-PTX (9.3 +/- 0.21 micrograms oil/10(7) PMNL/min) and CRF-V (9.5 +/- 0.22 micrograms oil/10(7) PMNL/min) rats. The values of phagocytosis in normal and normal-V rats were 9.6 +/- 44 and 9.6 +/- 0.18 micrograms oil/10(7) PMNL/min, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Decreased O2 consumption by PMNL from humans and rats with CRF: role of secondary hyperparathyroidism.

Bactericidal ability of polymorphonuclear leukocytes (PMNL) is impaired in chronic renal failure (CRF). This function of PMNL is mediated by the generation of oxidizing radicals and the latter event requires O2 consumption by these cells. The present study examined both basal and FMLP-stimulated rise in cytosolic calcium ([Ca2+]i) and O2 consumption of PMNL from normal subjects and hemodialysis patients and from CRF rats, and evaluated the potential role of secondary hyperparathyroidism of CRF on these properties of PMNL. Basal levels of [Ca2+]i were significantly higher, and FMLP-induced increments in [Ca2+]i were significantly lower in PMNL of both humans and rats with CRF than in normals. Basal and FMLP-stimulated O2 consumption were significantly lower in CRF subjects and rats than in normals. These derangements were prevented by prior parathyroidectomy of CRF rats or by their treatment with verapamil from day one of CRF. Also, therapy of rats with pre-existing CRF with this drug reversed the abnormalities in [Ca2+]i and in O2 consumption of PMNL. The data indicate that: (1) CRF is associated with derangements in the homeostasis of [Ca2+]i of PMNL and their oxygen consumption, (2) these abnormalities are, most likely, mediated by the state of secondary hyperparathyroidism of CRF, and (3) verapamil, which blocks the PTH-induced entry of calcium into cells, and prevents as well as reverses these PMNL dysfunctions. These results implicate the excess PTH of CRF in the genesis of the defective bactericidal function of PMNL, and assign a new dimension to PTH toxicity in CRF.

Adult↗
PubMed1992

Effect of dietary sodium intake on intracellular calcium in lymphocytes of salt-sensitive hypertensive patients.

High dietary Na+ raises mean arterial pressure (MAP) by more than 10% in salt-sensitive (SS) patients with essential hypertension. To test whether the rise in MAP in these patients is caused by a Na(+)-linked increase in [Ca2+]i in vascular smooth muscle cells, we measured [Ca2+]i in the lymphocytes of 14 patients with essential hypertension kept on a Na+ intake of 20 mEq/day for 9 days, and 200-mEq/day for 14 days. Nifedipine gastrointestinal transport system (GITS) (30 mg/day) was given during the last 4 days of each diet. We isolated lymphocytes on Ficoll-Hypaque gradient and measured [Ca2+]i levels using Fura-2 fluorescent dye. During low Na+ intake, there was no difference in MAP (102 +/- 3.5 v 93 +/- 3.8 mm Hg) and in lymphocytes [Ca2+]i (80 +/- 3.0 v 87 +/- 5.4 nmol/L) between the seven salt-sensitive and the seven salt-resistant patients. During high Na+ intake, MAP (92 +/- 2.8 mm Hg) and [Ca2+]i (85 +/- 6.8 nmol/L) did not change in salt-resistant patients. On the contrary, MAP (115 +/- 3.4 mm Hg) and [Ca2+]i (130 +/- 11.1 nmol/L) increased significantly (P less than .01) in the salt-sensitive patients. Nifedipine did not significantly alter MAP and [Ca2+]i in both groups of patients during low Na+ and in salt-resistant patients during high Na+ intake. On the contrary, during high Na+ intake, nifedipine decreased significantly (P less than .01) both MAP (104 +/- 2.4 mm Hg) and [Ca2+]i (89 +/- 5.7 nmol/L) in salt-sensitive patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Verapamil reverses glucose intolerance in preexisting chronic renal failure: studies on mechanisms.

Glucose-induced insulin secretion is impaired in chronic renal failure (CRF), and this abnormality is due to the elevation of cytosolic calcium [Ca2+]i and other derangements in pancreatic islet metabolism. Verapamil given to rats from day 1 of CRF prevented the rise in [Ca2+]i of islets and the impairment in insulin secretion. However, it is not known whether verapamil can reverse the abnormalities of islet function and metabolism in animals with preexisting renal failure. Such a documentation has important clinical implications for the treatment of carbohydrate intolerance in patients with CRF. The present study examined this question. After 6 weeks of CRF, rats were randomized into two subgroups and maintained for additional 6 weeks. One subgroup received intraperitoneal injections of verapamil (0.1 micrograms/kg body weight twice daily) and the other received vehicle only. At the time of randomization, there were no significant differences between the two subgroups in their body weight, plasma levels of calcium, phosphorus and creatinine, serum parathyroid hormone and creatinine clearance. Similarly, at the time of sacrifice (12 weeks), there were no significant differences in these parameters except for a modestly lower plasma level of creatinine and modestly higher creatinine clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1992

Parathyroid hormone modulates the release of atrial natriuretic peptide during acute volume expansion.

In this study we investigated the effect of volume expansion on plasma and atrial concentrations of atrial natriuretic peptide (ANP) in the presence and absence of the parathyroid gland and under normocalcemic and hypocalcemic conditions. After volume expansion ANP concentration in plasma was significantly (p < 0.001) higher in intact (702 +/- 86 pg/ml) than in hypocalcemic parathyroidectomized (PTX) (271 +/- 38 pg/ml) rats. Plasma ANP of PTX rats rendered normocalcemic with oral calcium supplementation increased to 402 +/- 85 pg/ml after volume expansion. Results from this study suggest that parathyroid hormone (PTH) is required for augmented ANP secretion in response to acute volume loading and alterations of extracellular calcium may modulate volume-induced ANP release in PTX rats. We would discuss that a parathyroid gland-cardiac atria interaction exists and that changes in serum level of PTH may play a role in the regulation of fluid homeostasis via ANP secretion.

Animals↗
PubMed1992

Effect of chronic renal failure with and without secondary hyperparathyroidism on the activities of synaptosomal tyrosine hydroxylase and monoamine oxidase.

Norepinephrine (NE) content, release and uptake by brain synaptosomes are reduced in chronic renal failure (CRF), and this has been attributed to the state of secondary hyperparathyroidism. The decrease in NE content in CRF could not be explained by changes in NE uptake or release since in normal circumstances, NE content usually remains unchanged despite fluctuation in NE uptake and release. Since NE content is determined by its production and degradation, we examined the effect of CRF with and without excess parathyroid hormone (PTH) on the Michaelis-Menton constant (Km) and Vmax of tyrosine hydroxylase (TH), the rate-limiting enzyme for NE production, and monoamine oxidase (MAO), an enzyme involved in NE degradation of brain synaptosomes. Brain synaptosomes from rats with a 21-day CRF have a significantly (p less than 0.01) lower Vmax of TH (39.5 +/- 5.3 pmol tritiated H2O/mg protein/min) than that of normal rats (61. +/- 7.5 pmol tritiated H2O/mg protein/min) and a higher Km of MAO (59 +/- 2.9 nM tyramine) than normal animals (46 +/- 1.7 nM tyramine). Parathyroidectomy (PTX) in CRF rats normalized Vmax of TH (54 +/- 4.5 pmol tritiated H2O/mg protein) and Km of MAO (48.4 +/- 2.3 nM tyramine). Cytosolic calcium, [Ca2+]i, in brain synaptosomes is significantly (p less than 0.01) higher in rats with CRF (488 +/- 8.5 nM) than in normal (355 +/- 6.0 nM) or PTX-CRF (360 +/- 8.1 nM) rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Verapamil corrects abnormal metabolism of pancreatic islets and insulin secretion in phosphate depletion.

Phosphate depletion (PD) causes impaired insulin secretion and metabolic derangements in pancreatic islets. We studied PD, pair-weighed (PW), and PD and PW rats treated with verapamil (PD-V and PW-V) to examine the mechanisms of these derangements. Cytosolic calcium ([Ca2+]i) in PD islets was higher than that in PW, PD-V, and PW-V islets, and the values in the latter three groups were not different. Both basal and stimulated ATP in PD islets were lower than those in PW, PW-V, or PD-V islets. The maximum velocity (Vmax) of Ca(2+)-ATPase and the Km and Vmax of Na+,K(+)-ATPase were reduced in PD islets. In both PD-V and PW-V, the Vmax of Ca(2+)-ATPase was higher than that in PD, but lower than that in PW. Both initial and second phases of insulin secretion by PD islets were lower than those by PW and PW-V islets. In PD-V rats, insulin secretion was greater than that in PD rats, but only the second phase was significantly higher. The data are consistent with either of the following possibilities: 1) PD causes a change in the permeability of islets, allowing increased entry of Ca2+ into them and a fall in ATP of islets; the latter would impair the activity of both ATPases, leading to reduced Ca2+ extrusion from islets and, hence, an elevation in their [Ca2+]i; or 2) the primary defect in PD is a reduction in the activities of ATPases of islets due to the fall in ATP secondary to phosphorus deficiency. The decreased Ca2+ extrusion that ensues, even in the face of normal Ca2+ entry, will result in high [Ca2+]i. In either of these scenarios the rise in [Ca2+]i would inhibit mitochondrial oxygen consumption and ATP production, further lowering the ATP content of the islets. The higher [Ca2+]i and low ATP of PD underlie the impaired insulin secretion. Verapamil, by blocking normal or augmented Ca2+ entry into the islets, mitigates or prevents the derangements in islet function and metabolism.

Adenosine Triphosphate↗
PubMed1992

Parathyroid hormone activates protein kinase C of pancreatic islets.

Pancreatic islets are targets for PTH. The acute exposure of the islets to PTH results in a rise in their cytosolic calcium ([Ca2+]i). It also stimulates insulin secretion in a manner similar to that produced by phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C (PKC), suggesting that the hormone may stimulate the activity of this enzyme. The present study examined the effect of PTH (1-34) on both cytosolic and membrane bound PKC activity of pancreatic islets and compared it with that of glucose and TPA. In the basal state, PKC activity is predominantly found in the cytosol. Both PTH or high glucose concentration caused a significant increase in membrane-bound and total PKC activity, whereas cytosolic enzyme activity remained unchanged. The effects of these two agonists peaked at 5 min and declined thereafter. The effect of PTH on PKC activity was abolished by the PTH antagonist ([Tyr-34] bovine PTH (7-34) NH2). In contrast, TPA induced a rise in membrane-bound PKC activity with simultaneous decrease in cytosolic pool of PKC without a change in total PKC activity. Removal of calcium from the incubation media resulted in partial and significant loss of PTH-induced rise in membrane-bound PKC activity. The data demonstrated that 1) PTH stimulate PKC activity of pancreatic islets in a manner similar to that of glucose, 2) both of the agonists increases total PKC activity of islets and translocation of the enzyme activity to the membranes of the islets, and 3) the effect of PTH is mediated, in part, by its ability to augment calcium entry into the islets and is most likely receptor mediated.

Animals↗
PubMed1992

Evolution of metabolic and functional derangements of pancreatic islets in phosphate depletion.

Phosphate depletion (PD) causes a rise in basal level of cytosolic calcium ([Ca2+]i) of pancreatic islets, a decrease in their basal and stimulated ATP content, a reduction in the maximum velocity (Vmax) of Ca2+ adenosine triphosphatase (ATPase) and Na(+)-K+ ATPase, impaired glucose-induced calcium signal and decreased glucose-induced insulin secretion. The sequence of events that lead to these derangements during the evolution of PD are not defined. The present study examined this issue by measuring the metabolic and functional profile of pancreatic islets weekly during the evolution of PD over a period of 6 weeks, and whether phosphate repletion reverses these abnormalities. The results show that initial abnormalities are a rise in Vmax of Ca2+ ATPase and modest rise in basal [Ca2+]i. This was followed by a fall in basal and stimulated ATP content. With the fall in ATP content, the Vmax of Ca2+ ATPase and Na(+)-K+ ATPase decreases and the rise in [Ca2+]i becomes more pronounced. A decrease in glucose-induced insulin secretion becomes evident with the fall in ATP, the decrease in glucose-induced calcium signal, and/or delta[Ca2+]i/basal[Ca2+]i. All functional and metabolic derangements of the pancreatic islets returned to normal after phosphate repletion. Taken together, our data are consistent with the notion that PD is associated with an initial increase in calcium influx into the islets. This is followed by modest but significant rise in [Ca2+]i which, in turn, would inhibit mitochondrial oxidation and ATP generation leading to a decrease in ATP content. The latter compromises the activity of Ca2+ ATPase and Na(+)-K+ ATPase which are involved, directly or indirectly, in calcium extrusion out of the islets. The increased influx of calcium combined with decreased calcium extrusion is followed by a further rise in basal levels of [Ca2+]i. This sequence of events continues until a steady state is reached and is characterized by reduced basal and stimulated ATP content, reduced Vmax of Ca2+ ATPase and Na(+)-K+ ATPase and elevated basal level of [Ca2+]i. Phosphate repletion reverses all these abnormalities.

Adenosine Triphosphate↗
PubMed1992

On the mechanisms of impaired phagocytosis in phosphate depletion.

Phosphate depletion (PD) impairs the phagocytic ability of polymorphonuclear leukocytes (PMNL). This derangement has been attributed to the low ATP content of PMNL in PD. The mechanisms responsible for the low ATP content are not well defined. Phosphorus deficiency, per se, and/or other cellular metabolic consequences of PD such as a rise in cytosolic calcium ([Ca2+]i) could be responsible. Indeed, PD is associated with a rise in [Ca2+]i in other cells, and such an event may inhibit mitochondrial ATP production. It is also not evident whether the impaired phagocytosis in PD is due to low ATP content and/or a rise in the [Ca2+]i of PMNL. The study presented here examined levels of [Ca2+]i, ATP content, and the phagocytic ability of PMNL from PD and pair-weighed (PW) rats and evaluated the potential beneficial effect of treatment with verapamil (V), which may prevent a rise in [Ca2+]i and the consequent effects on ATP content and the phagocytosis of PMNL. The resting levels of [Ca2+]i of PMNL from PD rats (148 +/- 3.9 nM) were significantly (P less than 0.01) higher, and the ATP contents (4.8 +/- 0.2 nmol/5 x 10(6) PMNL) were significantly (P less than 0.01) lower than in PW (111 +/- 2.8 nM and 9.3 +/- 0.3 nmol/5 x 10(6) PMNL), PW-V (114 +/- 2.2 nM and 9.3 +/- 0.28 nmol/5 x 10(6) PMNL), and PD-V (112 +/- 1.8 nM and 6.6 +/- 0.19 nmol/5 x 10(6) PMNL) animals. Despite the normal [Ca2+]i in the PMNL of PD-V rats, their ATP contents were still significantly (P less than 0.01) lower than those of PW or PW-V rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1992

Reduced activity of Na(+)-K+ ATPase of pancreatic islets in chronic renal failure: role of secondary hyperparathyroidism.

The activity of Na(+)-K+ ATPase of pancreatic islets modulates their insulin secretion. The study presented here examined the activity of this enzyme in pancreatic islets of chronic renal failure (CRF) rats in an effort to further delineate the mechanisms of impaired insulin secretion in CRF. The Vmax of Na(+)-K+ ATPase, but not its Km, and the ATP content are significantly reduced in islets of CRF rats that have elevated levels of parathyroid hormone (PTH). These derangements are prevented by prior parathyroidectomy of CRF rats (low blood levels of PTH) or by their treatment with the calcium channel blocker verapamil; these latter rats have sustained elevation of blood levels of PTH. The data indicate that the chronic excess blood levels of PTH in CRF initiates events (augmented entry of calcium) that lead to the reduction in ATP content and in Vmax of Na(+)-K+ ATPase of pancreatic islets. Reducing the blood levels of PTH by parathyroidectomy or blocking the action of PTH on calcium entry into cells by verapamil prevents these derangements. The results suggest that chronic inhibition of Na(+)-K+ ATPase may participate in the processes underlying the impaired insulin secretion in CRF.

Animals↗
PubMed1992

Chronology of cellular events leading to derangements in function of pancreatic islets in chronic renal failure.

In chronic renal failure (CRF), a multitude of metabolic derangements occur in the pancreatic islets, resulting in impaired glucose-induced insulin secretion. These abnormalities include a rise in the basal level of cytosolic calcium ([Ca2+]i) in the islet, a decrease in their basal and stimulated ATP and ATP/ADP ratio, a reduction in the Vmax of Ca2+ATPase and Na(+)-K+ATPase, and an impaired glucose-induced calcium signal. The sequence of events that lead to these derangements and to the impairment in insulin secretion during the evolution of CRF are not defined. The study presented here examined this issue by measuring the metabolic profile of pancreatic islets weekly during the evolution of CRF over a period of 6 wk. The results show that serum levels of parathyroid hormone (PTH) begin to rise during the first week of CRF. The Vmax of Ca2+ATPase and Na(+)-K+ATPase increased during weeks 1 to 3 of CRF but fell to low levels thereafter. At week 3 of CRF, the basal level of [Ca2+]i began to rise, whereas basal and the stimulated ATP content and ATP/ADP ratio started to fall. Glucose-induced calcium signal, delta[Ca2+]i/basal [Ca2+]i, and insulin secretion became abnormally low between weeks 3 and 6 of CRF. The data allow the following formulation: as serum levels of PTH begins to rise, calcium entry into islets is augmented; this in turn will stimulate the activity of Ca2+ATPase and the Na(+)-Ca2+ exchanger, and hence, calcium extrusion out of the islets is increased. As a result, [Ca2+] remains normal during the first 2 wk of CRF.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1992

Acute effect of parathyroid hormone on Ca2+ ATPase of pancreatic islets.

The Vmax of Ca2+ ATPase of pancreatic islets is reduced in states of chronic excess of PTH. This has been attributed to the reduced ATP content of pancreatic islet and to impaired response of the enzyme to calmodulin. It is also possible that excess PTH directly inhibits the activity of islet Ca2+ ATPase. The present study examined this issue. Small doses of 1-84 PTH (0.0625 and 0.125 x 10(-7) M) stimulated while larger doses (0.25, 0.5, 1.0, 2.0 and 4.0 x 10(-7) M) inhibited the activity of Ca2+ ATPase of intact islets. PTH has no effect on Ca2+ ATPase when the hormone was added to preparation of membrane homogenate of islets. Verapamil abolished both the stimulatory as well the inhibitory effects of PTH on Ca2+ ATPase of intact islets. The data indicate that PTH does not have a direct effect on the Vmax of islet Ca2+ ATPase of islet. Its effect on the enzyme activity of intact islet is most likely mediated through the hormone-induced calcium influx.

Animals↗
PubMed1992

Mechanism of organ dysfunction in phosphate depletion: a critical role for a rise in cytosolic calcium.

Phosphate depletion (PD) is associated with multiorgan dysfunction. It has been proposed that this phenomenon is due to two metabolic derangements: (a) there is a reduction in ATP content of cells and hence reduced availability of energy-rich phosphate compounds, and (b) there is a decrease in 2,3-diphosphoglycerate in red blood cells, a change that would increase the affinity of hemoglobin to oxygen resulting in tissue hypoxia. Recent studies have demonstrated that PD is associated with a significant elevation in basal levels of cytosolic calcium [Ca2+]i in many cells. This is due to an increased entry into and decreased extrusion of calcium out of cells. This rise in [Ca2+]i plays a major role in organ dysfunction in PD and in the genesis of decreased ATP content of cells.

Animals↗
PubMed1991

Nephrology.

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Humans↗