Urinary Cyclic AMP Levels Research Articles

Urine osmolality, cyclic AMP and aquaporin-2 in urine of patients under lithium treatment in response to water loading followed by vasopressin administration

Lithium is the drug that is most frequently associated with acquired nephrogenic diabetes insipidus (NDI). The exact mechanism of lithium-induced NDI in man is unknown. The aim of the present study was to investigate the kidney response to minimal and maximal stimulation of the kidney urine concentrating mechanism by measuring urine osmolality, and urine levels of cAMP and AQP-2 in urine of patients under long-term lithium treatment. Twenty patients under long-term lithium treatment were included. The kidney urinary 3′,5′-cyclic adenosine monophosphate (cyclic AMP), aquaporin-2 levels and urine osmolality were determined during a situation of minimal kidney urine concentrating activity (induced by water loading) and during a situation following maximal stimulation of kidney urine concentrating activity (induced by 1-desamino-8- d-arginine-vasopressin). Patients were classified as NDI, partial NDI and non-NDI based on maximal reached urine osmolality. The partial correlation ( r) between urinary cyclic AMP levels (mol/l) and urine osmolality was 0.94 ( P < 0.001). No significant correlation was observed between urinary aquaporin-2 levels (mol/mol creatinine) and osmolality nor between urinary cyclic AMP and aquaporin-2 levels. The rise in urinary cyclic AMP but not aquaporin-2 levels upon 1-desamino-8- d-arginine-vasopressin administration after water loading significantly differed between the three categories, decreasing with increasing NDI category. In conclusion we found that in lithium-induced kidney urine concentrating deficit in man, the cyclic AMP generation in response to 1-desamino-8- d-arginine-vasopressin administration after water loading, is impaired. It remains to be elucidated whether principal cells, G-proteins or adenylate cyclase e.g. are the major targets for the mechanism underlying lithium-induced NDI in man.

Effect of Calcium/Phosphorus Ratio on Mineral Retention in Parenterally Fed Premature Infants

SummaryWe hypothesized that retention of parenterally delivered calcium (Ca) and phosphorus (P) is affected by the ratio of the delivered minerals and that a 1.7:1 ratio would be optimal since this is the ratio of retention of these minerals by the fetus. Forty‐one very low birth weight (VLBW) infants were randomly assigned to one of three total parenteral nutrition (TPN) solutions that were different only in their Ca:P ratios: 2:1 (76 mg/kg/day Ca and 38 mg/kg/day of P), 1.7:1 (76 mg/kg/day Ca and 45 mg/kg/day P), and 1.3:1 (58 mg/kg/day of Ca and 45 mg/ kg/day of P). Serum levels of calcium, phosphorus, and alkaline phosphatase, retentions of calcium and phosphorus and urinary cyclic AMP levels were measured after 48 h on the assigned Ca to P ratio. Calcium retentions were higher with the 2:1 and 1.7:1 ratios and phosphorus retentions were higher with the 1.3:1 and 1.7:1 ratios. The 1.7:1 ratio allowed for the highest absolute retention of both minerals and was the closest to published in utero accretion of calcium and phosphorus. The serum and urine studies demonstrated no abnormalities on any of the three ratios. Cyclic AMPs were not different among groups and were not elevated compared to previous reports suggesting that none resulted in parathyroid hormone (PTH) stimulation. We conclude that the 1.7:1 ratio is better than higher or lower ratios for delivery of calcium and phosphorus in TPN solutions at the quantities studied.

Effects of Theophylline on Erythropoietin Production in Normal Subjects and in Patients with Erythrocytosis after Renal Transplantation

Erythrocytosis occurs in 10 to 15 percent of renal-transplant recipients, and there is in vitro evidence that the production of erythropoietin is modulated by adenosine. We prospectively evaluated the effects of theophylline, a nonselective adenosine antagonist, in eight patients with erythrocytosis after renal transplantation and in five normal controls. After an eight-week course of theophylline treatment, the mean (+/- SEM) serum erythropoietin levels were significantly reduced in both the renal-transplant recipients (from 60 +/- 14 units per liter at base line to 9 +/- 7 units after treatment; P less than 0.05) and the normal subjects (from 6.9 +/- 0.8 units per liter at base line to 4.7 +/- 0.5 units per liter after treatment; P less than 0.05). Similarly, the hematocrits were reduced in both the transplant recipients (from 0.58 +/- 0.04 at base line to 0.46 +/- 0.03 after treatment; P less than 0.05) and the normal subjects (from 0.43 +/- 0.01 at base line to 0.39 +/- 0.01; P less than 0.05). In the renal-transplant recipients, red-cell mass was also reduced after eight weeks of theophylline (from 3197 +/- 82 ml at base line to 2273 +/- 69 ml after treatment; P less than 0.05). The previous requirement of weekly phlebotomy was eliminated in all recipients. Plasma and urinary cyclic AMP levels were not increased. These effects were reproducible when the subjects were rechallenged with theophylline after a recovery period. Theophylline attenuates the production of erythropoietin in both normal subjects and patients with erythrocytosis after renal transplantation and may be useful in the treatment of the latter condition.

High doses of fluoride do not affect cyclic AMP levels in human and rat plasma or urine.

The effect of fluoride ingestion on plasma and urinary cyclic AMP levels was studied in healthy volunteers, children undergoing prophylactic fluoride treatment and in rats. In the first series of experiments fluoride ingestion led to a 20-fold increase in plasma fluoride concentration, which was unrelated to changes in plasma cyclic AMP. The only significant effect on plasma cyclic AMP occurred prior to fluoride, an effect attributed to stress. In the second series performed in children increases in urinary F- of up to 200-fold were associated with slight but nonsignificant changes in cyclic AMP excretion. In rat experiments the blood sampling procedure was associated with a rise in plasma cyclic AMP. When this was prevented by pretreatment with propranolol (3 mg/kg), the effect of fluoride (50 ppm in the drinking water) was tested. A fall in urine production was not associated with any change in cyclic AMP excretion or in nephrogenic cyclic AMP. It is concluded that if fluoride alters cyclic AMP in rats and man the effect is small and easily masked by other factors such as catecholamine release following stress.

Cyclic AMP responses to parathyroid hormone and glucagon during lithium treatment.

Inhibition of adenylate cyclase has been proposed as a mechanism for hypothyroidism and nephrogenic diabetes insipidus occurring during lithium treatment, but these disorders are rarely found in the same patients. We have measured plasma levels of adenosine 3':5'-cyclic monophosphate (cyclic AMP) after an intravenous injection of glucagon in eight patients receiving long term lithium treatment and in six control subjects. Urinary cyclic AMP levels after an intravenous injection of bovine parathyroid hormone (PTH) were also measured in the patients. The plasma cyclic AMP response to glucagon in the patient group was significantly lower than that of the controls. No correlation was demonstrated between the plasma cyclic AMP response after glucagon and the urinary cyclic AMP response after PTH. We have previously shown that impairment of the response to PTH correlates with reduced urine concentrating ability during lithium treatment. In contrast, there was no correlation between the responses to PTH and glucagon in individual patients. These results are consistent with the hypothesis that inhibition of adenylate cyclase is an important factor in lithium-induced endocrine dysfunction.

Urinary adenosine cyclic 3',5'-monophosphate in idiopathic calcium stone-formers: response to an oral calcium load.

Idiopathic calcium stone-formers with hypercalciuria during fasting have significantly lower urinary cyclic AMP levels (nmol/dl of glomerular filtrate) than fasting normocalciuric stone-formers. Female subjects, including both normal subjects and idiopathic calcium stone-formers, have higher urinary cyclic AMP levels than their male counterparts, and this difference is significant when urinary cyclic AMP is expressed in the units mumol/g of creatinine. Expressing urinary cyclic AMP in nmol/dl of glomerular filtrate reduces this difference but does not abolish it. Thus, in comparing urinary cyclic AMP levels in various subgroups of the calcium stone-formers and in normal subjects, both sex differences and the units of urinary cyclic AMP expression must be taken into consideration. The magnitude of the change in urinary cyclic AMP in response to an oral calcium load appears to depend on the antecedent urinary cyclic AMP excretion rate, whereby those individuals (either normal subjects or calcium stone-formers) having the highest urinary cyclic AMP levels demonstrate the greatest fall in urinary cyclic AMP after a calcium load.

ANALYSIS OF THE COMPONENTS OF THE HYPERCALCAEMIA IN A 14‐YEAR‐OLD BOY FOLLOWING PROLONGED IMMOBILISATION

A fourteen-year-old boy developed severe symptomatic hypercalcaemia following prolonged supine bed rest for major trauma. Treatment consisted initially of intravenous saline and frusemide together with oral phosphate, followed by intramuscular salmon calcitonin. Only after mobilisation and weight bearing was a sustained fall of plasma calcium to normal achieved. Plasma immunoreactive parathormone levels using both N-terminal and mixed terminal specific antisera were always undetectable and urinary cyclic AMP levels were within the normal range throughout. However, before mobilisation, the tubular reabsorption of phosphate was reduced and that of calcium was increased thus indirectly suggesting increased parathormone activity. The hypercalcaemia was due to a combination of increased calcium release from bone and increased tubular reabsorption. We suggest that a factor other than parathormone is responsible for altered tubular handling of calcium and phosphate which develop following prolonged immobilisation in these patients.

Reduction of experimental gentamicin nephrotoxicity in rats by dietary calcium loading.

Since gentamicin accumulates in the renal cortex before renal failure and calcium reduces gentamicin binding to cell membranes, we examined the effect of dietary calcium loading on gentamicin toxicity in male F344 rats. Rats were fed either a normal (0.5%)- or a high (4%)-calcium-content chow. Calcium loading did not alter inulin clearance, urinary excretion of sodium or total osmoles, or serum ionized calcium. However, calcium loading caused elevation of urinary calcium excretion and lowered urinary cyclic AMP levels. The data suggest that calcium loading may have slowed the accumulation of gentamicin (40 mg/kg per day) by the renal cortex. Histological and functional evidence of nephrotoxicity was delayed in onset and attenuated in magnitude. The results indicate that dietary calcium loading reduces experimental gentamicin nephrotoxicity. Protection may be associated with slower renal cortical accumulation of gentamicin. Calcium-dependent membrane or intracellular events may mediate this effect.

Hypercalcemia in carcinoma of the breast without evidence of bone destruction: beneficial effect of hormonal therapy.

A premenopausal woman with soft tissue metastases from a carcinoma of the breast developed hypercalcemia with hypophosphatemia, reduced tubular reabsorption of phosphate, elevated urinary cyclic AMP levels and normal serum PTH levels was observed. Hormonal therapy with testosterone followed by tamoxifen induced normalization of her serum calcium concomitant with the disappearance of the pleural effusion and reduction in the size of her lung metastases. The correlation between the efficacy of antitumor treatment on pleural effusion, lung metastases, and normalization of serum calcium, as well as the elevated PTH level in the pleural effusion, suggest that this breast carcinoma secreted a PTH-like substance.

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.

Primary hyperparathyroidism: Preoperative evaluation and correlation with surgical findings

The clinical and operative findings in 101 patients with the diagnosis of primary hyperparathyroidism are reviewed, with particular emphasis on the current methods of preoperative evaluation. Of these patients seventy-two (72 per cent) underwent neck exploration. The twenty-nine patients who did not have an operation either refused operative treatment or were not granted an operation because of medical reasons (multiple system disease in elderly patients). Fourteen of the surgical patients (20 per cent) required re-exploration. Two patients had negative neck explorations. Preoperative evaluation included routine serum calcium (X3), serum phosphorus, and alkaline phosphatase determinations, and appropriate radiologic evaluation. Urinary cyclic AMP levels were helpful in differentiating primary hyperparathyroidism from nonparathyroid hypercalcemia. Phosphorus clearance studies were helpful as were twenty-four hour urinary calcium determinations. Parathyroid scans and arteriography were not helpful diagnostically and intravenous toluidine blue was of no benefit intraoperatively. Eleven patients had selective neck vein catheterizations for parathyroid hormone immunoassays with 63 per cent localization. Of seventy patients with positive surgical findings, eleven had chief cell hyperplasia, six had adenomatous hyperplasia, and fifty-three had adenoma(s).

METABOLIC RESPONSE TO I.V. GLUCAGON IN CHILDREN WITH CHRONIC LIVER DISEASE

Studies were performed to evaluate glucose homeostasis in children with intrahepatic biliary hypoplasia (IBH) with chronic cholestatic syndrome and growth retardation. Eight I.V. glucagon tolerance tests (30 μg/kg) on five IBH patients (4-12 yrs of age) were compared to 8 controls. Fasting (14-16 hr) glucose was lower in IBH (67 ± 4 mg% vs 80.8 ± 3.67; p < 0.025), and peak rise was significantly less (107 ± 10.6 vs 147 ± 7.9; p < 0.01). Baseline urinary cyclic AMP levels in IBH vs controls (5.8 ± 2 M ± S.E.M. nmoles/mg creatinine vs 4.5 ± 0.4) and 2 hour excretion response to glucagon (31.1 ± 3 vs 28.6 ± 5.2) were not significantly different. Insulin response to glucagon were similar in IBH vs control. Glucagon has previously been shown to lower plasma gluconeogenic amino acids as a indication of hepatic uptake and gluconeogenesis. Fasting plasma alanine was not significantly different in IBH vs control (210 ± 38 umoles/L vs 245 ± 40). Controls had a significant delta decline at 30 minutes post - glucagon of 100 umoles/L for alanine, 66 for glycine and 39 for glutamine plus asparagine. IBH patients failed to elicit a consistent reduction in gluconeogenic amino acids. These studies suggest that hepatic gluconeogenesis and glycogen storage are impaired in chronic liver disease. The noted cyclic AMP response may reflect adequate adenyl cyclase activity in spite of hepatocellular damage.

Urinary Cyclic AMP in Periodic Catatonia

Urinary excretion of 3',5'-cyclic adenosine monophosphate (cyclic AMP) was measured in two patients with long-established periodic catatonia. One patient exhibited profound stupor in his psychotic phases, while the other exhibited catatonic excitement. No significant differences in urinary cyclic AMP levels were found in either patient between the interval and psychotic phases, nor were there any significant changes in cyclic AMP excretion at or just before the time of abrupt switch from the interval of normality to catatonic stupor or excitement.