Increase In Urinary Cyclic AMP Research Articles

The kidney and essential hypertension: a link to osteoporosis?

Abnormalities of calcium metabolism independent of changes in intracellular calcium have been described in patients with essential hypertension. These include increased urinary calcium excretion for a given salt intake, a raised parathyroid hormone level, an increase in urinary cyclic AMP, a tendency for a low serum ionized calcium level, a raised 1,25-dihydroxyvitamin D level and an increased intestinal calcium reabsorption. These changes have been seen as a consequence of a primary renal calcium leak. We propose that these changes are secondary to a genetic defect in the ability of the kidney to excrete sodium. On the high salt intake in most Western countries (i.e. approximately 170 mmol/day sodium) compensatory mechanisms occur to try to overcome this defect. These compensatory mechanisms are responsible for the rise in blood pressure, but also cause an increase in central blood volume which is the direct cause of the increase in urinary calcium excretion. This causes a slightly negative calcium balance, and the other abnormalities of calcium metabolism can then be seen as a compensatory response to try to restore calcium balance to normal. This hypothesis explains the increase in kidney stones in essential hypertension and predicts that hypertensives, in the long term, will be more likely to develop bone demineralization (osteoporosis), as has been demonstrated in some animal models of hypertension. Increases in salt intake will not only cause a further rise in blood pressure, but will also increase urinary calcium excretion and aggravate the other abnormalities. A moderate reduction in salt intake from 170 to 70 mmol/day will lower the blood pressure and will tend to correct the abnormalities of calcium metabolism. It should simultaneously reduce the incidence of renal stones and the long-term risk of bone demineralization.

The effects of oral furosemide on the response of urinary excretion of cyclic adenosine monophosphate and phosphate to parathyroid extract in normal subjects.

We studied the effects of oral furosemide, 80 mg/day for 7 days, on the response of urinary excretion of phosphate and cyclic AMP to exogenous parathyroid extract (PTE) in 6 normal subjects. All 6 subjects had marked increases in urinary calcium and a significant increase in urinary cyclic AMP from the control to the furosemide periods: this suggests that furosemide-induced hypercalciuria produced elevated parathyroid activity. After treatment with furosemide, the response of urinary cyclic AMP and phosphate to PTE was blunted. During the subsequent calcium infusion (4 mg/kg), urinary cyclic AMP was suppressed to subnormal values, and the response to PTE returned to normal. The evidence suggests that furosemide may blunt the response to PTE, perhaps as a result of the elevated parathyroid activity produced by furosemide-induced hypercalciuria and lowering of plasma-ionized calcium. This blunting effect of furosemide on the response of urinary phosphate and cyclic AMP to PTE should be considered in the evaluation of parathyroid function in patients taking furosemide.

Calcium Metabolism in the Young Adult Male as Affected by Level and Form of Phosphorus Intake and Level of Calcium Intake

A 60-day human metabolic study was conducted to measure polyphosphate hydrolysis and to compare the effects of supplements of phosphorus from ortho- and polyphosphates as well as supplements of both calcium and orthophosphates on calcium metabolism. The experiment was arranged in a 4 × 4 latin square design with eight subjects and four 15-day dietary periods. During its passage through the digestive tract, the polyphosphate supplement was 80.5 ± 5% hydrolyzed to orthophosphate. Calcium absorption was significantly lower when the polyphosphate supplement was given than when the orthophosphate supplement was given. Both forms of phosphate caused a reduction in fractional renal tubular reabsorption of calcium, but only the orthophosphate supplement improved calcium balance. Calcium equlibrium was achieved, however, only when supplements of both calcium and orthophosphate were given. Both phosphorus supplements caused an increase in urinary cyclic AMP, indicating an increase in parathyroid hormone (PTH) secretion, but bone resorption as measured by urinary hydroxyproline was not affected by either phosphate supplement. The combined supplement of calcium and orthophosphate, however, caused decreases in the excretion of both cyclic AMP and hydroxyproline, suggesting a decrease in PTH-mediated bone resorption.Calcium metabolism phosphate supplement cyclic AMP parathyroid hormone excretion

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.

Calcium-dependent, parathyroid hormone-independent regulation of 1,25-dihydroxyvitamin D.

The increase of plasma 1,25-dihydroxyvitamin D (1,25(OH)2D) in response to Ca restriction has been suggested to be essentially mediated by parathyroid hormone (PTH). In this study, we have assessed the influence of variations in calcium intake on plasma 1,25(OH)2D in pair-fed sham-operated (sham) and in hypocalcemic hypoparathyroid rats after thyroparathyroidectomy (TPTX). In sham rats, plasma 1,25(OH)2D increased from 189 +/- 16 to 486 +/- 41 pM when dietary calcium was inreased from 1.2% Ca to 0.2% Ca. This increase was associated with an increase in plasma PTH level. In TPTX rats, plasma 1,25(OH)2D increased from 112 +/- 9 to 332 +/- 36 pM when dietary calcium was decreased. In this case, the increase was not associated with a rise in plasma PTH level nor with an increase in urinary cyclic AMP. When TPTX rats were infused chronically with PTH (60 U/day), plasma 1,25(OH)2D was 62 +/- 9 pM when the 1.2% Ca diet was given and 281 +/- 45 pM with the 0.2% Ca diet. These reults confirm that the thyroparathyroid glands influence plasma 1,25(OH)2D but they also provide evidence for a PTH-independent response of plasma 1,25(OH)2D to Ca restriction.

ACUTE RESPONSE OF PARATHYROID HORMONE IN CONGENITAL OSTEOPETROSIS

Indices of calcium and phosphorus metabolism were studied in 3 children with osteopetrosis before and after infusion of bovine parathyroid hormone extract. Basal plasma concentrations of calcium, alkaline phosphatase and 25-hydroxy vitamin D tended to be low. Plasma immunoreactive PTH levels were at the upper normal range in two patients. A marked increase in urinary cyclic AMP in all patients was solely due to an increase in the nephrogenous cAMP. After vitamin D treatment urinary cAMP was essentially unchanged with the same preponderance of nephrogenous cAMP. Following PTH infusion plasma cAMP showed a brisk rise. There was also a prompt rise in urinary cAMP and a distinct decrease in the calcium to sodium clearance ratio indicating increased calcium reabsorption. Phosphaturic effect was only observed when PTH was given in the highest dose level. The findings are consistent with a state of low grade hyperparathyroidism which could not be related to the plasma levels of 25-hydroxy vitamin D or calcium.

Acute response of parathyroid hormone in osteopetrosis

Congenital osteopetrosis is characterized by severe impairment of bone resorption. Inactivation and/or resistance to parathyroid hormone (PTH) have been suggested as pathogenetic factors. The response to an acute infusion of bovine parathyroid extract (4-8 units/kg) was studied in 3 children with osteopetrosis. Serum calcium, phosphorus and alkaline phosphatase were within normal limits and did not show any consistent change 120 min. after infusion. Plasma cyclic AMP showed a brisk rise with peak levels 4-28 times above the basal values 10 min. after the infusion. The response was most marked at the highest PTH dose level. There was also a prompt increase in urinary cyclic AMP with increments in the range of 100 to 4000 per cent of the basal values when calculated as nmol excreted per min., whereas urinary phosphate excretion was essentially unchanged. The serum levels of 25-hydroxy-vitamin D were subnormal: 28.2 ± 4.4 nmol/1 (normal value 64.4 ± 14.7 nmol/1; range 38.2-98.9 nmol/1). The relative resistance of these patients to the effect mediated by cyclic AMP on calcium and phosphorus metabolism might be related to a relative vitamin D deficiency.

Congenital nephrogenic diabetes insipidus in a baby girl.

A 6-week-old girl with fever, hypernatraemia, dehydration, and polyuria failed to concentrate urine in response to exogenous vasopressin administration. There was no family history of nephrogenic diabetes insipidus. When she was 15 months old, the infusion of vasopressin did not produce an increase in urinary cyclic-AMP.

The Mechanism of Urinary Concentration in Nephrogenic Diabetes Insipidus

The authors have evaluated urinary adenosine 3',5'-monophosphate (cyclic AMP) excretion and renal function during Pitressin administration, hypertonic saline administration, and water deprivation in two siblings with vasopressin-resistant diabetes insipidus and in normal control subjects. After vasopressin administration normal subjects experienced a 2-fold rise in urinary cyclic AMP excretion from 3.2 +/- 0.7 to 5.6 +/- 1.3 nmol/min (P less than 0.001) whereas cyclic AMP excretion was unchanged in both patients (patient AC 4.4 +/- 0.9 to 4.3 +/- 2.1; patient TC 2.2 +/- 0.9 to 2.6 +/- 0.9 nmol/min) with nephrogenic diabetes insipidus (NDI). Urinary cyclic AMP excretion was measured during infusion of 2.5% saline, after vasopressim administration, and after water deprivation. Cyclic AMP excretion was not different from control values in the NDI patients during any of the experimental conditions. Furthermore, there was no difference in cyclic AMP excretion when periods of dilute urine excretion (patient AC 4.5 +/- 1.1; patient TC 2.1 +/- 0.8 nmol/min) were compared with periods when urine concentration was greater than that of plasma (AC 3.5 +/- 1.3; TC 1.8 +/- 0.9 nmol/min). Both subjects responded to parathyroid hormone infusion with a 2-fold increase in urinary cyclic AMP excretion. Excretion of concentrated urine was paralleled by a marked decrease in urine flow to less than 1 ml/min/m2. During periods of hypotonic urine excretion (Uosm/Posm less than 1.0) average glomerular filtration rate (GFR) in patient AC was 67.0 +/- 3.0 ml/minm2 whereas in patient TC it was 70.1 +/- 8.1 ml/min/m2. When each patient was excreting a hypertonic urine (Uosm/Posm greater than 1.0) after fluid deprivation their GFR had decreased significantly (P = 0.001) to 31.6 +/- 8.9 and 33.3 +/- 10.3 ml/min/m2, respectively. Ability of these two subjects with NDI to concentrate their urine to Uosm/Posm greater than 1.0 in the absence of an increase in urinary cyclic AMP but associated with a decrease in GFR to 50% normal indicates that urinary concentration was effected by a reduction in GFR rather than a partial response to antidiuretic hormone (ADH). Their ability to concentrate their urine during periods of modest volume depletion would protect them from progressing to more severe stages of dehydration and result in the relatively benign course of their disease. It is feasible that in patients previously reported to have had clinically "partial" NDI this mechanism may have been operative.

Lithium Does Not Inhibit the Parathyroid Hormone-Mediated Rise in Urinary Cyclic AMP and Phosphate in Humans

To test the hypothesis that lithium is a general inhibitor of hormone-activated adenylate cyclase, we infuse parathyroid hormone (PTH) into human subjects prior to and during lithium carbonate administration. PTH infusion caused a significant increase in urinary cyclic AMP and urinary phosphate excretion. There was no significant difference in these responses in the lithium compared to the control period. In four patients with primary hyperparathyroidism, lithium had no significant effect on serum calcium or phosphate or on tubular reabsorption of phosphate. The data do not substantiate the hypothesis that lithium (at therapeutic concentrations) is a general inhibitor of hormonally-activated adenylate cyclase, nor do they support its potential clinical utility in primary hyperparthyroidism.

Urinary 3'5' cyclic AMP. Diagnostic test in pseudohypoparathyroidism.

Measurement of urinary cyclic AMP (adenosine 3'5'-cyclic phosphate) and examination of calcium and phosphorus metabolism was carried out in two children with pseudohypoparathyroidism. In both patients infusion of parathyroid hormone failed to elicit any change in urinary cyclic AMP, while a dose-dependent increase in urinary cyclic AMP occurred in a normal control. The findings agree with concept of unresponsiveness of renal cortical tissue to parathyroid hormone in pseudohypoparathyroidism and provide further evidence that measurement of urinary cyclic AMP during parathyroid hormone infusion may be the method of choice in the diagnosis of this disease.

Urinary and Plasma Cyclic Adenosine 3′,5′-Monophosphate in Patients with Idiopathic Edema

Urinary excretion and plasma concentrations of adenosine 3',5'-monophosphate were determined in idiopathic edema patients both at rest and after assumption of the upright position. Patients and normal subjects responded similarly to upright posture with decreases in urinary volume and creatine excretion and their urinary excretion of cyclic AMP was not significantly different. The plasma concentration of cyclic AMP was high in patients, both in the recumbent and upright positions, and its renal clearance (unlike that of creatinine) was low. Plasma cyclic AMP increased in response to upright posture both in patients and normal subjects. Even if the significance of elevated plasma cyclic AMP is unknown, its presence without an increase in urinary cyclic AMP suggests that the renal handling of cyclic AMP is abnormal is idiopathic edema; this may be related to an excessive beta-adrenergic tone.

Preliminary study of the treatment of nephrolithiasis (calcium stones) with diphosphonate

Eight patients with absorptive hypercalciuria and renal stones received disodium ethane-1-hydroxy-1, 1-diphosphonate (EHDP) orally at dosages ranging from 5 to 20 mg/kg/day. Examination of their urine revealed a marked inhibition of crystal growth of brushite, the nidus for certain renal stones, coincident with the appearance in urine of EHDP. In three cases, there was an inhibition of nucleation of brushite as well. Except for a transient rise in serum alkaline phosphatase activity and a slight increase in urinary cyclic AMP, no significant side effects have been encountered. Intestinal calcium absorption and bone density did not change significantly during 6 mo of treatment. EHDP may therefore be clinically useful in the prevention of the formation of renal stones of calcium phosphate origin.

Urinary cyclic AMP in renal polyuric disorders

It is widely held that adenosine-3'-5'-monophosphate (cyclic AMP) is a mediator of the hormonal effect of antidiuretic hormone (ADH) in renal tubules. A recent report (J. Clin.End.Metab. 1972, 35, 35-47) demonstrated a 70 percent increase in urinary cyclic AMP in normals after infusion of ADH. To see if the sensitivity of the method could be increased, we gave ADH together with theophyllamin, an inhibitor of cyclic AMP degradation, but urinary cyclic AMP remained the same as without theophyllamin. We studied normal children and children with renal polyuric disorders: urinary tract abnormalities, interstitial nephritis and inheritable nephrogenic diabetes insipidus (NDI). ADH (15 mU/min) was infused and urinary cyclic AMP and osmolality measured. Patients with NDI do not show increment in either parameter, whereas other patients show increased values in one or both. The measurement of urinary cyclic AMP is of some value in the differential dignosis of renal polyuric disorders. The etiologic diagnosis should, however, be confirmed by renal biopsi and renal X-ray.

A METABOLIC BASIS FOR SEVERE INTRACTABLE ASTHMA

We have previously reported that severe asthmatics after receiving catecholamines have decreased urinary cyclic AMP as compared to normals. To better define this abnormality, which suggests B-adrenergic blockade, 15 severe asthmatic children were studied prospectively. Whereas, normals had a mean 3.2±0.4 Nm/min/1.73M2 increment in 2 hour urinary cyclic AMP, asthmatics had a mean 1.6±0.3 Nm/min/1.73M2 increment after 6 μg/Kg of epinephrine. After 12 μg/Kg epinephrine the asthmatics had a mean 2.2±0.4 Nm/min/1.73M2 increment in 2 hour urinary cyclic AMP: individually, 7 asthmatics had no increased urinary cyclic AMP excretion with double the epinephrine; whereas, 8 patients had 1.0 to 5.2 Nm/min/1.73M2 increment after 12 μg/Kg epinephrine. Clinical evaluation the past 18 months demonstrated that 6 of 7 asthmatics who had no increase in urinary cyclic AMP to 12 μg/Kg epinephrine persisted with severe intractable asthma. However, 5 of 8 asthmatics who demonstrated with the dose response test an increase in urinary cyclic AMP had clinical improvement: their asthma is intermittent and less severe. These data support the hypothesis that severe asthmatic patients have a defect in formation of cyclic AMP after B-adrenergic stimulation. Also, lack of a dose response to epinephrine has delineated a unique group of asthmatics.

Phosphaturic effect of I.V. Administered calcitonin in man.

Porcine calcitonin (CT) was administered intravenously to 4 patients whose kidney function and plasma Ca and P levels were normal. A significant increase in urinary P excretion with an increase in urinary cyclic AMP (cAMP) excretion was observed. Plasma P and cAMP levels which were determined simultaneously did not show any significant change. Furthermore, plasma PTH levels determined by the radioimmunoassay revealed that the increased PTH levels provoked by the CT infusion was not responsible for an increase in urinary P or cAMP excretion, since no increase in plasma PTH levels was found during the period when an increase in urinary P or cAMP excretion was observed. In addition, the CT infusion caused an increase in urinary excretion of Ca, Na and Mg as well as P.Based on these data, it can be concluded that CT administered intravenously acts directly on the kidney, resulting in an increase in urinary P excretion which could be mediated through cAMP in the kidney.

NEWBORN URINARY CYCLIC AMP AND DEVELOPMENTAL RENAL RESPONSIVENESS TO PARATHYROID HORMONE

Since the renal action of parathyroid hormone is known to be mediated via 3',5'-adenosine monophosphate (cyclic AMP), urinary cyclic AMP studies were used to determine proximal tubular maturation. Ten formula fed full-term male infants showed a thirty- to sixtyfold increase in phosphate clearance and excretion with a three- to fourfold increase in urinary cyclic AMP comparing their first and third day 24-hour urines (2.37 ± 0.41 to 6.93 ± 0.96 Nm/mg creatinine M. ± S.E.M. first and third days respectively). Seven breast-fed infants showed cyclic AMP excretion of 3.6 ± 0.3 S.E.M. and 6.5 ± 0.3 S.E.M. on Day 1 and Day 3 respectively, showing an insignificant difference to the formula-fed infants. An additional 10 formula-fed infants 5 to 10 days of age excreted 7.0 ± 0.9 S.E.M. Nm/mg of creatinine which is comparable to the 3 to 4 days of age group. The threefold increase in cyclic AMP after the first day of life may possibly reflect increasing parathyroid renal responsiveness. One- and 3-day-old infants and adults were given a 1-hour parathyroid (PTH) infusion (5 U/kg/hr) with measurement of urinary cyclic AMP in time periods before and after the infusions. Peak increases in responses from baseline of cyclic AMP were 1.64 ± 0.34, 7.1 ± 1.5, and 36.0 ± 0.73 Nm/mg of creatinine M. ± range on first day, third day, and in adults respectively with similar relationships of increasing phosphate excretion. Thus, there is most likely a maturational renal proximal tubular responsiveness to PTH on the cellular cyclic AMP level.

Newborn urimary cyclic. AMP and developmental renal responsiveness to parathyroid hormone

Since the renal action of parathyroid hormone (PTH) is known to be mediated via 3′, 5′-adenosine monophosphate (cyclic AMP), urinary cyclic AMP studies were used to determine proximal tubular maturation. Ten formula fed full-term male infants showed a 30 to 60 fold increase in phosphate clearance and excretion with a 3–4 fold increase in urinary cyclic AMP comparing their first and third day 24-hour urines.This 3–4 fold increase in cyclic AMP could reflect increasing pTH renal responsiveness and/or increasing secretion of PTH. One and 3 day old infants and adults were given a one hour PTH infusion (5 μ/kg/hr) measuring urinary cyclic AMP in time periods before and after the infusions. Peak increases in responses from baseline of cyclic AMP were 1.64 ± 0.34, 7.15 ± 1.15 and 36.30 ± 0.73 μmoles/gm creatinine mean ± range on first day, third day and adults respectively with similar relationships of increasing phosphate excretion and decreasing % TRP. Thus, the development of newborn renal responsiveness to parathyroid hormone is on the cellular cyclic AMP level suggesting increasing maturation of the enzyme adenyl cyclase which forms cyclic AMP from ATP.

Effects of glucagon on adenosine 3',5'-monophosphate and guanosine 3',5'-monophosphate in human plasma and urine.

Glucagon, infused intravenously into fasting, well-hydrated, normal men in doses of 25-200 ng/kg per min, induced up to 30-fold increases in both plasma and urinary cyclic AMP. Cyclic GMP levels were unaffected by glucagon. Simultaneous cyclic AMP and inulin clearance studies demonstrated that the glucagon-induced increase in urinary cyclic AMP was entirely due to glomerular filtration of the elevated plasma levels of the nucleotide. The cyclic AMP response to glucagon was not mediated by parathyroid hormone or epinephrine, and trypsintreated glucagon was completely inactive. The perfused rat liver released cyclic AMP into the perfusate in response to glucagon, indicating that the liver is a possible source of the cyclic AMP entering the extracellular fluids in response to glucagon in vivo.