Rapid recovery of plasma ionized calcium after acute induction of hypocalcaemia in parathyroidectomized and nephrectomized rats.
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BACKGROUND: Plasma ionized calcium (Ca2+) is extremely tightly regulated in normal mammals. Even a small decline in Ca2+ is followed by a fast and steep increase of the parathyroid hormone (PTH) secretion and the current understanding of the calcium homeostasis indicates that PTH is the main factor responsible for this tight minute-to-minute regulation of the normal plasma Ca2+ concentration. However, experiments from our laboratory and some clinical experiences points towards the existence of factors, other than PTH, involved in the rapid minute-to-minute calcium homeostasis. Thus, the aim of the present study was to examine whether PTH plays an important role in the rapid upregulation of plasma Ca2+ after induction of hypocalcaemia in the rat. METHODS AND RESULTS: I. Parathyroidectomy (PTX) was performed in seven rats; 60 min later no PTH was detectable in the circulation. Then by a brief infusion of EGTA plasma Ca2+ was reduced from 1.26+/-0.02 to 0.86+/-0.02 mmol/l, P<0.001. Despite there being no PTH in the circulation plasma Ca2+ increased significantly to 0.97+/-0.02 mmol/l already 10 min after discontinuation of the EGTA infusion, P<0.04, and plasma Ca2+ was normalized within another 2 h. II. To evaluate a possible role of renal Ca2+ handling in the rapid upregulation of plasma Ca2+ a group of eight rats had acute PTX and bilateral nephrectomy (NX) performed; 60 min later plasma Ca2+ was reduced from 1.18+/-0.01 to 0.86+/-0.02 mmol/l by an EGTA infusion. Despite there being no PTH and no kidneys present plasma Ca2+ increased significantly already 10 min after discontinuation of EGTA to 0.96+/-0.02 mmol/l, P<0.02. After another 1.5 h the plasma Ca2+ reached the levels of the PTX/NX control rats. III. In order to exclude a possible action of receptor-bound PTH, which may have lasted for more than 1 h, seven rats were PTX 24 h before the induction of hypocalcaemia. Basal plasma Ca2+ was significantly reduced to 1.07+/-0.01 mmol/l, P<0.01. Then plasma Ca2+ was further reduced to 0.79+/-0.03 mmol/l by EGTA. Ten minutes after discontinuing EGTA plasma Ca2+ increased to 0.91+/-0.02 mmol/l, P<0.03 and 60 min later plasma Ca2+ reached the level of the control PTX rats. Normal rats with intact parathyroid glands had an exactly similar response of plasma Ca2+ to EGTA as that of 24 h PTX rats, but at significantly higher levels of plasma Ca2+ with a fall from 1.28+/-0.01 to 0.96+/-0.03 mmol/l and again a significant increase of plasma Ca2+ to 1.13+/-0.03 (P<0.001) 10 min after discontinuation of EGTA. After another hour basal levels were reached. CONCLUSIONS: Despite there being no PTH in the circulation a rapid increase of plasma Ca2+ occurs immediately after a brief induction of hypocalcaemia. The kidneys are not responsible for this phenomenon. The present results suggest the existence of a mechanism other than the effect of PTH, which is responsible for the rapid minute-to-minute regulation of plasma Ca2+ in the rat. (+info)
Dual mechanisms of regulation of Na/H exchanger NHE-3 by parathyroid hormone in rat kidney.
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Parathyroid hormone (PTH) is a potent inhibitor of mammalian renal proximal tubule sodium absorption via suppression of the apical membrane Na/H exchanger (NHE-3). We examined the mechanisms by which PTH inhibits NHE-3 activity by giving an acute intravenous PTH bolus to parathyroidectomized rats. Parathyroidectomy per se increased apical membrane NHE-3 activity and antigen. Acute infusion of PTH caused a time-dependent decrease in NHE-3 activity as early as 30 min. Decrease in NHE-3 activity at 30 and 60 min was accompanied by increased NHE-3 phosphorylation. In contrast to the rapid changes in NHE-3 activity and phosphorylation, decrease in apical membrane NHE-3 antigen was not detectable until 4-12 h after the PTH bolus. The decrease in apical membrane NHE-3 occurred in the absence of changes in total renal cortical NHE-3 antigen. Pretreatment of the animals with the microtubule-disrupting agent colchicine blocked the PTH-induced decrease in apical NHE-3 antigen. We propose that PTH acutely cause a decrease in NHE-3 intrinsic transport activity possibly via a phosphorylation-dependent mechanism followed by a decrease in apical membrane NHE-3 antigen via changes in protein trafficking. (+info)
gamma-L-glutamyl-L-DOPA inhibits Na(+)-phosphate cotransport across renal brush border membranes and increases renal excretion of phosphate.
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BACKGROUND: For treatment of phosphate (Pi) overload in various pathophysiological states, an agent that selectively increases renal Pi excretion would be of major value. Previously, we have shown that dopamine (DA) inhibits Na(+)-Pi cotransport in renal epithelia. However, the administration of DA or its immediate precursor L-DOPA increases DA in multiple tissues. Synthetic dipeptide gamma-L-glutamyl-L-DOPA (gludopa) can serve as an inactive precursor (pro-pro-drug) of DA. This study tested the hypothesis that, because of the unique colocalization of gamma-glutamyltransferase (gamma-GT), aromatic amino acid decarboxylase, Na(+)-Pi cotransporter, and Na(+)-L-DOPA cotransporter in brush border membrane (BBM) of proximal tubular cells, gludopa may elicit phosphaturia by action of DA generated within the kidney. METHODS: Thyroparathyrectomized rats were given placebo, or gludopa, or gludopa + gamma-GT inhibitor acivicin. Urinary excretion of Pi, Ca2+, Na+, K+, DA, cAMP, and cGMP was determined, and Na(+)-Pi cotransport was measured in BBM prepared from kidneys of rats at the end of the experiment. RESULTS: The administration of gludopa resulted in: (a) an inhibition of Na(+)-Pi cotransport, but not cotransport of Na(+)-proline and Na(+)-alanine in BBM; (b) an increase (+300%) of fractional excretion (FE) of Pi and a drop (-35%) of plasma Pi, whereas the plasma levels and FEs of Ca2+, Na+, and K+ were unchanged; (c) an increase in urinary excretion of cAMP. but not cGMP; (d) a 1000-fold increase of urinary excretion of DA, without a change in excretion of norepinephrine; and (e) an incubation of gludopa with BBM in vitro, which caused a release of L-DOPA, and the in vivo administration of acivicin, which blocked actions of gludopa to inhibit Na(+)-Pi cotransport and to increase urinary excretions of Pi and DA. CONCLUSIONS: We conclude that colocalization of enzymes of biotransformation, BBM transporters, and the autocrine/paracrine DA system in cells of proximal tubules constitutes a cellular basis for the potent and specific phosphaturic action of gludopa. (+info)
Improved success rate in reoperative parathyroidectomy with intraoperative PTH assay.
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OBJECTIVE: The clinical usefulness of preoperative localization and intraoperative PTH assay (QPTH) in primary hyperparathyroidism have been established. However, without the use of QPTH, the parathyroidectomy failure rate remains 5% to 10% in large reported series and is probably much higher in the hands of less experienced parathyroid surgeons. Persistent hypercalcemia requires another surgical procedure. The authors compared the outcomes in 50 consecutive patients undergoing more difficult secondary parathyroidectomy with and without the adjunctive support of QPTH. METHODS: Two groups of similar patients underwent reoperative parathyroidectomy for failed surgery or recurrent disease. The successful return to normocalcemia in group I, with QPTH used to localize and confirm complete excision of all hyperfunctioning glands, was compared with group II, who did not have this intraoperative adjunct. RESULTS: In 31/33 patients in group I, calcium levels returned to normal. With good preoperative localization studies, 17 patients underwent successful straightforward parathyroidectomies as predicted by QPTH. In the other 14 patients, QPTH assay proved extremely beneficial by facilitating localization with differential venous sampling; measuring the increase in hormone secretion after massage of specific areas; recognizing suspicious nonparathyroid tissue excised without a decrease in hormone levels, avoiding frozen-section delay; and correctly identifying the excision of abnormal tissue despite false-positive/false-negative sestamibi scans. In group II, who underwent surgery before QPTH was available, 4 of 17 patients (24%) remained hypercalcemic after extensive reexploration. CONCLUSION: With the intraoperative hormone assay used to facilitate localization and confirm excision of all hyperfunctioning tissue, the success rate of reoperative parathyroidectomy has improved from 76% to 94%. (+info)
Hepatic HDL receptor, SR-B1 and Apo A-I expression in chronic renal failure.
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BACKGROUND: Chronic renal failure (CRF) is associated with hypertriglyceridaemia and depressed plasma high-density lipoprotein (HDL)-cholesterol and apolipoprotein A-I (Apo A-I) concentrations. Uraemic hypertriglyceridaemia is due, in part, to lipoprotein lipase and hepatic lipase deficiencies, which are causally linked to excess parathormone (PTH). This study was designed to test the hypothesis that depressed plasma concentration and abnormal composition of HDL in CRF may be due to dysregulation of hepatic expression of Apo A-I and/or the newly discovered HDL receptor. METHODS: Hepatic Apo A-I and HDL receptor mRNA abundance (Northern blot), and HDL receptor protein mass (Western blot) were determined in CRF rats (5/6 nephrectomy), parathyroidectomized CRF rats (CRF-PTx) and sham-operated controls. RESULTS: The CRF group exhibited normal hepatic HDL receptor mRNA and HDL receptor protein abundance coupled with reduced hepatic Apo A-I mRNA. Hepatic Apo A-I mRNA, HDL receptor mRNA and protein abundance were not affected by PTx. CONCLUSIONS: CRF results in the down-regulation of hepatic Apo A-I gene expression, which accounts for the known reduction in plasma Apo A-I concentration. However, CRF does not affect HDL receptor mRNA or protein expression in this model. Neither Apo A-I nor HDL receptor expression were modified by PTx in CRF rats. (+info)
New technique of parathyroidectomy to prevent parathyromatosis and hypoparathyroidism.
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A 54-year-old woman with end-stage renal disease and on haemodialysis for 4 years developed severe secondary hyperparathyroidism and was operated upon. The two upper and the largest lower parathyroid glands were resected. The right lower gland was dissected from the lower pole of the thyroid and, by gently pulling upwards, the lateral walls were dissected using electrocautery. The lower aspect of the gland maintained the blood supply through small mediastinal and thymic vessels of the neopedicle, which allowed its mobilization to a more superficial plane. Because of the large size of the gland, the part opposite to the neopedicle was resected and the cutting surface was sealed with fibrin adhesive. Pre-thyroidal muscles were reapproximated and the remnant of the parathyroid gland was pulled out through a small hole in the inferior part of the midline and sutured with fine silk to the muscle. The gland was therefore placed in a subcutaneous position in the lowest part of the operative field just above the sternal border. The postoperative course was uneventful and, 8 months after surgery, the patient maintains a normal parathyroid function. (+info)
Calcitonin is a major regulator for the expression of renal 25-hydroxyvitamin D3-1alpha-hydroxylase gene in normocalcemic rats.
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Regulation of vitamin D metabolism has long been examined by using vitamin D-deficient hypocalcemic animals. We previously reported that, in a rat model of chronic hyperparathyroidism, expression of 25-hydroxyvitamin D3-1alpha-hydroxylase (CYP27B1) mRNA was markedly increased in renal proximal convoluted tubules. It is believed that the major regulator for the expression of renal CYP27B1 is parathyroid hormone (PTH). However, in the normocalcemic state, the mechanism to regulate the renal CYP27B1 gene could be different, since plasma levels of PTH are very low. In the present study, the effect of PTH and calcitonin (CT) on the expression of renal CYP27B1 mRNA was investigated in normocalcemic sham-operated rats and normocalcemic thyroparathyroidectomized (TPTX) rats generated by either PTH or CaCl2 infusion. A single injection of CT dose-dependently decreased the expression of vitamin D receptor mRNA in the kidney of normocalcemic sham-TPTX rats. Concomitantly, CT greatly increased the expression of CYP27B1 mRNA in the kidney of normocalcemic sham-TPTX rats. CT also increased the expression of CYP27B1 mRNA in the kidney of normocalcemic TPTX rats. Conversion of serum [3H]1alpha,25(OH)2D3 from 25-hydroxy[3H]vitamin D3 in vivo was also greatly increased by the injection of CT into sham-TPTX rats and normocalcemic TPTX rats, but not into hypocalcemic TPTX rats. In contrast, administration of PTH did not induce the expression of CYP27B1 mRNA in the kidney of vitamin D-replete sham-TPTX rats and hypocalcemic TPTX rats. PTH increased the expression of renal CYP27B1 mRNA only in vitamin D-deficient hypocalcemic TPTX rats. These results suggest that CT plays an important role in the maintenance of serum 1alpha,25(OH)2D3 under normocalcemic physiological conditions, at least in rats. (+info)
Germline mutation of the multiple endocrine neoplasia type 1 (MEN1) gene in a family with primary hyperparathyroidism.
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Familial primary hyperparathyroidism (FHP) is a rare hereditary disorder characterized by isolated parathyroid tumors without any other lesions related to multiple endocrine neoplasia (MEN). Primary hyperparathyroidism is usually expressed at an early age and is highly penetrated in MEN type 1 (MEN1), suggesting that some FHP may be a variant type or early stage of MEN1. The MEN1 gene has recently been cloned and its germline mutations have been considered to play an important role in the tumorigenesis of MEN1. We studied a Japanese family with primary hyperparathyroidism which included 4 patients. To investigate the possible relationship between primary hyperparathyroidism in this family and the MEN1 gene, we analyzed a proband for a germline mutation of the MEN1 gene in this study. We identified a novel heterozygous mutation (1350del3) at codon 414 in exon 9. Restriction digestion analysis revealed the same mutation pattern in his brother with hyperparathyroidism. These findings suggest that our patients may belong to a variant type of MEN1. (+info)