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Biomedical subjects

Z S Agus

Publications and source records attributed to Z S Agus.

At least 37 records · Page 2Linked to original sources
PubMed1983

Hypocalcemia and inhibition of parathyroid hormone secretion after administration of WR-2721 (a radioprotective and chemoprotective agent).

We investigated the causes of the hypocalcemia associated with WR-2721, an investigational drug that protects normal tissues against the toxic effects of radiation and chemotherapy. Sixteen patients with advanced cancers had serial measurements of serum calcium and other studies of blood chemistry before and after taking the compound. In all 16 patients (18 courses) the mean serum calcium level fell from 2.33 to 1.90 mmol per liter (9.33 to 7.62 mg per deciliter, P less than 0.001) after WR-2721, and in all 8 patients from whom data were obtained, serum calcium levels remained depressed at 24 hours. In 12 patients, ionized calcium levels dropped from 0.98 to 0.80 mmol per liter (P less than 0.01). Serum magnesium values fell from 0.96 to 0.74 mmol per liter (1.91 to 1.48 mg per deciliter, P less than 0.001). There were no changes in arterial pH or serum phosphate concentrations. In nine patients urinary calcium excretion rose from 3.96 to 10.68 mumol per minute (P less than 0.01) after WR-2721. Despite hypocalcemia, parathyroid hormone levels fell in all subjects. WR-2721 also inhibited the release of parathyroid hormone from bovine parathyroid cells incubated in vitro in low (0.5 mM) concentrations of calcium. We conclude that WR-2721 inhibits the secretion of parathyroid hormone and enhances calciuria, thereby leading to hypocalcemia.

Amifostine↗
PubMed1983

Potassium secretion in the rabbit proximal straight tubule.

The renal handling of potassium is generally thought to involve proximal reabsorption and distal secretion. To evaluate transport in the pars recta, we perfused S2 and S3 segments from superficial and juxtamedullary proximal straight tubules isolated from the rabbit kidney. The data indicate net potassium secretion in the isolated perfused perfused proximal straight tubule (PST). K+ secretion (JK, pmol X mm-1 X min-1) was -2.51 +/- 0.53 in superficial PST S2 segments, -2.80 +/- 1.05 in superficial PST S3 segments, and -1.36 +/- 0.84 in juxtamedullary PST. Secretion was inhibited by 10(-5) M ouabain in the bath in superficial S2 and S3 segments. When a solution resembling late proximal tubular fluid was perfused in superficial PST, JK fell from -3.86 +/- 1.77 to -0.45 +/- 0.63 pmol X mm-1 X min-1. When luminal flow rate was varied in the physiologic range in individual superficial S2 and S3 segments, JK varied directly; K+ secretion increased by -0.5 pmol X mm-1 X min-1 per 1 nl X min-1 increment in luminal flow, while collected K+ concentration did not vary significantly. When a favorable bath-to-lumen K+ gradient (10 vs. 5 mM) was imposed, K+ secretion was markedly enhanced; when an equal but oppositely directed gradient was imposed, net K+ reabsorption was observed. These data are consistent with a gradient-limited process. In midcortical tubule segments (S2 and S3), 10(-3) M amiloride in perfusate inhibited net K+ secretion from -2.77 +/- 0.52 to -0.18 +/- 1.08 pmol X mm-1 X min-1 and fluid absorption from 0.42 +/- 0.10 to 0.18 +/- 0.05 nl X mm-1 X min-1. Net K+ secretion in S2 and S3 segments of PST may contribute to previously reported K+ secretion prior to the bend of Henle's loop. The magnitude of this process in vivo is uncertain in the absence of measurements of interstitial K+ concentration in the milieu of the PST.

Amiloride↗
PubMed1982

Disorders of calcium and magnesium homeostasis.

The components of calcium and magnesium balance and the factors responsible for the maintenance of the serum concentration of these cations are reviewed. Within this framework, the causes and treatment of disturbances of the serum concentration are discussed. Hypercalcemia is usually a reflection of increased bone resorption and/or gut absorption with the kidney playing a secondary role. Hypocalcemia is usually due to either a disturbance in the parathyroid hormone-adenylate cyclase system or a disturbance in vitamin D metabolism. As vitamin D is required for expression of the action of PTH at bone and as PTH is a prime regulator of vitamin D metabolism, the absence of either component results in important disturbances in calcium balance. In contrast to calcium homeostasis, the kidney plays a major role in the determination and regulation of serum magnesium. The major causes of hypermagnesemia therefore are associated with loss of renal function, and hypomagnesemia is frequently due to renal magnesium wasting.

Calcium Metabolism Disorders↗
PubMed1982

Phosphate transport in the light segment of the rabbit cortical collecting tubule.

The mode and mechanism of phosphate transport in the light portion of the rabbit cortical collecting duct were studied with isolated tubular perfusion. Control studies (n = 48) revealed a mean transepithelial potential difference (PD) of -16.5 +/- 1.3 mV and net phosphate absorption (JPO4) of 0.58 +/- 0.07 pmol.mm-1.min-1. To characterize transport, the effects of flow rate, ouabain, amiloride, and phosphate concentration, and parathyroid hormone (PTH) were analyzed. There was a significant linear relationship between JPO4 and flow rate (n = 48) (r = 0.71, P less than 0.025). Increasing the difference between lumen and bath phosphate concentration from -8.0 to +8.0 mg/dl was associated with a stepwise increase in JPO4 from -0.18 +/- 0.02 to 0.93 +/- 0.05 pmol.mm-1.min-1. PTH had no effect on JPO4. To assess the effects of PD, the tubules were treated with either amiloride (n = 6) or ouabain (n = 7). JPO4 fell significant in both circumstances with reduction of PD, although there remained significant residual transport following amiloride addition. The data demonstrate significant phosphate transport in this segment that is independent of PTH and altered by transepithelial electrical and concentration gradients as well as flow rate.

Amiloride↗
PubMed1982

Magnesium transport in the cortical thick ascending limb of Henle's loop of the rabbit.

Isolated cortical thick ascending limbs of Henle's loop were perfused in order to directly evaluate magnesium transport in this segment. Transepithelial potential difference was altered by varying the NaCl concentration in perfusate and bath and adding 50 microM furosemide to the perfusate. Perfusion under standard conditions with isotonic solutions resulted in a mean transepithelial potential difference of +8.8 +/- 0.7 mV and net magnesium absorption at a rate of 0.32 +/- 0.06 pmol/mm per min. Perfusion with a hypotonic solution significantly increased potential difference and the net absorptive rate of magnesium, calcium, and potassium. Conversely, reversal of the polarity of the potential difference with low NaCl bath and luminal furosemide produced net secretion of magnesium, calcium, and potassium. Parathyroid hormone in a bath concentration of 1.0 U/ml increased magnesium absorption from 0.32 +/- 0.06 to 0.63 +/- 0.06 pmol/mm per min (P less than 0.001) and calcium from 0.52 +/- 0.08 to 0.97 +/- 0.08 pmol/mm per min (P less than 0.001). Dibutyryl cyclic AMP produced similar effects on both calcium and magnesium absorption. Increasing bath calcium concentration twofold significantly inhibited net calcium absorption from 0.79 +/- 0.27 to 0.16 +/- 0.02 pmol/mm per min but magnesium transport was unaffected. Increasing bath magnesium concentration twofold significantly inhibited net magnesium absorption from 0.56 +/- 0.14 to -0.09 +/- 0.13 pmol/mm per min but had no effect upon net calcium transport. Net absorption of magnesium was significantly increased with increased concentration in the perfusate but calcium transport was unchanged. Similarly, increasing perfusate calcium concentration produced an increase in net calcium transport but did not alter magnesium transport. These data indicate that this segment of the loop of Henle is an important site for magnesium transport. Transport is influenced by luminal and bath concentration and is stimulated by parathyroid hormone and cyclic AMP. The data do not provide support for the concept of an interactive process between calcium and magnesium, and suggest that the positive transepithelial voltage is an important driving force for net reabsorption of magnesium, as well as calcium and potassium in this segment.

Animals↗
PubMed1982

Effects of phosphate administration on tubular calcium transport.

To evaluate the mode and tubular sites of action of PO4 administration on renal Ca reabsorption, micropuncture and clearance experiments were performed on acutely parathyroidectomized rats: (1) control (n=7), 2.5% saline expansion + furosemide infusion (0.5 mg/kg/hr); (2) PO4 infusion (n=6), treated as were the controls plus intravenous neutral PO4 (25 mg/kg/hr). CaCI2 was infused to keep plasma UF Ca comparable in both groups [2.68 +/- 0.08 mEq/l (mean +/- S.E.) vs 2.52 +/- 0.10, N.S.]. Po4 infusion increased plasma PO4 (14.0 vs 8.4 mg/dl, p less than 0.001) and FE PO4 (9.03% vs. 0.09%, p less than 0.001) but decreased FE Ca (1.83% vs. 5.95%, p less than 0.02) while GFR and FE Na were similar. FD of Na, PO4 and Ca were similar in late proximal and ED tubule punctures. In the LD tubule, PO4 infusion increased FD PO4 (18.5% vs. 7.9%, p less than 0.005) and reduced FD Ca (3.51% vs. 6.66%, p less than 0.01) and (TF/UF) Ca/Na (0.69 vs. 1.40, p less than 0.001). LD tubule FD Ca (y) was inversely related to TF/P PO4 concentration (X) in LD tubules: (y=7.2 - 0.12x, r=0.68, p less than 0.02). Significant Ca reabsorption (1.68% of filtered load) was observed beyond the superficial LD tubule only during PO4 infusion. These data indicate that phosphate infusion enhances Ca reabsorption independently of PTH, plasma Ca, and renal Na handling at a site within and possible beyond the distal convoluted tubule of the superficial nephron. (J Lab Clin Med 99:317, 1982).

Animals↗
PubMed1982

Proximal tubular defects in idiopathic hypercalciuria: resistance to phosphate administration.

Of 100 consecutive patients with recurrent renal calculi, 43 had idiopathic hypercalciuria (IH) on outpatient evaluation. Hypercalciuria was classified as diet-dependent or fasting; all patients had normal serum iPTH and urinary cyclic AMP, and serum phosphate and TmPO4/GFR were reduced in IH compared to normocalciuric stone formers. In 16 patients with IH, clearance studies revealed an elevated urine flow are factored for GFR (V/GFR) as compared with normal controls (p less than 0.05). In 12 patients, serum PTH was normally suppressed by calcium infusion but TmPO4/GFR was persistently reduced. Acute and chronic phosphate administration significantly reduced urine calcium excretion but did not correct the abnormal V/GFR. We conclude that in IH of both the fasting and the diet-dependent type, there is a defect in the proximal tubular reabsorption of sodium and fluid as well as PTH-independent tubular phosphate wasting. The proximal tubular defect is not a consequence of hypercalciuria nor of phosphate depletion but may be a cause of these abnormalities.

Absorption↗
PubMed1980

Effects of two nonsteroidal anti-inflammatory drugs, indomethacin and oxaprozin, on the kidney.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been found to cause sodium retention and to decrease glomerular filtration rate (GFR). We studied the effects of two such drugs, indomethacin and oxaprozin, a new propionic acid derivative, on renal function of awake, normal human subjects during sustained water diuresis. Although neither drug had a long-term effect on GFR or sodium clearance (CNa), indomethacin (six subjects) but not oxaprozin (seven subjects) transiently reduced GFR and CNa. Given over the short term, oxaprozin caused a reduction in GFR from 113.7 +/- 5.7 to 99.8 +/- 4.7 ml/min (p < 0.01) and CNa from 0.84 +/- 0.07 to 0.61 +/- 0.08 ml/min (p < 0.005). The results were much the same when an additional dose of indomethacin was given to subjects who had been receiving the drug for a week. Inference from clearance data at a time when urinary osmolality (Uosm) remained constant but urine flow per GFR (V/GFR) fell suggests that both drugs stimulated proximal tubular sodium and fluid resorption. Both suppressed renin and aldosterone levels comparably and reduced potassium excretion transiently, but only indomethacin caused a sustained change in serum potassium concentration; serum potassium rose from 4.32 +/- 0.10 to 4.56 +/- 0.11 mEq/l (p < 0.05) after 1 wk. These disparate findings suggest that prostaglandin synthesis inhibition may not be the sole mechanism of action of NSAIDs.

Aldosterone↗
PubMed1980

Effects of methyldopa on renal hemodynamics and tubular function.

To determine the effects of methyldopa on renal function, clearance studies were performed on hypertensive subjects during sustained steady-state water diuresis. The data reveal an acute fall in glomerular filtration rate and sodium clearance, whereas renal blood flow was unchanged. The antinatriuresis was the result of decreased filtration of sodium and possibly enhanced proximal tubular sodium reabsorption. These changes occurred before any demonstrable fall in systemic blood pressure; thus a direct effect of the drug on arteriolar resistance within the renal circulation is suggested. Chronic administration of methyldopa for 1 wk induced sustained reduction in blood pressure and resulted in the same changes in renal hemodynamics and sodium excretion noted after acute administration. These data suggest that methyldopa, like other antihypertensives, reduces glomerular filtration rate and increases sodium retention.

Adult↗
PubMed1980

Calcium and phosphate metabolism in tumoral calcinosis.

We have recently seen a patient with tumoral calcinosis, a syndrome comprising hyperphosphatemia, normocalcemia, normal glomerular filtration rate (GFR), and extensive periarticular calcific masses. Parathyroid hormone (PTH) deficiency or target organ resistance was ruled out by demonstration of normal serum PTH and urinary 3'5'cyclic AMP excretion and normal response to exogenous PTH and to endogenous stimulation by ethylenediaminetetraacetate. An intrinsic proximal tubular defect allowing enhanced renal PO4 reabsorption was probably present because there was no phosphaturic response to acetazolamine and renal PO4 threshold remained abnormally elevated even after PTH infusion. We then studied the mechanism by which serum calcium level is maintained in the normal range despite hyperphosphatemia and absence of secondary hyperparathyroidism. Normal 1,25-(OH)2 vitamin D was found, suggesting normal gastrointestinal calcium absorption. This, combined with markedly reduced urinary calcium excretion, perhaps a direct effect of hyperphosphatemia, may maintain calcium balance and prevent secondary hyperparathyroidism. A rise in urinary cyclic AMP excretion after furosemide-induced calciuria supports this hypothesis.

Adult↗
PubMed1979

Evidence for an intrinsic renal tubular defect in mice with genetic hypophosphatemic rickets.

To investigate the role of parathyroid hormone (PTH) and(or) an intrinsic renal tubular reabsorptive defect for phosphate in mice with hereditary hypophosphatemic rickets, we performed clearance and micropuncture studies in hypophosphatemic mutants and nonaffected littermate controls. Increased fractional excretion of phosphate in mutants (47.2+/-4 vs. 30.8+/-2% in controls) was associated with reduced fractional and absolute reabsorption in the proximal convoluted tubule and more distal sites. Acute thyropara-thyroidectomy (TPTX) increased phosphate reabsorption in both mutants and controls with a fall in fractional phosphate excretion to congruent with7.5% in both groups indicating that PTH modified the degree of phosphaturia in the intact mutants. Absolute reabsorption in the proximal tubule and beyond remained reduced in the mutants, however, possibly because of the reduced filtered load. Serum PTH levels were the same in intact mutants and normals as was renal cortical adenylate cyclase activity both before and after PTH stimulation. To evaluate the possibility that the phosphate wasting was caused by an intrinsic tubular defect that was masked by TPTX, glomerular fluid phosphate concentration was raised by phosphate infusion in TPTX mutants to levels approaching those of control mice. Phosphate excretion rose markedly and fractional reabsorption fell, but there was no change in absolute phosphate reabsorption in either the proximal tubule or beyond, indicating a persistent reabsorptive defect in the absence of PTH. We conclude that hereditary hypophosphatemia in the mouse is associated with a renal tubular defect in phosphate reabsorption, which is independent of PTH and therefore represents a specific intrinsic abnormality of phosphate transport.

Animals↗
PubMed1979

Renal tubular sites of altered calcium transport in phosphate-depleted rats.

Increased calcium (Ca) excretion is characteristic of chronic phosphate (PO(4)) depletion (PD). To study the changes in tubular transport and the site of the hypocalciuric effect of PO(4) administration, clearance and micropuncture experiments were performed in intact rats pair fed either a control diet (0.5% PO(4)) or a PO(4)-depleted (PD) diet (0.01% PO(4)) plus Al(OH(3)) and in parathyroidectomized (PTX) PD rats, infused either with saline or with neutral sodium PO(4). Intact PD rats, compared with intact rats on a control diet, exhibited a lower plasma ultrafiltrable (UF) PO(4) (5.8+/-0.5 vs. 7.8+/-0.3 mg/dl), higher fractional excretion (FE) of Ca (4.1+/-1.2 vs. 0.6+/-0.1%), and reduced FE PO(4) (0.1+/-0.01 vs. 10.2+/-1.8%). Tubular fluid/plasma inulin was lower in the late proximal tubule of PD rats, associated with increases in fractional delivery (FD) from the proximal tubule of Na and Ca.The%FD of Ca to the early distal tubule of PD rats was increased (20+/-3 vs. 11+/-2%), but this difference was abolished by the late distal tubule (5.1+/-1.2 vs. 3.3+/-0.9%). In PTX-PD rats, PO(4) infusion increased plasma UF PO(4) (13.8+/-0.7 vs. 7.8+/-0.7 mg/dl). FE of Ca was reduced (1.08+/-0.35 vs. 4.59+/-1.57%) without correcting the increased Ca delivery to the late distal tubule. These data indicate that PD impairs Ca reabsorption in tubular segments before but not within the distal convoluted tubule, so that hypercalciuria is ultimately a result of decreased Ca transport either in the terminal nephron or in deeper nephrons where PO(4) infusion stimulates Ca transport independent of parathyroid hormone or changes in the filtered load of Ca.

Animals↗