Source of urinary cyclic AMP in response to calcitonin and parathyroid hormone in the rat.

Administration of calcitonin (CT) or parathyroid hormone (PTH) in rats, induced phosphaturia with a concomitant increase in urinary excretion of cyclic AMP. CT produced a rise in arterial cAMP and filtered cAMP, with no increase in urinary nephrogenous cAMP. PTH on the other hand, produced an elevation in urinary nephrogenous cAMP with no increase in arterial cAMP and filtered cAMP. These results indicate that the source of urinary cAMP after CT is non-renal, whereas after PTH it is renal in origin.

Skeletal contribution of cyclic adenosine monophosphate in response to parathyroid hormone and calcitonin in vivo in the rat.

Cyclic adenosine monophosphate (cAMP) is thought to be a second messenger for the actions of both parathyroid hormone (PTH) and calcitonin (CT). We examined the release of cAMP from rat bone in vivo after administration of synthetic rat PTH-(1-34) (rPTH), synthetic human PTH-(1-34) (hPTH), or synthetic human CT (hCT). Blood from the venous effluent of the femoral bone of rats (bone blood) was drawn at 5 and 10 minutes after the administration of hormones. The cAMP content of the bone blood was then compared to the cAMP content of arterial blood. In both kidney-clamped and non-kidney-clamped rats, hCT led to a significantly greater concentration of cAMP in the bone blood than in the arterial blood. We interpret this to be due to bone production and release of cAMP. Neither hPTH nor rPTH produced a significantly greater amount of cAMP in the bone blood than in arterial blood. These data do not preclude the possibility that there was a production of cAMP within the bone tissue itself after PTH but suggest that there was no release of cAMP from the bone into the bone blood.

The effect of hypomagnesemia with or without associated hypercalcemia on renal concentrating ability in rats.

The effect of hypomagnesemia on renal concentrating ability was assessed in rats fed diets either low in magnesium or low in magnesium and calcium for 30 days. The rats fed a low-magnesium diet became hypomagnesemic (0.26 +/- 0.03 versus 1.53 +/- 0.04 mEq/L in controls), hypercalcemic (5.96 +/- 0.04 versus 5.22 +/- 0.11 mEq/L in controls), and hypokalemic (3.1 +/- 0.1 versus 4.2 +/- 0.4 mEq/L in controls) with decreased muscle content of potassium. Despite being hypomagnesemic, hypercalcemic, and potassium depleted, the rats had normal renal concentration ability (2499 +/- 65 versus 2415 +/- 119 mOsm/kg H2O in control). Those rats fed a diet low in both magnesium and calcium became hypomagnesemic (0.41 +/- 0.08 versus 1.53 +/- 0.04 mEq/L in controls) but were hypocalcemic. They also had normal renal concentrating ability (2399 +/- 109 versus 2415 +/- 119 mOsm/kg H2O in controls). It is concluded that hypomagnesemia does not decrease renal concentrating ability in rats. Furthermore, a normal concentrating ability demonstrated in hypomagnesemic rats, in spite of hypercalcemia and potassium depletion suggests that hypomagnesemia may ameliorate the deleterious effects of hypercalcemia and/or potassium depletion on renal concentrating ability.

Magnesium and zinc deficiency and growth retardation in offspring of alcoholic rats.

Alcohol ingestion during pregnancy is known to cause fetal malformation and growth retardation. We investigated the effect of alcohol on mineral content and fetal development in rats fed 24% (v/v) alcohol eight weeks prior to and during pregnancy. Rats ingesting alcohol produced fewer fetuses (6.3 +/- 0.3 vs 9.6 +/- 0.3 in control) with lower fetal weight (3.48 +/- 0.09 vs 4.12 +/- 0.08 gm in control) and heavier placentas (0.66 +/- 0.05 vs 0.50 +/- 0.01 gm in control). The fetuses of alcoholic rats contained lower zinc (423.8 +/- 4.5 vs 459.9 +/- 5.4 microEq/100 gm dry weight in control) and magnesium (12.4 +/- 0.1 vs 12.7 +/- 0.1 mEq/100 gm dry weight in control) in the total carcass.

Urinary excretion of cyclic nucleotides and phosphate in response to parathyroid hormone and calcitonin in man.

The response to parathyroid hormone (PTH) and calcitonin (CT) was studied in eight children with various bone diseases by determining the serum calcium (Ca) and phosphate (P) concentration, urinary phosphate excretion rate, renal phosphate clearance, the percentage of filtered phosphate reabsorbed by the renal tubule (%TRP), creatinine clearance (Ccr), urinary cyclic adenosine 3',5' monophosphate excretion rate (UcGMPV). Administration of PTH caused no significant change in serum Ca and P values, whereas CT produced a decrease in Ca (delta Ca, -1.4 +/- 0.1 mg/100 ml) and P (delta P; -1.1 +/- 0.1 mg/100 ml). There was an increase in UcAMP V (delta UcAMP; 437 +/- 74 nmoles/min/100 ml Ccr) without any significant change in UcGMPV after administration of PTH. Phosphaturia was produced by both PTH (delta TRP, -18 +/- 3%) and CT (delta TRP, -13 +/- 2%). However, CT did not elicit any increase in either UcAMPV or UcGMPV.

Hereditary bone dysplasia with hyperphosphatasaemia: response to synthetic human calcitonin.

Four cases of familial bone dysplasia with hyperphosphatasaemia were treated with synthetic human calcitonin. Prior to therapy, all four cases were characterized by marked bone deformity, pain, tenderness and elevated levels of serum alkaline phosphatase and urinary hydroxyproline. Treatment with calcitonin produced in each case a striking clinical, biochemical and radiographic remission. Pain and tenderness was greatly diminished and urinary hydroxyproline and serum alkaline phosphatase levels were significantly decreased. Radiographic regression of the bony abnormalities was apparent as early as 4 1/2 months after the start of treatment. Prior to therapy bones exhibit no real organization. After calcitonin treatment, the radiographic appearance of a normal cortex and medullary cavity was clearly evident for the first time.

Pathogenesis of hypocalcemia in primary hypomagnesemia: normal end-organ responsiveness to parathyroid hormone, impaired parathyroid gland function.

Hypocalcemia is a frequent feature of hypomagnesemia in man and several other species. To elucidate the cause of this hypocalcemia, we have studied a child with primary hypomagnesemia and secondary hypocalcemia during magnesium supplementation when he was normomagnesemic and normocalcemic and after magnesium restriction for 16 days when he quickly became hypomagnesemic (0.5 meq/liter) and hypocalcemic (3.4 meq/liter) and had positive Chvostek's and Trousseau's signs. Whether in the normomagnesemic or hypomagnesemic state, intravenous bovine parathyroid extract (PTE) 8 U. S. P. U/kg promptly caused transient increases in the urinary phosphate excretion, renal phosphate clearance and cyclic AMP excretion. The magnitudes of these responses were similar in the two states, and similar to those observed in a hypoparathyroid patient. When the patient was hypomagnesemic and hypocalcemic, intramuscular PTE, 8 U/kg at 8-h intervals for four doses promptly caused hypercalcemia. The findings indicate that the end-organs were responsive to parathyroid hormone. The concentrations of serum parathyroid hormone (PTH) were normal in the normomagnesemic state ranging from 0.15 ng/ml to 0.40 ng/ml. Serum PTH did not increase in the hypomagnesemic state in spite of hypocalcemia. Indeed, PTH became unmeasurable in four consecutive samples at the end of the period of magnesium restriction. The concentrations of serum calcitonin remained unmeasurable (< 0.10 ng/ml) throughout the study, implying that excess calcitonin was not the cause of hypocalcemia in magnesium depletion. The findings in this study support our thesis that magnesium depletion causes impaired synthesis or secretion of parathyroid hormone. This impairment would account for the hypocalcemia observed in the hypomagnesemic state.

Pathogenesis of hypocalcemia in magnesium depletion. Normal end-organ responsiveness to parathyroid hormone.

Hypocalcemia in the hypomagnesemic state in man is usually attributed to refractoriness of end-organs to the calcemic action of parathyroid hormone. We studied the responsiveness of end-organs to bovine parathyroid extract (PTE) in magnesium-depleted and control dogs by the following three methods after thyroparathyroidectomy: (a) assessment of the calcemic response to a set dose of PTE (0.3 U/kg per hr); (b) assessment of PTE dose required to attain normocalcemia; (c) evaluation of regression lines of plasma calcium concentration on PTE dose. The calcemic response of magnesium-depleted thyroparathyroidectomized puppies to a set dose of PTE was similar to that of control puppies. There was no significant difference in the dose of PTE required to attain normocalcemia nor in the dose-response relations between the plasma calcium concentration and the PTE dose. In a group of magnesium-depleted puppies with intact thyroid and parathyroid glands, the dose of PTE required to attain normocalcemia was similar to that required in thyroparathyroidectomized animals, indicating calcitonin was not a factor contributing to hypocalcemia. We conclude that hypocalcemia in magnesium-depleted puppies is not due to refractoriness of end-organs to the calcium-mobilizing action of parathyroid hormone. Defective synthesis or diminished secretion of parathyroid hormone is suggested as an explanation.