Urinary Cyclic AMP Research Articles

Effect of indomethacin on the renal actions of theophylline

The effects of theophylline ethylenediamine (15 mg/kg i.v.) on plasma renin activity (PRA), diuresis, creatinine clearance and plasma and urinary adenosine 3′,5′-monophosphate (cyclic AMP) concentrations were studied in urethane-anaesthetized rabbits with and withoout pretreatment with indomethacin (5 mg/kg i.v.). Theophylline induced a several-fold increase in urinary sodium and water excretion, raised PRA from 76 ± 15 to 239 ± 83 (S.E.M) ng/ml/h ( p < 0.05) and increased urinary cyclic AMP excretion from 0.21 ± 0.04 to 0.50 ± 0.08 nmol/min/kg/kidney ( p < 0.05) without any change in arterial plasma cyclic AMP concentration. The ratio between the clearance of creatinine and cyclic AMP was unchanged. After indomethacin pretreatment the theophylline-induced natriuresis was significantly reduced ( p < 0.05), while the effects of theophylline on PRA and urinary cyclic AMP exretion were unchanged. Under the present experimental conditions, indomethacin reduced renal prostaglandin biosynthesis by over 95%. Our results indicate that prostaglandins might be concerned with the natriuretic effects of theophylline but not with the effect on PRA.

Nonautonomy of parathyroid hormone and urinary cyclic AMP in primary hyperparathyroidism

This study demonstrates that appreciable changes in serum parathyroid hormone and urinary cyclic AMP occur during experimentally induced hyper- and hypocalcemia in almost all patients with primary hyperparathyroidism regardless of histology. A single patient with tertiary hyperparathyroidism also demonstrated a significant elevation of serum parathyroid hormone and urinary cyclic AMP in response to EDTA induced reduction in ionized calcium. Thus, total autonomy of hormone secretion was not present in the great majority of the patients with a parathyroid adenoma, parathyroid hyperplasia, or the single patient with tertiary hyperparathyroidism. Therefore, preoperative evaluation of the response of urinary cyclic AMP and serum parathyroid hormone to EDTA or calcium infusion will not distinguish parathyroid adenomas from hyperplasia on the basis of total autonomy of hormone secretion. If a difference in secretory control is present between parathyroid adenomas and parathyroid hyperplasia, it is more subtle than total autonomy for adenomas and nonautonomy for hyperplasia.

Effect of sodium fluoride on concentrating and diluting ability in the rat

Mechanisms for the concentrating defect produced by fluoride were examined in the rat. Free-water clearance at all levels of delivery was normal after 5 days of chronic fluoride administration in the hereditary hypothalamic diabetes insipidus rat. In the Sprague-Dawley rats, during moderate fluoride administration (120 micronmol/kg per day), urine osmolality and cyclic AMP excretion decreased and urine volume increased, but after exogenous vasopressin, volume decreased and osmolality and cyclic AMP increased appropriately. During larger daily doses of fluoride (240 micronmol/kg per day) urinary osmolality and cyclic AMP decreased and volume increased, which was similar to the changes seen during lower fluoride dosages, but these parameters did not change after exogenous vasopressin. These data suggest that ascending limb chloride reabsorption is unaltered by fluoride administration; in the presence of sufficient fluoride, collecting tubular cells apparently do not generate cyclic AMP or increase permeability appropriately in response to vasopressin. The postulated defect is felt to be due to either a decrease in ATP availability or to a direct inhibitory effect of fluoride on the vasopressin-dependent cyclic AMP generating system.

Mechanism of resistance to the phosphaturic effect of the parathyroid hormone in the hamster.

The effect of parathyroid hormone and calcitonin on the renal excretion of phosphate, calcium, and cyclic AMP was evaluated in the thyroparathyroidectomized hamster, a mammal apparently reisstant to the phosphaturic effect of parathyroid hormone. Parathyroid hormone did not increase phosphate excretion, although it decreased excretion of calcium and increased urinary excretion of cyclic AMP. This lack of a phosphaturic response to parathyroid hormone was not reversed by administration of 25-OH vitamin D or infusions of calcium or phosphate. Calcitonin, another potentially phosphaturic hormone, also vailed to increase phosphate excretion but markedly elevated urinary excretion of cyclic AMP. In hamsters pretreated with infusion of urinary ammonium chloride, which decreased plasma and urinary pH, both parathyroid hormone and calcitonin increased excretion of phosphate as well as that of cyclic AMP. Acetazolamide had no phosphaturic effect in ammonium chloride-loaded hamsters, and it decreased cyclic AMP and calcium excretion. Alkalinization of urine by acetazolamide did not prevent the phosphaturic effect of parathyroid hormone in ammonium chloride-loaded hamsters, but it blocked the increase in urinary cyclic AMP excretion. Parathyroid hormone and calcitonin both stimulated adenylate cyclase in a cell-free system (600-g pellet) from hamster renal cortex, elevated tissue cyclic AMP levels, and activated protein kinase in tissue slices from hamster renal cortex. In acid medium, the increase in cyclic AMP and activation of protein kinase in response to parathyroid hormone was diminished, but addition of acetazolamide restored responsiveness of both parameters to control values. Acetazolamide, on the other hand, did not influence adenylate cyclase or its response to parathyroid hormone or cyclic AMP phosphodiesterase activity. We conclude that the lack of a phosphaturic effect of parathyroid hormone and calcitonin in the hamster depends on steps in the cellular action of these hormones, steps that are sensitive to pH subsequent to cyclic AMP generation and protein kinase activation. In addition, acetazolamide may potentiate the phosphaturic effect of parathyroid hormone by promoting accumulation of cyclic AMP in tissue. Thus, the hamster is a particularly useful model for studies of syndromes in which there is renal resistance to phosphaturic hormones.

Hyperparathyroidism: Influence of glomerular filtration rate on urinary excretion of cyclic AMP

Urinary cyclic AMP excretion per 24 h or per g creatinine in primary hyperparathyroidism (1 degrees HPT) has been evaluated by several authors with conflicting results. In 50 patients with 1 degrees HPT, 25 patients with secondary (2 degrees) HPT and 35 healthy control persons we determined urinary cyclic AMP per 24 h or per g creatinine. These parameters did not satisfactorily discriminate patients from controls, especially when glomerular filtration rate (GFR) as determined by creatinine clearance was reduced. Since urinary cyclic AMP is derived from plasma by glomerular filtration and from kidney by tubular production-the amount of tubules is reflected by GFR-the cyclic nucleotide was related to GFR. In controls urinary cyclic AMP correlated better with GFR than with creatinine excretion. Additionally, in 45 of 50 patients with 1 degrees HPT and in all with 2 degrees HPT, urinary cyclic AMP/GFR was raised. In 1 degrees HPT serum levels of parathyroid hormone correlated closer with urinary cyclic AMP/GFR than with urinary cyclic AMP/g creatinine. The ratio cyclic AMP/GFR decreased to normal or subnormal values after removal of adenomatous or hyperplastic glands in 1 degrees HPT and during infusion of calcium in 2 degrees HPT. In 50 patients with renal lithiasis caused by diseases other than 1 degrees HPT (anatomical variations, pyelonephritis, immobilization after tetraplegia) the ratio cyclic AMP/GFR was not raised. Urinary cyclic AMP/GFR, therefore, reflects parathyroid hormone excess more reliably than cyclic AMP/g creatinine.

Urinary cyclic AMP and post-traumatic acute renal failure

Consecutive daily urinary excretion of cyclic AMP has been investigated in 16 patients with severe trauma or illness, five of whom developed acute renal failure (ARF). Fluctuations in the nucleotide excretion exceeded the range found in 20 healthy volunteers (1.26–14.74, mean 7.13 ± 1.18 vs. 2.04–10.10, mean 5.07 ± 2.21 μmiol/24 h). This resulted in a 41% increase of cAMP excretion in the group with normal renal function ( P < 0.003) with the highest individual increase of 87%. The excretion usually reached its peak by 24 h after trauma and its lowest value by the third day, (first day vs. third day: 7.82 ± 4.23 vs. 3.96 ± 2.58 μmol/24 h, P < 0.05 for a group of 11 patients), while creatinine clearance remained normal. In four patients with severe ARF, the mean urine volume was above control value but the cAMP excretion was reduced to 3.9 to 14.4% and in one patient with a mild ARF to 60.6%. Creatinine excretion of the group was less reduced than that of cAMP (41.2% vs. 19.6%, resp.). cAMP excretion declined proportionally with diminishing creatinine clearance. In the category of 33–65 ml/min it decreased by 33.4% to 3.39 μmol ± 1.16 μmol/24 h. cAMP/creatinine ratio proved to be a less sensitive indicator thane AMP/24 h. Daily output of cAMP and creatinine correlated highly with diuresis in ARF patients, controls (always P < 0.001) and less in patients with normal renal function ( P < 0.02). Urinary cAMP appears to be a very sensitive and early indicator of the onset of ARF and subsequent recovery. This warrants its further study.

Antidiuretic and Urinary Cyclic AMP Response of Vasopressin in Normal Rats and in Rats with Lithium‐polyuria

Abstract: The antidiuretic and urinary cyclic AMP response to supramaximal vasopressin infusion was studied in normal rats and in rats with lithium‐polyuria. The animals were anaesthetized and then infused with a solution designed to produce excessive water diuresis and to lower basal cyclic AMP excretion. In 6 control animals not infused with vasopressin (I) urinary cyclic AMP excretion decreased during the infusion period. Vasopressin infusion (300 μU/min.) consistantly induced antidiuresis in all of 13 control rats (II); but the urinary cyclic AMP response varied individually from a significant increase in 6 animals to either no change or to a decrease in the remaining animals. The antidiuretic response to vasopressin was inhibited by 85% in 10 animals with marked polyuria induced by lithium administration (III). None of the animals in this group showed a significant increase of cyclic AMP excretion in response to vasopressin. The average rate of cyclic AMP excretion, which was equal in the two groups before vasopressin, was signifimantly lower in group III than in group II during vasopressin infusion. It is suggested that the increase in cyclic AMP excretion during vasopressin antidiuresis, although not consistant, most likely reflects hormone‐induced changes of intracellular cyclic AMP levels in the renal medulla. Thus, the data suggest that the nephrogenic diabetes insipidus syndrome produced by lithium is associated with a defect in the renal formation of cyclic AMP in reponse to vasopressin.

Antidiuretic and Urinary Cyclic AMP Response of Vasopressin in Normal Rats and in Rats with Lithium‐polyuria

The antidiuretic and urinary cyclic AMP response to supramaximal vasopressin infusion was studied in normal rats and in rats with lithium-polyuria. The animals were anaesthetized and then infused with a solution designed to produce excessive water diuresis and to lower basal cyclic AMP excretion. In 6 control animals not infused with vasopressin (1) urinary cyclic AMP excretion decreased during the infusion period. Vasopressin infusion (300 muU/min.) consistantly induced antidiuresis in all of 13 control rats (II); but the urinary cyclic AMP response varied individually from a significant increase in 6 animals to either no change or to a decrease in the remaining animals. The antidiuretic response to vasopressin was inhibited by 85% in 10 animals with marked polyuria induced by lithium administration (III). None of the animals in this group showed a significant increase of cyclic AMP excretion in response to vasopressin. The average rate of cyclic AMP excretion, which was equal in the two groups before vasopressin, was signifimantly lower in group III than in group II during vasopressin infusion. It is suggested that the increase in cyclic AMP excretion during vasopressin antidiuresis, although not consistant, most likely reflects hormone-induced changes of intracellular cyclic AMP levels in the renal medulla. Thus, the data suggest that the nephrogenic diabetes insipidus syndrome produced by lithium is associated with a defect in the renal formation of cyclic AMP in response to vasopressin.

Urinary Excretion of Cyclic 3′, 5′-Adenosine Monophosphate and Cyclic 3′, 5′-Guanosine Monophosphate During and After Pregnancy

Urinary cyclic AMP and cyclic GMP excretions were measured in 24-h urine specimens obtained from 89 women at various times during their normal uncomplicated intrauterine pregnancies and from 49 women at various times after the births of their normal healthy infants. Cyclic AMP excretion increased steadily from the beginning of the second trimester or earlier until late in the third trimester, reaching a peak excretion approximately 40% greater than that of normal nonpregnant women. The cyclic AMP excretion dropped abruptly by the first day after parturition to levels which were not significant different from those of normal non-pregnant women. In contrast, cyclic GMP excretion increased rapidly during the first trimester and remained relatively constant during the remainder of the pregnancy, reaching a peak excretion of about 140% greater than that of normal nonpregnant women. Furthermore, it decreased slowly toward normal levels, but was still significantly elevated six weeks after parturition. The factors responsible for the increased excretion of cyclic AMP during pregnancy and for the increased cyclic GMP during and after pregnancy are not known.

THE EFFECT OF TREATMENT OF HYPERAND HYPOTHYROIDISM ON URINARY EXCRETION OF CYCLIC ADENOSINE 3′,5′-MONOPHOSPHATE

The urinary excretion of cyclic adenosine 3',5'-monophosphate (cyclic AMP) was examined in patients with hyperthyroidism and primary hypothyroidism, before treatment and at least six months later on return to euthyroid status. Urinary cyclic AMP excretion was significantly greater in the hyperthyroid group than in the hypothyroid group both in the basal state (P less than 0.01) and the ambulant state (P less than 0.001). In ambulant hyperthyroid patients absolute urinary cyclic AMP excretion (mumol/24 h) was significantly greater (P less than 0.05) prior to treatment than on return to euthyroid status. In the hypothyroid group no significant change occurred after treatment with 1-thyroxine (P greater than 0.05). The mechanism of changes in urinary cyclic AMP excretion in thyroid disease are discussed.

Plasma and Urinary Cyclic AMP Levels in Normal and Lithium‐treated Rats

Plasma and Urinary Cyclic AMP Levels in Normal and Lithium‐treated Rats

Plasma and Urinary Cyclic AMP Levels in Normal and Lithium‐treated Rats

Plasma and Urinary Cyclic AMP Levels in Normal and Lithium‐treated Rats

THE EFFECT OF PITUITARY-ADRENAL MANIPULATIONS UPON URINARY CYCLIC AMP EXCRETION IN MAN

The present studies demonstrate that the administration of pharmacologic amounts of ACTH is associated with small but significant increases in urinary cyclic AMP excretion and in urinary cyclic AMP/creatinine ratios which are most likely related to a release of cyclic AMP from adrenocortical tissue. Acute suppression of the pituitary-adrenal axis with dexamethasone and stimulation with metyrapone, however, is not associated with changes in urinary cyclic AMP excretion. These results suggest that physiological levels of ACTH and cortisol contribute little, if any, to the urinary excretion of cyclic AMP in man.

RENAL EFFECTS OF NATIVE PARATHYROID HORMONE AND SYNTHETIC BIOLOGICALLY ACTIVE FRAGMENTS IN PSEUDOHYPOPARATHYROIDISM AND HYPOPARATHYROIDISM1

To gain further insight into the biological significance of parathyroid hormone (PTH) metabolism, native parathyroid hormone and synthetic peptides, similar to PTH metabolites generated in vivo, have been given intravenously to human subjects. The resultant changes in renal excretion of adenosine 6':5' monophosphate (cyclic AMP) and inorganic phosphate have been measured in five pseudohypoparathyroid, four hypoparathyroid, and one pseudopseudohypoparathyroid patient. As anticipated, native PTH promptly increased urinary cyclic AMP and phosphate excretion in the hypoparathyroid and pseudo-pseudohypoparathyroid patients, and had little or no effect on their excretion in the pseudohypoparathyroid patients. Synthetic bovine parathyroid hormone 1-34 and synthetic human parathyroid hormone 1-34 had effects essentially identical to each other and to native PTH. We conclude that the PTH resistance of pseudohypoparathyroidism is probably not caused by a defect in PTH metabolism. We further conclude that synthetic human or bovine parathyroid hormone 1-34 could be used for diagnostic evaluation of patients.

Urinary Cyclic AMP: Relation to Calcium Balance and Comparison of Assay Methods

Urinary adenosine 3',5'-monophosphate (cyclic AMP, cAMP) has been determined in 84 males. Two protein-binding assays were used: the method of Gilman and the Amersham assay kit. The results were in close agreement. The excretion of cAMP was nor correlated to urinary calcium or to estimated calcium intake.

Urinary cyclic AMP analyzed as a function of the serum calcium and parathyroid hormone in the idfferential diagnosis of hypercalcemia.

Urinary cyclic AMP (UcAMP) appropriate for the serum calcium concentration was determined in normal subjects during the base-line state and during alteration in their serum calcium concentrations by saline and calcium infusions. This was compared to the UcAMP in 76 patients with hypercalcemia and 5 patients with hypocalcemia. In 54 of 56 patients with primary hyperparathyroidism, the UcAMP was inappropriately high for their serum calcium concentration, the 2 exceptions having renal failure. In four patients with vitamin D intoxication, sarcoidosis, milkalkali syndrome, and thiazide-induced hypercalcemia and in five patients with hypocalcemia due to hypoparathyroidism, the UcAMP was appropriately low for their serum calcium concentration. In 16 patients with nonparathyroid neoplasms, 10 had UcAMP levels that were inappropriately high suggesting ectopic parathyroid hormone (PTH)-mediated hypercalcemia and 6 had UcAMP levels that were appropriately low suggesting that their hypercalcemia was due to osteolytic factors other than PTH. Correlations between UcAMP, serum calcium concentration, and carboxyl-terminal immunoreactive PTH suggest that random UcAMP is a sensitive accurate reflection of circulating biologically active PTH. If there is adequate renal function (serum creatinine concentration less than 2.0 mg/dl), a random UcAMP expressed as mumol/g creatinine and analyzed as a function of the serum calcium concentration completely separates patients with PTH and non-PTH-mediated hypercalcemia.

Urinary cyclic AMP and renal concentrating capacity in infants

In 15 infants between 1 and 31 weeks the effect of antidiuretic hormone (ADH) on the renal concentrating capacity and urinary cyclic AMP (cAMP) was tested. A significant decrease of urine flow and a significant increase of osmolality, urea and cAMP was observed indicating that the distal nephron of the infant kidney is responsive to exogenous ADH and that its effect is mediated by cAMP. The results of a second series with 52 normally hydrated infants demonstrate that the nonlinear age-related increase of osmolality and urea in urine is accompanied by a similar pattern of cAMP excretion, pointing out that the maturation of the concentrating capacity seems to be related to an increasing responsiveness of the cAMP system to ADH. Furthermore the results raise the possibility that increasing concentrations of urea and solutes in the medulla and papilla of the infant kidney may have--in the presence of very low ADH secretion--an additional stimulating effect on cAMP formation.

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.

Urinary Excretion of Cyclic AMP and Cyclic GMP in Primary Hyperparathyroidism with Reference to Clinical Signs and Symptoms

35 patients with surgically proven primary hyperparathyroidism (PHPT) were evaluated with regard to urinary cyclic AMP and cyclic GMP excretion. They showed no signs of bone disease or impaired renal function. Preoperatively, cyclic AMP was increased in 28 patients (80%). Mean excretory value for the whole group was 8.5 ± 0.8 micromoles/g creat/24 hours, compared with controls, 4.2 ± 0.13 micromoles/g creat/24 hours. Cyclic AMP excretion was normalized after surgery.

Urinary cyclic AMP excretion by methadone subjects during gradual and acute withdrawal

Laboratory and animal investigations have supported the hypothesis that levels of cyclic AMP are stable during tolerance to narcotic drugs and increased during withdrawal. In order to test this hypothesis, serial 24-h urinary excretion of cyclic AMP by long-term methadone addicts was determined during a period of stable methadone intake, a period of gradual withdrawal, and a period of acute withdrawal. Cyclic AMP excretion during stable methadone intake is identical to that of normal control subjects. Neither gradual nor acute withdrawal appears to affect the urinary excretion of cyclic AMP. These data agree with previous reports in the literature which suggest that cyclic AMP levels are not altered during tolerance to narcotics, but do not support the hypothesis that levels of the nucleotide might be increased during withdrawal.