Biomedical subjects
Publications and source records attributed to S G Massry.
Captopril given in dosages of 25 mg reduced the doubling of serum creatinine levels by 48% in patients with insulin-dependent diabetes mellitus. Intensive insulin therapy in patients with IDDM delays the onset and slows the progression of diabetic nephropathy, retinopathy, and neuropathy.
Both animals and patients with chronic renal failure have impaired phagocytosis, which is most likely due to elevated basal levels of cytosolic calcium ([Ca2+]i) and reduced adenosine triphosphate (ATP) content of their polymorphonuclear leukocytes (PMNLs). In animals with chronic renal failure, these derangements are prevented or reversed by their treatment with a calcium channel blocker. This observation may have important clinical implications if these drugs exert a similar effect in humans with chronic renal failure. We examined the basal levels [Ca2+]i, ATP content, and phagocytosis in PMNLs from 11 normal subjects, 18 hemodialysis patients (seven of whom had diabetes mellitus), and 18 hemodialysis patients treated with nifedipine (eight of whom had diabetes mellitus). The basal levels of the [Ca2+]i content of the PMNLs in hemodialysis patients without nifedipine therapy were significantly (P < 0.01) elevated (nondiabetic patients, 77 +/- 3.2 nmol/L; diabetic patients, 75 +/- 1.9 nmol/L) compared with normal values (42 +/- 0.9 nmol/L). Treatment with nifedipine was associated with the return of [Ca2+]i toward normal values in both the nondiabetic (51 +/- 4.5 nmol/L) and diabetic (54 +/- 2.5 nmol/L) hemodialysis patients. The ATP content of PMNLs from hemodialysis patient was significantly (P < 0.01) reduced compared with normal, and nifedipine therapy restored the ATP content to normal values. Phagocytosis was significantly (P < 0.01) impaired in hemodialysis patients (nondiabetic patients, 78 +/- 4.0 micrograms oil/10(7) PMNLs/min; diabetic patients, 77 +/- 4.8 micrograms oil/10(7) PMNLs/min). Nifedipine therapy returned the impaired phagocytosis toward normal (nondiabetic patients, 133 +/- 2.5 micrograms oil/10(7) PMNLs/min; diabetic patients, 129 +/- 6.4 micrograms oil/10(7) PMNLs/min).(ABSTRACT TRUNCATED AT 250 WORDS)
The mRNA of PTH-PTHrP receptor in the kidney and liver of CRF rats is down-regulated. It is not known whether this is a generalized phenomenon and the signals that mediate such down-regulation are not evident. Excess PTH in CRF induces a rise in basal levels of cytosolic calcium ([Ca2+]i), and the high [Ca2+]i is implicated in the genesis of cell dysfunction in CRF. Therefore, it is reasonable to propose that the PTH-induced rise in [Ca2+]i provides a negative feedback control system for the down-regulation of the mRNA of the PTH-PTHrP in order to protect the cells from the harmful effects of progressive rise in blood levels of PTH in CRF. The heart contains the mRNA for this receptor and it is a target organ for PTH action. We examined whether the message of the PTH-PTHrP receptor is down-regulated in the heart of CRF animals and evaluated the role of [Ca2+]i in this process. The expression of the mRNA of the PTH-PTHrP was significantly reduced in the heart of CRF rats as compared to normal animals. Also, the CRF rats had elevated blood levels of PTH and high [Ca2+]i of cardiac myocytes. The parathyroidectomy of CRF rats prevented the rise in blood PTH levels and normalized [Ca2+]i of cardiac myocytes and returned the mRNA of their PTH-PTHrP receptor towards normal levels. The treatment of CRF rats with verapamil normalized [Ca2+]i of cardiac myocytes and returned the mRNA of their PTH-PTHrP receptor towards normal levels, despite marked elevation of blood levels of PTH.(ABSTRACT TRUNCATED AT 250 WORDS)
Calcification of the lungs occurs in chronic renal failure (CRF) and may adversely affect both pulmonary and right ventricular function. The present study examined the role of excess parathyroid hormone (PTH) in the genesis of pulmonary calcifications in dogs with experimental CRF and evaluated calcium content of lungs, diffusing lung capacity (DCO), mean pulmonary artery pressure (MPAP), right ventricular pressure (RVP), and right ventricular hypertrophy (RVH) in six normal, six with CRF, and six thyroparathyroidectomized (CRF-PTX) dogs. CRF-PTX animals were maintained normocalcemic and euthyroid. The degree and duration of CRF were not different between the two groups with CRF. The mean value of the serum PTH in CRF dogs was 166 +/- 42 microliters Eq/ml, but was undetectable in CRF-PTX animals. Thallium scan provided evidence consistent with RVH in CRF dogs but not in CRF-PTX animals. Calcium content of lungs was markedly elevated in CRF dogs (7656 +/- 1657 mg/kg dry wt) but modestly increased in CRF-PTX (1057 +/- 117 mg/kg dry wt) as compared to normal (673 +/- 34 mg/kg dry wt). RVP and MPAP were significantly (P < 0.01) higher and DCO significantly lower in CRF dogs than in normal or CRF-PTX animals. These parameters were not different in the latter two group of dogs. In three additional dogs with CRF of one year duration which were followed for an additional year after parathyroidectomy, these abnormalities were corrected.(ABSTRACT TRUNCATED AT 250 WORDS)
Chronic renal failure (CRF) is associated with increased calcium content of, and impaired lipase release from lipid cells. This has been attributed to a rise in the cytosolic calcium ([Ca2+]i) of these cells. However, data on [Ca2+]i of lipid cells in CRF and on the mechanisms responsible for such an abnormality are lacking. To study this issue we examined the [Ca2+]i and ATP content of lipid cells and Vmax of Na(+)-K(+)-ATPase and Ca2+ ATPase of membrane preparation and Na(+)-Ca2+ exchange of membrane vesicles of adipocytes from normal rats, 6 week CRF, CRF normocalcemic parathyroidectomized (CRF-PTX) and CRF, and normal rats treated with verpamil (CRF-V, normal-V). [Ca2+]i in adipocytes of CRF rats was higher (199 +/- 8.5 nM) and ATP lower (2.9 +/- 0.31 nmol/10(6) cells) than in normal (120 +/- 4.3 nM; 5.7 +/- 0.27 nmol/10(6) cells), CRF-PTX (128 +/- 4.7 nM; 5.8 +/- 0.39 nmol/10(6) cells), normal-V (121 +/- 3.2 nM; 5.3 +/- 0.36 nmol/10(6) cells), CRF-V (123 +/- 7.4 nM; 5.5 +/- 0.30 mmol/10(6) cells). Vmax Ca2+ ATPase and the activity of Na(+)-K(+)-ATPase and of Na(+)-Ca2+ exchanger were reduced in CRF rats as compared to the other four groups of rats. The values in normal, CRF-PTX, CRF-V and normal-V rats were not different.(ABSTRACT TRUNCATED AT 250 WORDS)
The basal levels of cytosolic calcium ([Ca2+]i) of polymorphonuclear leukocytes (PMNL) are elevated in hemodialysis (HD) patients, and this abnormality has been implicated in the dysfunction of the PMNL of these patients. The elevated [Ca2+]i appears to be due to PTH-induced entry of calcium into PMNL, an action that may be prevented by calcium channel blockers. We examined [Ca2+]i and carbohydrate metabolism of PMNL of normal subjects and of HD patients before, after eight to nine weeks of verapamil therapy (120 mg/day), and after eight to ten weeks of discontinuation of verapamil treatment. In HD patients, the basal levels of [Ca2+]i of PMNL are elevated and their glucose uptake, the activity of total and active forms of glycogen synthetase, and glycogen content are reduced compared to values in normal subjects (P < 0.01). These derangements were normalized after verapamil therapy and re-emerged after discontinuation of treatment with verapamil despite no change in blood levels of PTH. The results indicate that the elevation in [Ca2+]i of PMNL and the consequent derangements in carbohydrate metabolism of these cells are treatable with a calcium channel blocker. The data assign a valuable role for calcium channel blockers for the amelioration of some aspects of cell dysfunction of uremia.
Some hormones exert their action by inducing a rise in cytosolic calcium [Ca2+]i (calcium signal), and therefore, a blunting in hormone-induced calcium signal would engender resistance to the action of the hormone. Chronic renal failure (CRF) is associated with resistance to the action of a variety of hormones, a rise in [Ca2+]i and decrease in the amount of mRNA of one hormone receptor, the PTH-PTHrP receptor. We examined the calcium-signal induced by PTH, angiotensin II, vasopressin and glucagon in hepatocytes from CRF animals, evaluated the effect of the basal level [Ca2+]i on the calcium signal and explored the effect of [Ca2+]i on the mRNA of the receptors of these agonists. Hepatocytes from CRF rats have elevated basal levels of [Ca2+]i and display significantly reduced calcium signals induced by all these hormones, while the calcium signals were normal in PTX-CRF animals and those treated with verapamil both of which have normal levels of [Ca2+]i despite CRF. The calcium signals induced by dibutyryl cyclic AMP and G protein activator (GTP gamma S) were normal in hepatocytes from CRF animals despite the high levels of [Ca2+]i. Northern blotting experiments revealed that the levels of the mRNA of the receptors of PTH-PTHrP, angiotensin II and vasopressin were significantly reduced in hepatocytes from CRF animals but PTX-CRF rats and those treated with verapamil had either significantly greater or even normal amounts of the mRNA of these receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
Patients with advanced renal failure have derangements in the function of their nervous system. The available clinical and experimental data indicate that the state of the secondary hyperparathyroidism of renal failure plays a major role in the genesis of the nervous system dysfunction. The excess parathyroid hormone (PTH) mediates its deleterious effect by causing an elevation in cytosolic calcium of brain cells. This report reviews the evidence leading to the conclusion that PTH is a major uremic toxin.
Chronic renal failure (CRF) is associated with increased Ca2+ content of liver and reduced hepatic lipase activity. This has been attributed to a rise in cytosolic Ca2+ ([Ca2+]i) of the hepatocytes, but data on this issue are lacking. We examined the [Ca2+]i and ATP content of hepatocytes as well as the activity of Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase), Ca(2+)-ATPase, and Na+/Ca2+ exchanger of hepatic membrane vesicles from normal rats, animals with 6 wk of CRF, CRF normocalcemic parathyroidectomized (CRF-PTX) rats, and CRF and normal animals treated with verapamil (CRF-V, normal-V). [Ca2+]i in hepatocytes of CRF rats was higher (281 +/- 7.4 nM) and ATP lower (6.4 +/- 1.8 nmol/mg protein) than in normal (209 +/- 5.3 nM; 12.5 +/- 0.89 nmol/mg protein), CRF-PTX (212 +/- 1.0 nM; 13.7 +/- 0.79 nmol/mg protein), normal-V (215 +/- 2.3 nM; 14.2 +/- 0.77 nmol/mg protein), and CRF-V rats (209 +/- 7.4 nM; 14.8 +/- 0.72 nmol/10(6) cells). The Na(+)-K(+)-ATPase, the maximal velocity of Ca(2+)-ATPase, and the activity of the Na+/Ca2+ exchanger were reduced, whereas the Michaelis constant of Ca(2+)-ATPase was increase in CRF rats compared with the other four groups of rats. The values in the latter groups were not different.(ABSTRACT TRUNCATED AT 250 WORDS)
Parathyroid hormone (PTH) raises cytosolic Ca2+ concentration ([Ca2+]i) in isolated or cultured renal proximal tubule cells. The pathways through which this action is mediated are not fully delineated. This study explored these pathways utilizing fura 2. [Ca2+]i of freshly prepared renal proximal tubular cells increased from 150 +/- 3.6 to 281 +/- 9.0 nM after the exposure to 10(-7) M angiotensin II, which served as a positive control. Both PTH-(1-84) and PTH-(1-34) produced a dose-dependent rise in [Ca2+]i. The effects of both moieties were similar up to 10(-7) M, but with higher doses the rise in [Ca2+]i with PTH-(1-84) was greater (P < 0.01) than with PTH-(1-34). This effect of the hormone occurred in the presence or absence of calcium in the media, but the rise in [Ca2+]i was significantly greater in the presence of calcium. The PTH-induced rise in [Ca2+]i was markedly inhibited by PTH antagonist [Nle8,18,Tyr34]bPTH-(7-34)-NH2 (bPTH is bovine PTH), verapamil, or nifedipine. 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C, increased [Ca2+]i of cells, but its effect was less than PTH. Staurosporine abolished the TPA effect and partially inhibited that of PTH. A G protein activator raised [Ca2+]i, whereas a G protein inhibitor and pertussis toxin partially blocked the effect of PTH. Sodium or chloride channel blockers or sodium-free media did not modify the effect of PTH.(ABSTRACT TRUNCATED AT 250 WORDS)
The outcome of renal transplantation in 64 patients with end-stage renal disease (ESRD) secondary to lupus nephritis is the subject of this report. The patients were transplanted over a 150-month (12.5-year) period (between July 5, 1979, and January 30, 1992). The study population is predominantly made up of young females (mean age, 34.7 +/- 9 years, n = 54, 81.3%). Fifty-one transplants (79.7%) are cadaveric, and 13 (20.3%) are from living-related donors. Fifty-eight patients (90.6%) had primary (first) allografts, and 6 (9.4%) received a second allograft. Posttransplantation immunosuppression consisted of azathioprine and prednisone (AZA group, n = 22, 34.3%) or AZA, prednisone and cyclosporine (CsA group, n = 42, 65.6%). For all 64 patients combined, the 1-year graft and patient survival rates are 68.8 and 86.5%, respectively, whereas 5-year graft and patient survival rates are 60.9 and 85.9%, respectively. Patients whose immunosuppressive regimen was CsA-based had a 1-year graft survival of 71.5 versus 63.6% in the AZA group. However, this 7.9% difference did not reach statistical significance (p = 0.95). The 5-year graft survival of the CsA-based group was 69.1 versus 45.5% for the AZA group, p < 0.05. One-year patient survival was 77.3% for the AZA group and 92.9% for the CsA group, p < 0.05). The data show that patients with ESRD secondary to lupus nephritis can undergo renal transplantation with satisfactory outcome. Immunosuppression based upon CsA improves first-year patient and allograft survival by 15.6 and 7.9%. respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
The long-term effects of indapamide or hydrochlorothiazide on blood pressure and renal function were examined in patients with impaired renal function and moderate hypertension. Both drugs controlled hypertension and blood pressure remained normal during the 2 years of the study. Despite this comparable control of hypertension, indapamide therapy was associated with a 28.5 +/- 4.4% increase in creatinine clearance while treatment with hydrochlorothiazide was associated with a 17.4 +/- 3.0% decrease in creatinine clearance. The results of the study indicate that indapamide is superior to hydrochlorothiazide in the treatment of patients with impaired renal function and moderate hypertension.
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Chronic renal failure (CRF) is associated with an increase in calcium content of heart. This was attributed to the secondary hyperparathyroidism of CRF, since PTH augments entry of calcium into cardiac myocytes. At present, it is not known whether the increase in calcium content of heart reflects a rise in basal levels of cytosolic calcium ([Ca2+]) of cardiac myocytes. Further, in order for the PTH-induced entry of calcium into cardiac myocytes to raise their basal levels of [Ca2+]i, calcium extrusion out of these cells should be impaired as well. The present study examined the effect of CRF with and without excess PTH (PTX) and of the treatment of CRF rats with verapamil on basal levels of [Ca2+]i and ATP content of cardiac myocytes and on the activities of the pumps that are directly (Ca(2+)-ATPase and Na(+)-Ca2+ exchanger) and indirectly (Na(+)-K+ ATPase) responsible for calcium extrusion out of these cells. The basal levels of [Ca2+]i of cardiac myocytes increased (P < 0.01) and their ATP content decreased (P < 0.01) as the duration of CRF advanced. CRF was associated with significant decrement in Vmax of Ca2+ ATPase and Na(+)-K+ ATPase and in Na(+)-Ca2+ exchange. These derangements were prevented by prior PTX of the CRF rats or by their treatment with verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)
Available data indicate that the liver is a target organ for parathyroid hormone (PTH) and that this effect is most likely mediated by PTH-induced calcium entry into hepatocytes. The present study examined the effects of both PTH-(1-84) and its amino-terminal fragment [PTH-(1-34)] on cytosolic calcium concentration ([Ca2+]i) of hepatocytes and explored the cellular pathways that mediate this potential action of PTH. Both moieties of PTH produced a dose-dependent rise in [Ca2+]i, but the effect of PTH-(1-84) was greater (P < 0.01) than an equimolar amount of PTH-(1-34). This effect required calcium in the medium and was totally [PTH-(1-34)] or partially [PTH-(1-84)] blocked by PTH antagonist ([Nle8,18,Tyr34]bPTH-(7-34)-NH2] and by verapamil or nifedipine. Sodium or chloride channel blockers did not modify this effect. 12-O-tetradecanoylphorbol 13-acetate (TPA), an activator of protein kinase C, dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP), and G protein activator also produced a dose-dependent rise in [Ca2+]i. Staurosporine abolished the effect of TPA, and both staurosporine and calphostin C partially inhibited the effect of PTH. Staurosporine and verapamil together produced greater inhibition of PTH action than each alone. Rp-cAMP, a competitive inhibitor of cAMP binding to the R subunit of protein kinase A, and N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), a protein kinase A inhibitor, blocked the effect of both DBcAMP and PTH, but the effect of these agents was greater (P < 0.01) on DBcAMP action. G protein inhibitor and pertussis toxin partially blocked the action of PTH. The data indicate that 1) PTH increases [Ca2+]i of hepatocytes; 2) this action of the hormone is receptor mediated; 3) the predominant pathway for this PTH action is the stimulation of a G protein-adenylate cyclase-cAMP system, which then leads to stimulation of a calcium transport system inhibitable by verapamil or nifedipine or activation of L-type calcium channels; 4) activation of protein kinase C is also involved; and 5) the PTH-induced rise in [Ca2+]i is due, in major parts, to movement of extracellular calcium into the cell.
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.