Phosphaturic Effect Of Parathyroid Hormone Research Articles

Regulation of renal NaPi-2 expression and tubular phosphate reabsorption by growth hormone in the juvenile rat.

Growth hormone (GH) is an important factor in the developmental adaptation to enhance P(i) reabsorption; however, the nephron sites and mechanisms by which GH regulates renal P(i) uptake remain unclear and are the focus of the present study. Micropuncture experiments were performed after acute thyroparathyroidectomy in the presence and absence of parathyroid hormone (PTH) in adult (14- to 17-wk old), juvenile (4-wk old), and GH-suppressed juvenile male rats. While the phosphaturic effect of PTH was blunted in the juvenile rat compared with the adult, suppression of GH in the juvenile restored fractional P(i) excretion to adult levels. In the presence or absence of PTH, GH suppression in the juvenile rat caused a significant increase in the fractional P(i) delivery to the late proximal convoluted (PCT) and early distal tubule, so that delivery was not different from that in adults. These data were confirmed by P(i) uptake studies into brush-border membrane (BBM) vesicles. Immunofluorescence studies indicate increased BBM type IIa NaP(i) cotransporter (NaPi-2) expression in the juvenile compared with adult rat, and GH suppression reduced NaPi-2 expression to levels observed in the adult. GH replacement in the [N-acetyl-Tyr(1)-d-Arg(2)]-GRF-(1-29)-NH(2)-treated juveniles restored high NaPi-2 expression and P(i) uptake. Together, these novel results demonstrate that the presence of GH in the juvenile animal is crucial for the early developmental upregulation of BBM NaPi-2 and, most importantly, describe the enhanced P(i) reabsorption along the PCT and proximal straight nephron segments in the juvenile rat.

Parathyroid hormone activity increases during endotoxemia in conscious rats.

Our previous studies showed that the phosphaturic effect of parathyroid hormone (PTH) is blunted during acute-phase endotoxemia in anesthetized rats. However, the possibility that the antiphosphaturia was secondary to hyponatriuresis due to endotoxin (Et)-induced acute renal failure could not be ruled out. The objective of this study was to evaluate phosphate (Pi) excretion during early- and late-phase endotoxemia in conscious rats fed by total parenteral nutrition. Male Wistar rats weighing 270 g were used. Urine samples were taken to determine the Pi excretion rate for 12 h just after Et (E. coli B055) challenge (early-phase endotoxemia), and for 12 h after a 36-h recovery period following Et challenge (late-phase endotoxemia). Rats given isovolumetric saline instead of Et served as controls. Et injection reduced endogenous creatinine clearance markedly (0.88 +/- 0.12 ml/min, P < 0.0001, n = 7) and caused hyponatriuresis (0.80 +/- 0.19 microliters/min, P < 0.001) compared with saline injection (1.78 +/- 0.10 ml/min and 3.12 +/- 0.39 microliters/min, respectively, n = 8) during the early phase. Greater phosphaturia and hypocalciuria were observed simultaneously during early- (Pi excretion = 4.18 +/- 1.38 micrograms/min, P < 0.05; calcium excretion = 0.70 +/- 0.14 micrograms/min, P < 0.05) and late-phase (4.76 +/- 1.72 micrograms/min, P < 0.05; 0.60 +/- 0.18 micrograms/min, P < 0.05, respectively) endotoxemia (n = 8) in comparison with the respective control values (1.61 +/- 0.39 and 1.40 +/- 0.21 micrograms/min, early; 0.34 +/- 0.14 and 1.97 +/- 0.55 micrograms/min, late, n = 6). Et adminidstration resulted in a significantly increased plasma PTH concentration during the late phase (34.7 +/- 7.0 pg/ml, P < 0.05) compared with saline administration (15.4 +/- 2.4 pg/ml). In conclusion, these data suggest that the hyperphosphaturia during endotoxemia lasting longer than 12 h is attributable to elevated PTH secretion.

Regulation of renal phosphate handling: recent findings.

Our knowledge of renal phosphate handling and its regulation has expanded in the past 2 years because of the molecular identification of sodium-phosphate cotransport systems. New tools (molecular probes and antibodies) have allowed dissection out of some of the molecular and cellular mechanisms underlying the adaptation of phosphate transport to dietary content, the phosphaturic effect of parathyroid hormone or glucocorticoids and the renal phosphate leak in hypophosphataemic rickets.

22-Oxacalcitriol does not interfere with parathyroid hormone-induced phosphaturia or cyclic-AMP excretion.

The vitamin D analogue, 22-oxacalcitriol [22-oxa-1,25(OH)2 vitamin D3], has pleiotropic effects similar to or greater than calcitriol but has markedly fewer calcemic and phosphatemic effects. To test the hypothesis that the lesser phosphatemic effect of 22-oxacalcitriol is due, at least in part, to a lack of interference with the phosphaturic effect of parathyroid hormone, acute clearance experiments were performed in parathyroidectomized rats receiving continuous 1-34 parathyroid hormone (PTH) infusion together with 22-oxacalcitriol (200 pmol.100 g body weight-1.min-1) or vehicle. In contrast to the previously reported inhibitory effect of calcitriol on PTH-induced phosphaturia, fractional excretion of phosphorus increased similarly in both groups, from 0.05 +/- 0.01 to 0.26 +/- 0.02 (p < 0.01) in the vehicle-infused animals and from 0.04 +/- 0.01 to 0.24 +/- 0.02 (p < 0.01) in the 22-oxacalcitriol-treated rats (p between groups not significant [n.s.]). Urinary cyclic AMP excretion also increased similarly, from 45.5 +/- 5.2 to 101.6 +/- 21.6 (p < 0.01) and from 45.4 +/- 5.6 to 102.6 +/- 16.7 pmol/min (p < 0.01), respectively (p between groups n.s.). In search for a nongenomic mechanism that might account for the disparate effects of 22-oxacalcitriol and calcitriol, OK cells, which are reminiscent of the mammalian proximal tubule cell, were stimulated with calcitriol and 22-oxacalcitriol and free intracellular calcium concentration was determined. At high concentrations, calcitriol caused a dose-dependent increase in [Ca2+]i; 22-oxacalcitriol had no effect on [Ca2+]i at any concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Phosphaturic effect of PTH during hypoxia and hypocapnia in rats

This study examined the effect of acute hypoxia or hypocapnia on renal phosphate excretion in thyroparathyroidectomized rats. Hypoxia is usually accompanied by a secondary hypocapnia due to hypoxic hyperventilation. Respiratory alkalosis has been described as blunting the phosphaturic effect of parathyroid hormone (PTH). In the present study, to know the effect of hypoxia on renal phosphate excretion in the absence of hypocapnia, the rats were ventilated mechanically, and arterial PCO2 levels were controlled. The rats were divided into three groups depending on the arterial PO2 and PCO2 levels: 1) hypoxic normocapnic group; 2) normoxic normocapnic group; 3) normoxic hypocapnic group. Hypoxia was achieved by ventilating with 10% oxygen, and hypocapnia by hyperventilating with 25-30% oxygen. PTH infusion significantly increased fractional excretion of phosphate (FEPi) from 4.1 +/- 0.9 (mean +/- SE) to 37.7 +/- 2.6% in the hypoxic group (n = 7), from 1.4 +/- 0.3 to 27.4 +/- 2.5% in the normoxic group (n = 8), and from 1.5 +/- 0.4 to 19.5 +/- 1.2% in the hypocapnic group (n = 10). The change of FEPi (delta FEPi) after PTH infusion during hypoxia was significantly greater (33.6 +/- 2.1%) than that during normoxia (26.1 +/- 2.4%, p < 0.05). In contrast to this, hypocapnia blunted the phosphaturic response to PTH (18.0 +/- 1.1% delta FEPi, p < 0.05). Urinary adenosine 3', 5'-cyclic monophosphate (cAMP) increased similarly after PTH infusion in all three groups. To test whether the enhanced phosphaturic effect of PTH during hypoxia and the blunted phosphaturic effect of PTH during hypocapnia are due to steps beyond the production of cAMP, cAMP was administered to the three groups. Cyclic AMP infusion displayed greater phosphaturia in the hypoxic group (n = 6, 30.0 +/- 1.4%) and less phosphaturia in the hypocapnic group (n = 7, 11.3 +/- 1.8%) as compared the the normoxic group (n = 6, 24.1 +/- 1.0%). In conclusion, acute hypoxia enhances the phosphaturic effect of PTH, whereas acute hypocapnia attenuates the phosphaturic effect of PTH.

Phosphaturic effect of parathyroid hormone in the spontaneously hypertensive rat

The Okamoto spontaneously hypertensive rat (SHR) has been reported to have altered phosphate metabolism. Hypophosphaturia in the presence of increased serum parathyroid hormone (PTH) levels has been reported in the SHR. Therefore it has been postulated that the SHR may be hyporesponsive to the phosphaturic effect of endogenous PTH. In addition, the SHR exhibits enhanced renal sympathetic nerve activity. Recent studies demonstrated that stimulation of the renal adrenoreceptors decreases the phosphaturic response to PTH infusion. Thus a hyporesponsiveness to PTH in the SHR may be due in part to higher renal sympathetic tone. The present study determined the phosphaturic effect of a pharmacological dose of PTH (33 U/kg bolus and 1 U.kg-1.min-1 infusion) in the thyroparathyroidectomized SHR compared with its normotensive control, the Wistar Kyoto (WKY) rat. Three groups of clearance experiments were performed on male 10- to 14-wk-old SHR and WKY rats. In the first group of rats, the fractional excretion of phosphate (FEPi) in response to PTH infusion was 35.4 +/- 4.2% in the SHR (n = 6) and 26.2 +/- 3.0% in the WKY rat (n = 6), NS. In the second group, all animals underwent acute unilateral renal denervation (DNX). The FEPi in response to PTH was 35.3 +/- 1.5% in the innervated (INN) kidney of the SHR (n = 10) compared with 27.9 +/- 2.5% in the INN kidney of the WKY rat (n = 11), and 39.1 +/- 1.9% in the DNX kidney of the SHR compared with 30.5 +/- 2.0% in the DNX kidney of the WKY rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of acute hypoxia on phosphate excretion in rats

This study evaluated the effect of acute hypoxia on renal handling of phosphate in rats in the presence and absence of parathyroid hormone (PTH). Hypoxia causes respiratory alkalosis in spontaneously breathing humans and animals. Respiratory alkalosis has been reported to induce a blunted phosphaturic response to PTH. In this study, to avoid the confounding effect of hypocapnia accompanying the hypoxia on phosphate excretion, the rats were ventilated mechanically, and arterial PCO2 levels were controlled. Rats were divided into two main groups depending on the arterial PO2 levels: a hypoxic group (n = 16) and a normoxic group (n = 18). Hypoxia was produced by ventilating with 10% oxygen, and hypocapnia was produced by hyperventilation. In response to PTH, the hypoxic rats without hypocapnia showed a greater increase in fractional excretion of phosphate (FEPi; 37.7 +/- 2.6%, mean +/- SE) compared with normoxic rats (27.4 +/- 2.5%, P < 0.02). During hypocapnia, there was no difference in FEPi between hypoxic and normoxic groups (21.2 +/- 1.5 and 19.5 +/- 1.2%, respectively), and both groups showed a significantly blunted phosphaturic response to PTH compared with normocapnia (P < 0.05 and P < 0.01, respectively). Urinary adenosine 3',5'-cyclic monophosphate (cAMP) increased similarly after PTH infusion between each group. To test whether the phosphaturic effect of PTH in hypoxia and the blunted phosphaturic effect of PTH in hypocapnia are due to steps beyond the generation of cAMP, the phosphaturic response to cAMP infusion was evaluated in 1) hypoxic and normocapnic rats (n = 6), 2) normoxic and normocapnic (control) rats (n = 6), and 3) normoxic and hypocapnic rats (n = 7).(ABSTRACT TRUNCATED AT 250 WORDS)

Dopamine enhances the phosphaturic response to parathyroid hormone in phosphate-deprived rats.

Phosphate deprivation results in a resistance to the phosphaturic effect of parathyroid hormone. Dopamine is phosphaturic and is synthesized by kidney proximal tubule, the nephron subsegment where parathyroid hormone inhibits phosphate transport. Thus, to test the hypothesis that phosphate deprivation is associated with low intrarenal dopamine synthesis and that dopamine infusion will overcome the resistance to the phosphaturic response to parathyroid hormone, the following study was performed. The effect of dietary phosphate intake on intrarenal dopamine synthesis, as reflected by urinary dopamine excretion, was determined. Rats were placed in metabolic cages (N = 5) and were fed a low-phosphate diet (0.07% Pi) for 4 days and then a high-phosphate diet (1.8% Pi) for 4 days. Twenty-four-hour urinary dopamine excretion was significantly lower in rats fed a low-phosphate diet (2.53 +/- 0.06 versus 4.10 +/- 0.30 micrograms/day). Further, the effect of dopamine infusion on the blunted phosphaturic response to parathyroid hormone was studied in rats fed a low-phosphate diet for 1, 2, and 3 days. Control clearances were taken 2 h after thyroparathyroidectomy; then, parathyroid hormone (33 U/kg plus 1 U/kg/min), dopamine (25 micrograms/kg/min), or parathyroid hormone plus dopamine were infused for 60 min. Changes in the fractional excretion of phosphate were significantly greater in rats fed a low-phosphate diet infused with parathyroid hormone plus dopamine than in rats fed a low-phosphate diet infused with parathyroid hormone alone (delta 27.9 +/- 5.8 versus 11.2 +/- 2.6% for day 1; 28.4 +/- 1.4 versus 7.1 +/- 3.6% for day 2; and 10.7 +/- 2.8 versus -0.2 +/- 0.2% for day 3; N = 5 for all groups).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of propranolol on phosphate reabsorption by superficial nephron segments in response to parathyroid hormone in phosphate-deprived rats.

Phosphate deprivation causes a resistance to the phosphaturic effect of parathyroid hormone. The decreased phosphaturic response to parathyroid hormone in rats fed a low phosphate diet for 1 day can be restored by propranolol infusion. Free-flow micropuncture studies were performed to localize the nephron site of restoration of the phosphaturic effect of parathyroid hormone by propranolol in rats deprived of phosphate for one day. In animals fed low phosphate diet and in the presence of parathyroid hormone, propranolol infusion did not change phosphate delivery to the late proximal tubule; however, fractional delivery of phosphate to the early distal tubule was significantly increased from 18.3 +/- 2.9 to 32.2 +/- 4.1%. In rats fed a normal phosphate diet, propranolol infusion did not change phosphate delivery along the nephron. We conclude that the restoration of the phosphaturic effect of parathyroid hormone by propranolol infusion in rats deprived of phosphate for 1 day is primarily due to decreased reabsorption of phosphate by superficial loop segments, most likely the pars recta segment of the proximal tubule.

Site of restoration of the effect of PTH by propranolol in respiratory alkalosis

Respiratory alkalosis decreases the phosphaturic response to parathyroid hormone (PTH). beta-adrenoreceptor blockade by propranolol infusion restores the phosphaturic effect of PTH in respiratory alkalotic rats; however, the nephron site of these changes in phosphate reabsorption by propranolol is not known. The present study was performed to localize the nephron segment(s) involved in the restoration of the phosphaturic effect of PTH by propranolol infusion in respiratory alkalotic rats. PTH infusion increased the fractional delivery of phosphate (FDPi) to the late proximal tubule to similar levels in the propranolol and vehicle-infused respiratory alkalotic rats (FDPi 46.6 +/- 4.4% and 48.6 +/- 4.2%, respectively). In contrast, PTH only increased FDPi to the early distal tubules (to 17.1 +/- 0.9%) in the absence of propranolol compared to FDPi 41.9 +/- 2.5% in the presence of propranolol in respiratory alkalotic animals. We conclude that the restoration of the phosphaturic effect of PTH in respiratory alkalotic rats by propranolol infusion is due primarily to decreased reabsorption of phosphate by the straight segment of the proximal tubule.

Propranolol restores phosphaturic effect of PTH in short-term phosphate deprivation

Phosphate deprivation causes a resistance to the phosphaturic effect of parathyroid hormone (PTH). The present study evaluated the role of the beta-adrenergic system in this resistance phenomenon. In clearance experiments performed on acutely thyroparathyroidectomized male Sprague-Dawley rats, the phosphaturic response to PTH was determined in the presence and absence of propranolol in rats fed a low-phosphate diet (LPD) for 0.5, 1, 2, 3, or 4 days. Fractional excretion of phosphate (FEPi) in control rats fed a normal-phosphate diet (NPD) increased from 4.37 +/- 1.6 to 38.5 +/- 3.4% in response to PTH infusion. Propranolol did not change FEPi in NPD animals in the absence or in the presence of PTH (2.0 +/- 1.1 vs. 36.7 +/- 1.6%). LPD resulted in a gradual decrease in the phosphaturic response to PTH infusion as compared with NPD animals. PTH increased FEPi to 24.2 +/- 6.0% after one-half day of LPD, but when the infusion was supplemented with propranolol, PTH increased FEPi to 38.0 +/- 4.7%, similar to that in NPD animals. In the group fed LPD for one day, PTH increased FEPi to 16.9 +/- 4.3%, whereas in the presence of propranolol FEPi was restored to a similar level as in the NPD group (36.0 +/- 5.9%). Two days of LPD markedly decreased FEPi in response to PTH to 7.9 +/- 3.8% as compared with NPD rats, and propranolol infusion did not change this value significantly. Three and 4 days of LPD induced complete resistance to the phosphaturic effect of PTH in the presence as well as in the absence of propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Phosphate Deprivation on Enzymes of the Cyclic Adenosine Monophosphate Metabolism in Rat Proximal Convoluted and Proximal Straight Tubules

Phosphate deprivation causes a resistance to the phosphaturic effect of parathyroid hormone (PTH). The present study determined whether acute phosphate deprivation alters basal or stimulated activities of key enzymes of the cyclic adenosine monophosphate (cAMP) metabolism in microdissected proximal convoluted and proximal straight tubules, since blunted cAMP levels in these proximal subsegments might account for refractoriness to the effect of PTH on phosphate reabsorption in the proximal convoluted and proximal straight tubule segments. In the proximal convoluted tubules of rats fed a normal-phosphate diet (NPD), PTH increased the adenylate cyclase activity by tenfold. In the proximal convoluted tubule of rats fed a low-phosphate diet (LPD), PTH also increased the adenylate cyclase activity by tenfold. In addition, forskolin increased the adenylate cyclase activity to levels similar to PTH in the proximal convoluted tubule of rats fed NPD or LPD. In the proximal straight tubule of rats fed NPD, PTH resulted in an approximately fivefold increase in adenylate cyclase activity. In the proximal straight tubule of rats fed LPD, PTH resulted in a fourfold increase in adenylate cyclase activity. The forskolin-stimulated adenylate cyclase activity was markedly decreased (46%) in the proximal straight tubule of phosphate-deprived rats. The cAMP-phosphodiesterase activity in the proximal convoluted tubule was significantly increased by 26% in phosphate-deprived rats. The cAMP-phosphodiesterase activities in the proximal straight tubules from rats fed NPD or LPD were similar. We conclude that distinct differences in key enzymes of cAMP metabolism exist in the proximal convoluted and proximal straight tubule subsegments. Further, phosphate deprivation affects the cAMP-phosphodiesterase and adenylate cyclase activities differently in these nephron subsegments.(ABSTRACT TRUNCATED AT 250 WORDS)

Beta-receptors in resistance to phosphaturic effect of PTH in respiratory alkalosis.

Respiratory alkalosis results in a resistance to the phosphaturic effect of parathyroid hormone (PTH) and dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP). The present studies evaluated the role of the beta-adrenergic system in that resistance phenomenon. In clearance experiments on acutely thyroparathyroidectomized male Wistar rats, respiratory alkalosis blunted the PTH-mediated increase in absolute and fractional excretion of phosphate (FEPi). Propranolol infusion restored the phosphaturic response to PTH:FEPi, 0.8 +/- 0.3 vs. 8.1 +/- 2.5% (P less than 0.005). Similarly, the increase of FEPi during cAMP infusion was also diminished by respiratory alkalosis: FEPi, 15.5 +/- 2.2 vs. 5.5 +/- 1.1% (P less than 0.005). This hypophosphaturic effect of respiratory alkalosis in the presence of cAMP was not observed in rats infused with propranolol compared with the period of normal ventilation: FEPi, 21.1 +/- 1.7 vs. 15.3 +/- 1.6 (P less than 0.02). Also, during the infusion of the highly selective beta 2-adrenoceptor antagonist, ICI 118,551, cAMP was phosphaturic in respiratory alkalosis compared with FEPi in the absence of the antagonist: FEPi, 13.0 +/- 2.5 vs. 5.5 +/- 1.1% (P less than 0.02). Finally, the infusion of the beta 2-agonist, fenoterol, to the normally ventilated rats significantly decreased FEPi in cAMP-infused rats in comparison to the absence of the agonist: FEPi, 4.0 +/- 0.7 vs. 22.1 +/- 2.6% (P less than 0.001). We conclude that the resistance to the phosphaturic effect of PTH and cAMP in respiratory alkalosis is mediated by beta-adrenoceptors.

Effect of cAMP analogue infusion on phosphate reabsorption in phosphate-deprived rats.

The present study was performed to compare the effects of 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (cAMP analogue) and parathyroid hormone (PTH) infusion on segmental phosphate reabsorption in phosphate-deprived rats. Micropunctures of the late proximal and the early distal tubules were performed in acutely thyroparathyroidectomized (TPTX) rats fed either a normal (NPD) or low phosphate diet (LPD), and the phosphaturic response to infusion of PTH and cAMP analogue was evaluated. In NPD rats, PTH (n = 10) and the cAMP analogues (n = 11) markedly increased urinary phosphate excretion, due to inhibition of phosphate reabsorption along the proximal convoluted tubule and pars recta. In phosphate-deprived rats, PTH (n = 10) or the cAMP analogue (n = 11) did not increase urinary phosphate excretion. However, PTH and the cAMP analogue inhibited phosphate reabsorption along the proximal convoluted tubule but not in the pars recta in phosphate-deprived rats. We conclude that cAMP analogue infusion mimics the effect of PTH infusion on phosphate reabsorption along the proximal convoluted and proximal straight tubule in normal and phosphate-deprived rats. The resistance to the phosphaturic effect of PTH and cAMP infusions is a result of a blunted inhibition of phosphate reabsorption by the proximal convoluted tubule and also an increased phosphate reabsorption by the proximal straight tubule.

Prostaglandin E2 is an inhibitor of adenylate cyclase in rabbit proximal tubule.

Prostaglandin E1 and E2 (PGE) antagonize the phosphaturic effect of parathyroid hormone (PTH), but do not alter the phosphaturia evoked by adenosine 3',5'-cyclic monophosphate (cAMP) analogues. These findings support the idea that PGE interfere with activation of adenylate cyclase in the renal proximal tubule. We tested this hypothesis in the rabbit renal proximal straight tubule (PST). In the PST, adenylate cyclase was activated by PTH (Km = 10(-9) M PTH), but not by PGE2, which attenuated the activation of adenylate cyclase by PTH. The inhibition by PGE2 of PTH action was prevented by pertussis toxin, which deactivates the regulatory aggregate, Ni. In the PST, PGE2 also attenuated the activation of adenylate cyclase by cholera toxin. The inhibitory effect of PGE2 was selective; PGE2 did not inhibit activation of adenylate cyclase in glomeruli, but it inhibited the enzyme in proximal convoluted tubules (PCT) and PST. We conclude that PGE2 inhibits adenylate cyclase in rabbit proximal tubule. We propose that this action may, in part, regulate transport function in vivo.

Dibutryladenosine 3',5'-cyclic monophosphate (dBcAMP) does not mimic the action of parathyroid hormone (PTH) on canine proximal tubular basolateral membrane Na+:Ca2+.

We have previously demonstrated that the Na+:Ca2+ exchanger found by Gmaj et al (1) in rat renal cortical basolateral membrane vesicles (BLMV) is present in canine renal cortical BLMV (2). We showed that its activity is depressed in the thyroparathyroidectomized (TPTX) state and that it was restored by in vivo infusion of parathyroid hormone (PTH). This effect was achieved by a change in Vmax of the exchanger but no significant change in the Km. It has been established that the phosphaturic effect of PTH on the proximal tubule can be mimicked by cAMP analogues (3). We sought to examine the effect of dBcAMP on the activation of the Na+:Ca2+ exchanger in BLMV prepared from TPTX dogs. The dose of dBcAMP used was chosen to achieve the same phosphaturic effect as the previously used 2 µg/Kg PTH (4).KeywordsParathyroid HormoneProximal TubuleProximal TubularClearance PeriodBasolateral Membrane VesicleThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Nephron site of resistance to phosphaturic effect of PTH during respiratory alkalosis.

This study was performed to evaluate the nephron site(s) responsible for the blunted phosphaturic effect of parathyroid hormone during respiratory alkalosis. In normocapnic thyroparathyroidectomized rats, parathyroid hormone administration markedly increased the fractional excretion of phosphate (FEp) from 2.1 +/- 0.5 to 36.6 +/- 5.0%. However, in the respiratory alkalotic rats, parathyroid hormone administration did not significantly increase the FEp (1.4 +/- 0.9 to 5.9 +/- 2.2%). This blunted phosphaturic response to parathyroid hormone was not due to a blunted inhibition of phosphate reabsorption by the superficial proximal tubule, since parathyroid hormone administration significantly increased the fractional delivery of phosphate (FDp) at the superficial late proximal tubule in both normal (25.3 +/- 3.0 to 36.2 +/- 3.8%, delta 10.9 +/- 3.2%) and respiratory alkalotic rats (12.2 +/- 3.1 to 30.3 +/- 4.9%, delta 18.0 +/- 4.7%). Parathyroid hormone administration significantly increased the FDp at the superficial early distal tubule from 9.3 +/- 3.9 to 38.7 +/- 7.4% (delta 29.4 +/- 5.1%) in normal rats and from 4.5 +/- 1.7 to 12.9 +/- 3.4% (delta 8.5 +/- 3.2%) in the respiratory alkalotic rats. We conclude that the blunted phosphaturic response to parathyroid hormone in respiratory alkalotic rats is not due to a blunted inhibition of phosphate reabsorption by the proximal convoluted tubule but is primarily due to enhanced reabsorption by the pars recta segment of the proximal tubule.

Developmental changes in the phosphaturic response to parathyroid hormone in the rat.

The need for young, immature rats to maintain positive phosphate balance for growth is well recognized. However, whether this process is associated with a resistance to the phosphaturic effect of parathyroid hormone (PTH) is not clear. In these experiments we examined the effect of PTH on urinary phosphate and cAMP excretion in rats at 3, 6, 12, and 20 wk of age. Clearance experiments were performed in acutely thyroparathyroidectomized (TPTX) rats fed a normal phosphate diet (0.86%). Basal fractional excretion of phosphate (FEPi) was low in all TPTX rats (less than 1%). The phosphaturic response to a high dose of PTH (1 U X kg-1 X min-1) increased with development (from 4 to 29%). The responses to increasing doses of PTH demonstrated a decrease in sensitivity to PTH in 6- compared with 20-wk-old rats. Urinary cAMP excretion (either per milliliter glomerular filtrate or per gram kidney weight) following PTH was not different among 6-, 12-, and 20-wk-old rats, thus demonstrating a dissociation between the increase in phosphate excretion and cAMP excretion. These results indicate that the phosphaturic response to PTH is blunted in immature, acutely TPTX rats and that the phosphaturia increases progressively with development.

Pi transport, phosphorylation, and dephosphorylation in renal membranes from HYP/Y mice.

To ascertain whether cAMP-dependent phosphorylation could be demonstrated in brush border membrane vesicles (BBMV) isolated from kidneys of mice with X-linked hypophosphatemic rickets (HYP/Y) and normal littermates (+/Y) and, if so, to determine whether the absence of dephosphorylation might underlie differences in Na+-dependent 32Pi transport in BBMV, we measured 1) 32Pi transport, 2) cAMP-dependent phosphorylation, and 3) dephosphorylation in BBMV from +/Y and HYP/Y mice. Na+ gradient-dependent 32Pi transport was decreased in BBMV from HYP/Y mice as reflected in a decreased apparent Vmax. cAMP-dependent phosphorylation of a 62,000 Mr protein was demonstrated in sodium dodecyl sulfate polyacrylamide gels of BBMV from +/Y and HYP/Y mice and was associated with decreased Na+-dependent 32Pi transport. Dephosphorylation of the 62,000 Mr band was demonstrable in both types of membranes. Thus, both cAMP-dependent protein kinase and phosphoprotein phosphatase activities were demonstrable in BBMV isolated from +/Y and HYP/Y mice. These results are consistent with the renal tubular defect in the HYP/Y mouse reflecting an intrinsic abnormality of Pi transport in the brush border membrane independent from mediation of the phosphaturic effect of parathyroid hormone.

Effect of phosphate deprivation on phosphate reabsorption in rat nephron: role of PTH.

The sites of enhanced phosphate (PO4) reabsorption after PO4 deprivation were investigated before and after infusion of parathyroid hormone (PTH) in acutely thyroparathyroidectomized rats. Animals were fed either a control PO4 diet (1.6% P) or a low PO4 diet (0.025% P) for 2 days or 7-10 days. In control rats, PTH decreased PO4 reabsorption in the proximal tubule, loop of Henle, and distal convolution. PO4 reabsorption in the proximal tubule was enhanced after 2 days of PO4 deprivation. In this group, proximal PO4 reabsorption was decreased by PTH but remained greater than in control rats (70 +/- 6 vs. 45 +/- 6 pmol/min; P less than 0.025). After PTH, PO4 reabsorption increased in the loop of Henle from 3 +/- 0.5 to 13 +/- 2 pmol/min (P less than 0.005), whereas it was unaltered in the distal convolution in PO4-deprived rats. PTH markedly increased fractional excretion of PO4 in control rats but not in PO4-deprived rats. After prolonged PO4 deprivation, PO4 reabsorption along the nephron was unaltered by PTH. These results demonstrate that acute PO4 deprivation enhances PO4 reabsorption in the proximal tubule, although the phosphaturic effect of PTH in this segment is not abolished. Resistance to the inhibitory effect of PTH on PO4 reabsorption in some portion of the loop of Henle and possibly also in the distal convolution accounts for the absence of a significant phosphaturic effect of the hormone in acutely PO4-deprived rats. Prolongation of PO4 deprivation results in unresponsiveness to PTH extending to the proximal tubule.