Refractoriness to phosphaturic action of parathyroid hormone occurring independent of phosphate depletion in hyperparathyroid rats

In an attempt to clarify the underlying mechanism(s) in the disappearance of phosphaturic response to bolus parathyroid hormone (PTH) in hyperparathyroid patients, the effects of bolus bovine PTH (10 USP U) were studied in conscious thyroparathyroidectomized (T . PTX) male Wistar rats that had been infused with a dose of PTH (2.5 U/hr, for 16 hours) so as to reproduce hyperparathyroidism. These animals responded with an increase in urinary cyclic AMP, but without an increase in renal clearance of phosphate. The loss of phosphaturic response was not prevented by pretreatment with actinomycin D at a dosage close to full toxicity (0.1 mg/kg BW, ip, for 3 days). Actinomycin D at this dosage did not affect the normal stimulatory effects of bolus PTH on urinary cyclic AMP and renal clearance of phosphate in T . PTX rats. The continuous infusion of PTH produced nearly maximal phosphaturia throughout in the face of a significant depletion of phosphate. In addition, pretreatment with actinomycin D did not cause a further increase in urinary phosphate excretion during the infusion. These results, along with the report of Shah et al. (1979) indicating that the development of antiphosphaturic adaptation to acute phosphate depletion was prevented by comparable amounts of actinomycin D, indicate that the disappearance of phosphaturic response to bolus PTH by prior PTH infusion simply signifies the continuation of maximal phosphaturic response to the preceding PTH infusion. It is also suggested that the continuous action of PTH prevents, at least phenomenologically, the development of the gene-activation-mediated refractoriness to PTH or antiphosphaturia induced by acute phosphate depletion.     

Renal handling of phosphate, calcium, sodium, and potassium in intact and parathyroidectomized Rana pipiens

Renal excretion of phosphate, calcium, sodium, and potassium in intact and parathyroidectomized male Rana pipiens was studied by renal clearance techniques using 14C-inulin. In intact frogs, 57% of filtered phosphate, 60% of filtered calcium, 97% of filtered sodium, and 89% of filtered potassium was reabsorbed by the renal tubules. Following parathyroidectomy, the rate of reabsorption of phosphate became significantly higher than that of the intact frog, and the relative phosphate clearance (fractional excretion) decreased. These changes corresponded with a gradual rise in serum phosphate values. There was no major effect on excretion patterns of calcium, sodium, or potassium after parathyroidectomy. These results suggest that in frogs the parathyroid glands strongly influence phosphate excretion patterns but have little effect on the excretion of calcium, sodium, or potassium.     

Hypercalcemic effect of insulin in thyroparathyroidectomized alloxan-treated rats

The acute effect of a hypoglycaemic dose of 0.5 U/100 g BW insulin administered intramuscularly on calcium metabolism was investigated in fasted alloxan-treated rats. It was found that the hypercalcaemic effect of insulin was evident only in thyroparathyroidectomized (TPTX) and not in parathyroidectomized (PTX) rats. A subcutaneous administration of 180 MRC mU/100 g BW calcitonin abolished the calcium raising effect of insulin in TPTX rats suggesting a protective role of calcitonin against insulin action in intact rats. In an attempt to elucidate the mechanism of the calcium raising effect of insulin 45Ca administered intravenously was used to indicate the movement of calcium from the plasma pool. Insulin administration delayed the plasma 45Ca disappearance rate but had no effect on bone 45Ca uptake within 120 min. In contrast, insulin administration resulted in a 31% reduction of urinary 45Ca excretion while the urine volume remained unchanged. However, the insulin-induced reduction of urinary calcium excretion could not totally account for the calcium raising effect of insulin in TPTX animals.     

Effects of atrial natriuretic factor on renal handling of water and electrolytes in rats

The intravenous injection of an extract of atrial myocardium into anesthetized rats during a hypotonic diuresis resulted in an increase in the renal excretion of water, sodium, potassium, calcium, magnesium, and phosphate. There was an increase in urine concentration which was probably a result of the secretion of vasopressin since it did not occur in Brattleboro (di/di) rats. A transient increase in glomerular filtration rate and renal plasma flow occurred during the first five minutes with a more sustained rise in filtration fraction. Injection of atrial extract also caused a partial inhibition of solute-free water formation in Brattleboro rats subjected to water diuresis and a partial inhibition of solute-free water reabsorption in rats subjected to maximal antidiuresis by infusing vasopressin. In neither case was the degree of inhibition as profound as that observed after injecting furosemide in a dose which caused a comparable natriuretic response. A large dose of furosemide blocked the natriuretic response to atrial extracts whereas, when a comparable level of sodium and water output was produced by massive infusions of saline, the natriuretic response to atrial extract was increased. It is suggested that atrial natriuretic factor might inhibit sodium transport in nephron segments beyond the medullary thick ascending limb. Furosemide might also act at the same tubular site or inhibit tubular secretion of the atrial natriuretic factor.     

Ultimobranchial body and parathyroid gland of the frog, Rana tigrina in response to calcitonin administration

The effects of salmon calcitonin (0.25 MRC mU/g body wt) on the serum calcium and phosphate levels as well as on the activity of ultimobranchial body and parathyroid glands was investigated in the frog, Rana tigrina for 15 days. The hormone evokes hypocalcemia (on day 1 and day 3) which is followed by a significant hypercalcemia on day 10. Thereafter, the level of calcium decreases again on day 15. Calcitonin induces hypophosphatemia (on day 3 and day 5). Thereafter, hyperphosphatemia is recorded on day 10. By day 15 normal serum phosphate value is achieved. After treatment with calcitonin, the ultimobranchial body becomes inactive and the parathyroid glands get activated.     

Plasma calcium and calcitonin in the marine teleost, Gadus morhua

Total, free and ionic plasma levels of calcium as well as total plasma magnesium and inorganic phosphate levels were studied in the Atlantic cod, Gadus morhua, in relation to salmon calcitonin injections. Plasma ion levels and endogenous levels of calcitonin were studied during environmentally induced hypercalcemia. It is concluded that no apparent relationship between calcitonin and calcium levels was found, and it is implied that calcitonin in fish may have a physiological function not related to blood calcium regulation.     

Reversible resistance to the phosphaturic effect of db-cAMP in lithium-treated rats

Acute lithium administration (5 mmol/kg b.w.) to parathyroidectomized (PTX) rats induces extracellular acidosis, lower plasma phosphate concentration and increased phosphate reabsorption. The present studies evaluate the effect of lithium administration on tissue phosphate distribution, metabolites content in the kidneys and renal phosphate, 2-oxoglutarate and citrate transport in the presence and absence of db-cyclic AMP. Lithium decreased plasma and renal phosphate concentrations and increased phosphate concentration in the skeletal muscle, db-cyclic AMP was not phosphaturic in lithium-treated PTX rats. In PTX rats infused with 20 mM phosphate lithium depressed fractional phosphate excretion induced by db-cyclic AMP from 20 +/- 0.3% to 3.2 +/- 1.0%. However, metabolic or respiratory acidosis restored the responsiveness to db-cyclic AMP. Citraturia and ketoaciduria induced by lithium were depressed in db-cyclic AMP-treated rats. Kidney citrate and 2-oxoglutarate concentrations increased drastically, ATP level fell significantly whereas cAMP content did not change after lithium. We conclude that lithium administration increases phosphate uptake by the muscle which largely accounts for hypophosphatemia. The kidney responds with increased phosphate reabsorption independent of plasma and kidney phosphate concentrations, and with refractoriness to the phosphaturic effects of db-cyclic AMP. Acute lithium administration to rats induces extracellular acidosis and, probably, renal intracellular alkalosis as reflected by citraturia and ketoaciduria as well as the renal metabolite profile. The phosphaturic responsiveness to db-cyclic AMP is dependent, at least in part, on intracellular pH.     

Alterations induced by large doses of furosemide in chronic renal insufficiency.

Eleven patients with different degrees of renal failure with creatinine clearances between 7 and 32 ml/min have been studied. After a standard water overload and control periods of clearances, furosemide 1 g was given/i.v. There followed significant increase of renal plasma flow and glomerular filtration rate. In one case the increase was maintained during a follow up period of 3 hours. A significant increase was evident in phosphate, uric acid, sodium, potassium, and calcium clearances, as well as an increase in the sodium delivery to the distal nephron and a decrease in tubular reabsorption of phosphate. All this may be interpreted as the result of renal vasodilation induced by furosemide and its effect upon the proximal tubule and on Henle's loop.     

Circadian rhythms of electrolyte and 17-hydroxycorticosteroid excretion in hyperthyroidism and hypothyroidism.

The circadian rhythms of excretion of sodium, potassium, calcium, magnesium, phosphorus and 17-hydroxycorticosteroid (17-ohcs) were determined in five normal subjects, in six patients with hyperthyroidism and five with hypothyroidism. Constant diets with identical 3-hourly feedings were employed, and urine collections were made every 3 hrs during a 3-day study period. The circadian patterns of urinary excretion of sodium, potassium and 17-OHCS were similar in all three groups with distinct daytime peaks and nighttime nadirs. The total quantities of the ions and 17-OHCS excreted were greater in hyperthyroid than in hypothyroid patients with the greatest difference noted with the 17-OHCS. The rhythms for calcium, magnesium and phosphorus excretion were accentuated in hyperthyroid patients but similar to those in normal subjects with early morning calcium and magnesium peaks and a phosphorus peak approximately 12 hrs later. While a similar although blunted circadian pattern for calcium and perhaps magnesium excretion was noted in hypothyroid patients, their phosphorus rhythms were distorted and rather flat. These latter results confirm the observation of MINTZ et al. and are compatible with their interpretation that thyroid hormone is permissibly necessary for the expression of a normal phosphaturic rhythm and that the circulating level of thyroid hormone influences the amplitude of the phosphaturic rhythm.     

Acute effect of salmon calcitonin on renal magnesium transport in the magnesium-loaded rat

The present studies were undertaken to examine whether salmon calcitonin, by increasing magnesium reabsorption in the thick ascending limb, and presumably the tubulointerstitial magnesium concentration gradient, would lead to an increase in fractional magnesium delivery to the end-descending limb (magnesium secretion) in magnesium-loaded rats. Thyroparathyroidectomized, postprandial Munich--Wistar rats were prepared for micropuncture of papillary end-descending limbs and of superficial end-accessible proximal tubules. Group 1 served as clonidine-water diuresis time controls; group 2 was treated as group 1 but also received synthetic salmon calcitonin (10 mU/min); and group 3 was treated as group 2 but also received calcium chloride intravenously. Calcitonin, alone or with calcium, produced a significant fall in fractional magnesium excretion. A significant relationship was also observed between fractional magnesium excretion and urine flow rate (r = 0.56, p less than 0.01). Calcitonin did not modify fractional magnesium delivery to the end-descending limb. A highly significant relationship was observed between tubule fluid-to-ultrafiltrate magnesium ratio and tubule fluid-to-plasma inulin ratio (r = 0.88, p less than 0.001). Within each group, fractional magnesium delivery to the end-descending limb was similar to the corresponding value in the superficial end-accessible proximal tubule. Our results suggest that despite intense magnesium reabsorption, presumably in the thick ascending limb, magnesium secretion does not occur in the juxtamedullary pars recta and (or) thin descending limb.     

Effect of calcitonin on fractional delivery of sodium and solutes to the juxtamedullary end-descending limb of the rat

The purpose of the present studies was to examine, by micropuncture, the effect of salmon calcitonin on fractional sodium and solutes deliveries to the juxtamedullary end-descending limb of the rat. All animals were postprandial and thyroparathyroidectomized Munich-Wistar rats. Group 1 (N = 8) consisted of time control water-diuretic rats; group 2 (N = 8) received synthetic salmon calcitonin (10 mU/min) intravenously while undergoing water diuresis; group 3 (N = 8) was treated as group 2 but also received calcium intravenously to prevent the calcitonin-induced fall in plasma calcium. Calcitonin, alone and with calcium, produced a marked fall in urine flow rate and a marked increase in urinary osmolality. Concomitant fractional water delivery to the end-descending limb fell significantly (28 +/- 0.8 to 21 +/- 1.0%, p less than 0.05), while fractional solute and sodium deliveries increased significantly (36 +/- 1.3 to 55 +/- 2.6%, p less than 0.05; 34 +/- 2.0 to 48 +/- 3.5%, p less than 0.05, respectively). The three groups did not significantly differ in fractional water and sodium deliveries to the superficial end-accessible proximal tubule. We conclude that salmon calcitonin is antidiuretic in the rat and that it also produces an increase in fractional sodium and total solute deliveries to the end-descending limb, which we suggest is due to transepithelial sodium addition. The physiological significance of these observations to water homeostasis in vivo remains to be determined.     

Renal clearance of phosphate and calcium in vitamin D-deficient chicks: effect of calcium loading, parathyroidectomy, and parathyroid hormone administration.

Serum and renal clearance values of phosphate and calcium were measured and compared in 4 week-old vitamin D-deficient and vitamin D-replete chickens (Gallus gallus). D-deficient chicks had significantly lower body weights and serum calcium values; however, their renal functions were not different from D-replete controls. Serum calcium values in D-deficient birds did not change in response to parathyroid hormone (PTH) administration; however, they did drop significantly in response to parathyroidectomy (PTX). Serum phosphate values of D-deficient birds, but not D-replete birds, rose significantly after PTX. Clearance of phosphate is known to increase after administration of PTH. This conspicuous effect was absent in PTH-injected vitamin D-deficient chickens. PTX caused the excretion of phosphate to drop in both D-deficient and D-replete birds to near zero. Conversely, PTX of both D-deficient and D-replete chickens stimulated the excretion of more calcium than in controls. Calcium loading elevates the fractional excretion of calcium in both D-deficient and D-replete birds. It also causes a decrease in phosphate excretion in both groups, presumably by inhibiting the secretion of PTH. PTH administration to D-replete, calcium-loaded birds caused increased phosphate excretion (as it did in normal controls), an effect that was not seen in similarly treated D-deficient birds. Therefore, most renal functions studied after calcium loading, PTH administration, or PTX are not altered by vitamin D deficiency in the chicken. The major significant finding is that vitamin D-deficient chickens do not excrete increased amounts of phosphate in response to PTH stimulus.     

Sulphur and phosphorus requirements of Curvularia pallescens Boed

The effect of different sulphur and phosphorus compounds on the growth and sporulation ofCurvularia pallescens Boed. has been studied. Nine different sulphur sources were tried but among them only magnesium sulphate yielded the best dry weight of the fungus. Zinc sulphate, sodium sulphate, sodium thiosulphate, potassium sulphate and calcium sulphate supported good growth. Poor growth was recorded on sodium bisulphite, ammonium sulphate, sodium sulphide and control. Sporulation was excellent on magnesium sulphate. It was good on zinc sulphate, sodium sulphate and potassium sulphate. On sodium thiosulphate, calcium sulphate, sodium bisulphite and control it was fair. Sodium sulphide and ammonium sulphate had inhibitory effect as sporulation was poor and nil on these two compounds respectively.Six phosphorus compounds were studied. Tripotassium phosphate gave best growth and excellent sporulation. Good growth and excellent sporulation was recorded on monobasic potassium phosphate and magnesium phosphate. Growth and sporulation were good on dibasic potassium phosphate and sodium dihydrogen phosphate. Ammonium phosphate was poorly utilized.     

Influence of Medetomidine on Acid-base Balance and Urine Excretion in Goats

Seven goats were given medetomidine 5 μg/kg as an iv bolus injection. Venous blood samples were taken repeatedly and urine was collected continuously via a catheter up to 7h after the injection. Medetomidine caused deep clinical sedation. Base excess, pH and PCO2 in venous blood rose after medetomidine administration. There were no significant changes in plasma concentrations of sodium, calcium, magnesium, creatinine or osmolality, whereas potassium and bicarbonate concentrations increased, and phosphate and chloride decreased. Medetomidine increased plasma glucose concentration, and in 4 of 7 goats glucose could also be detected in urine. Medetomidine did not influence urine flow rate, free water clearance, bicarbonate and phosphate excretion or pH, but renal chloride, sodium, potassium, calcium, magnesium and creatinine excretion were reduced. The results suggest that the metabolic alkalosis recorded after medetomidine administration is not caused by increased renal acid excretion.     

Acute effect of hydrochlorothiazide on renal calcium and magnesium handling in postmenopausal women

A single 50 mg dose of hydrochlorothiazide (HCTZ) decreases the urinary excretion of calcium (U(Ca)V), clearance (C(Ca)) and fractional excretion (FE(Ca)) of calcium. This is accompanied by an increase of total calcium and ionized calcium (Ca2+) concentrations in the serum. On the other hand, HCTZ increases fractional excretion of magnesium (FE(Mg)) and decreases serum Mg2+ concentrations. Moreover, HCTZ decreases markedly clearance of phosphate (C(Pi)) and fractional excretion of phosphate (FE(Pi)) and increases serum phosphate (Pi) concentrations in healthy postmenopausal women. It is concluded that intrinsic renal cellular control promptly uncouples calcium and magnesium tubular reabsorption even without K+ depletion.     

Metabolic balance studies in patients with Paget's disease receiving salmon calcitonin over long periods.

Metabolic balance and calcium kinetic studies were performed in four patients with Paget''s disease before treatment with salmon calcitonin and during the early and late stages of the treatment, which lasted 9 to 19 months, A significant decrease in bone turnover and 24-hour urine hydroxyproline and serum alkaline phosphatase values was observed in all patients. In contrast, the calcium, phosphorus and magnesium balances did not change significantly. In agreement with this, the partial body calcium, measured by in vivo neutron activation analysis, did not change. Intestinal calcium absorption increased initially, but returned to baseline levels 9 to 19 months after the study began. During the initial period there was a small, significant, but transient decrease in tubular reabsorption of phosphorus; this was accompanied by a significant decrease in serum phosphorus values--probably a direct effect of calcitonin rather than evidence of secondary hyperparathyroidism. Administration of salmon calcitonin to patients with Paget''s disease decreases bone turnover without affecting calcium and phosphorus balances.     

Calcitonin increases pyruvate carboxylase activity in hepatic mitochondria of rats

The effect of calcitonin (CT) on calcium content and enzyme activity in the hepatic mitochondria of intact rats was investigated. A single subcutaneous administration of CT (80 MRC mU/100 g BW) produced a significant increase in the content of calcium, the activity of pyruvate carboxylase, succinate dehydrogenase and ATPase 15 min after the hormone treatment. The significant increases in calcium content and pyruvate carboxylase activity were also observed 30 min after CT administration, while succinate dehydrogenase and ATPase activity began to decrease. A physiological dose of CT (20 MRC mU/100 g BW) caused a marked increase in calcium content and pyruvate carboxylase activity but not succinate dehydrogenase of ATPase-activity. The removal of calcium by 10 mM EGTA washing of the mitochondria produced a remarkable reduction in pyruvate carboxylase activity increased by CT administration. The addition of calcium ion of 2.5 x 10(-2) - 2.5 x 10(1) nmoles Ca2+ per mg mitochondrial protein produced a marked increase in pyruvate carboxylase activity. The present results suggest that calcium taken up by the hepatic mitochondria after CT administration activates pyruvate carboxylase.     

Decreased calcium and magnesium urinary excretion during prostaglandin synthesis inhibition in the rat

The effect of endogenous renal prostaglandins on calcium and magnesium reabsorption was investigated. Renal tubular handling of calcium and magnesium was studied by clearance methods in anesthetized Sprague-Dawley and Brattleboro rats, either intact or thyroparathyroidectomized (ATPTX), before and during prostaglandin synthesis inhibition by meclofenamate, indomethacin, or piroxicam infusion. These three inhibitors had similar effects on calcium and magnesium excretion: A significant decrease in absolute and fractional excretions of both cations was observed in intact Sprague-Dawley rats, and in ATPTX rats of both strains, but not in intact Brattleboro rats. These results suggest an inhibitory effect of prostaglandins on vasopressin-, glucagon-, but not PTH-mediated calcium and magnesium reabsorption. This effect is likely to occur in the thick ascending limb of Henle, which is both a target site for these polypeptidic hormones, and a segment where the bulk of calcium and magnesium is reabsorbed.     

The temperature hysteresis of water-salt metabolism in the frog Rana temporaria]

Frogs acclimated to 4 degrees C were transported to a medium with temperature 20 degrees C, which caused polyuria; recovery of normal diuresis took about 24 h. During this period, hypernatremia was observed together with the increase in natriuresis, the rate of renal excretion of potassium ions with urea remaining constant. Water content of skeletal muscles decreased. Transportation of frogs acclimated to 20 degrees C into a medium with a temperature 4 degrees C decreased their diuresis. Renal excretion of sodium, calcium and magnesium ions remained unchanged, whereas that of potassium ions significantly decreased. The content of potassium and magnesium in the blood serum increased, that of sodium--decreased. Hydratation of muscled and kidneys was accompanied by the decrease of calcium, potassium and magnesium ions calculated per wet weight of the tissues, the level of sodium remaining unaffected. The data obtained indicate significant changes in the pattern of water and salt metabolism in frogs during temperature hysteresis.     

Serum levels of calcitonin, parathyroid hormone and 25-hydroxycholecalciferol in patients with diabetes mellitus

Blood serum levels of calcitonin, parathyroid hormone, calcium, magnesium and inorganic phosphate have been measured in basal condition and following intravenous administration of calcium in 31 patients with diabetes of type I, in 31 patients with diabetes of type II and in 29 healthy subjects. The level of 25-hydroxy cholecalciferol was measured in all these patients in basal condition only. It was found that the basal calcitonin level was significantly higher in patients with both types of diabetes than in healthy subjects. The administration of calcium caused a significantly higher increase in the blood calcitonin level in patients with type I diabetes than in those with type II diabetes. It was found in addition that in women with type II diabetes blood serum level of parathyroid hormone was significantly higher than that in men suffering from diabetes of the same type, suggesting the participation of some sex-related factor in the pathogenesis of the abnormal parathyroid level in these patients.