Urinary Cyclic AMP Research Articles

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.

HYPERTENSIVE VIRILIZING ADRENAL HYPERPLASIA WITH MINIMAL IMPAIRMENT OF SYNTHETIC ROUTE TO CORTISOL

One of the first described cases of hypertensive virilizing adrenal hyperplasia (VAH) (Pediatrics 8:805, 1951) has been followed from age 2 1/2 until age 26. Blood pressure as an infant was 150/90, and at age 25 was 220/160. During childhood patient was lost to follow-up for prolonged periods, and received no therapy from age 20 to 25. At this time 24 hr. urinary excretion of 17-KS was 89 mg.; tetrahydro 11-deoxycortisol (tetrahydro S), 47 mg. and pregnanetriol 5.7 mg. Hourly measurements of several plasma steroids by competitive protein binding were made during 24 hrs; concentration ranges were as follows (μg./100 ml): 11-deoxycortisol 6-26; cortisol 3-25; total corticoids 16.5- > 40. Urinary cyclic AMP per 24 hrs. ranged from 5.3-11.6 nmoles/mg. creatinine before therapy, and was 1.9 nmoles after therapy. The results suggest either the formation of an alternate pathway to cortisol synthesis, or the existence of a form of VAH with 2 independent 11-B hydroxylating systems, exhibiting only minimal impairment of the synthetic route to cortisol. The latter would support the presence of 2 independent 11-B hydroxylating systems in the normal human adrenal. This has been suggested by Zachmann et al (JCE 33:501, 1971) to be true in infancy. Our observations on an adult indicate that these 2 systems may not be transitory, but persist into adulthood.

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.

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.

Urinary Cyclic Adenosine Monophosphate Excretion in Diabetes Insipidus of Childhood Effect of Vasopressin and Chlorpropamide

Excretion of urinary cyclic AMP (cAMP) was determined in 7 children suffering from central diabetes insipidus (CDI), 3 children suffering from nephrogenic diabetes insipidus (NDI), and 5 normal children. Excretion of cAMP was found to be depressed in both types of DI. Administration of long-acting vasopressin in physiologically effective dosage (ADH, 5.1 U per 1.7 m2) decreased the absolute rate of cAMP excretion slightly in reference and CDI children, but had no effect on NDI children. Infusion of large doses of ADH (600 mU per 1.7 m2 per h) into CDI children also reduced cAMP excretion slightly, but in relation to creatinine excretion, an increase of about 30 per cent was found. This increase of the cAMP/creatinine ratio was due to a greater decrease in creatinine than in cAMP excretion. Chlorpropamide had no effect on cAMP excretion in CDI patients.

Pseudohypoparathyroidism type II: a possible defect in the reception of the cyclic AMP signal.

A22 month old boy with grand-mal seizures and hypocalcemia, had an elevated serum concentration of parathyroid hormone, increased urinary excretion of cyclic AMP, and a marked rise in urinary cyclic AMP in response to exogenously administered parathyroid extract. However, neither the renal tubular handling of phosphate nor the serum calcium concentration responded appropriately to administered parathyroid hormone. This defect appears to represent a failure of intracellular reception of the cyclic AMP message, and the disorder might be called pseudohypoparathyroidism Type II. (N Engl J Med 289:1056–1060, 1973)

Urinary cyclic 3',5'-adenosine monophosphate levels in diabetes mellitus before and after treatment.

ABSTRACT Urinary cyclic AMP excretion was studied in a group of 8 patients with uncontrolled diabetes mellitus before and after treatment with insulin. Blood glucose, urinary cyclic AMP and creatinine were measured before and after treatment. Total cyclic AMP and cyclic AMP/creatinine ratios were both significantly higher in the diabetic patients before treatment compared with values after treatment. Urinary cyclic AMP/creatinine ratios were significantly higher in the diabetic patients before treatment compared to ratios in 8 normal subjects and treatment consistently returned these to normal. Total cyclic AMP excretion tended to be higher in the uncontrolled diabetics compared with that in normal subjects but differences were not significant. These studies reveal still another clinical disorder characterized by aberrations in cyclic AMP metabolism.

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.

Urinary excretion of cyclic-3',5'-adenosine monophosphate in hyperthyroidism.

Urinary cyclic AMP excretion was studied in twelve females and three males with untreated Graves' disease and one female with thyrotoxicosis factitia. Cyclic AMP/creatinine ratios were elevated both in male (6.84 ± 0.58, ± SEM) and female patients (6.80 ± 0.34) as compared with normal male and female controls (3.20 ± 0.20 and 3.83 ± 0.18, respectively). However, total cyclic AMP excretion was elevated only in the male hyperthyroid patients. The consistently elevated cyclic AMP/creatinine ratios were to a great extent a reflection of significantly decreased creatinine excretion in these patients.

Urinary and plasma cyclic AMP responses to epinephrine in asthmatic and normal subjects

Urinary and plasma cyclic AMP responses to epinephrine in asthmatic and normal subjects

Urinary cyclic AMP excretion in toxaemia of pregnancy.

The excretion of urinary cyclic AMP (cAMP) and estriol was determined in a group of women in late toxaemic pregnancy and in 26 women with normal pregnancies. Fifteen of the toxaemic patients were not receiving medication at the time of analysis and nine were receiving medication for various reasons. The excretion of cAMP was found to be decreased in late untreated toxaemia (to half of the value in normal pregnancy). Some of these drugs (di-hydralazine, hydrochlorothiazide) seemed to normalize the cAMP excretion in toxaemic patients. There was no correlation between cAMP excretion and estriol excretion.

Evaluation of urinary cyclic 3'5'-adenosine monophosphate excretion in the differential diagnosis of hypercalcemia.

ABSTRACT Urinary cyclic 3′,5′-adenosine monophosphate (cyclic AMP) was determined in two normocalcemic control groups and five groups of hypercalcemic patients. Immunoreactive parathyroid hormone was also measured by immunoassay in many of the patients. Eighteen healthy controls excreted 6.2 ± 0.5 μmoles of cyclic AMP per 24 hr; 28% excreted greater than 7.0 μmoles. Sixteen surgically proven hyperparathyroid patients excreted 7.3 ± 0.7 μmoles/24 hr, not statistically different from normal, but 73% of these patients excreted more than 7 μmoles/ hrs. Urinary cyclic AMP excretion usually decreased in these patients after surgical correction of their hyperparathyroidism. A group of four patients with suspected hyperparathyroidism excreted 5.6 ± 1.2 μmoles/24 hr, no different from either normals or surgically proven hyperparathyroid patients. Plasma parathyroid hormone was inappropriately increased for the serum calcium in all of the patients with proven or suspected hyperparathyroidism in whom it was measured...

Urinary Cyclic AMP in Graves's Disease

Urinary Cyclic AMP in Graves's Disease

Effects of catecholamines and adrenergic-blocking agents on plasma and urinary cyclic nucleotides in man.

Studies were performed in healthy volunteers to determine the effects of catecholamines and adrenergic-blocking agents on plasma and urinary levels of adenosine 3',5'-monophosphate (cyclic AMP) and guanosine 3',5'-monophosphate (cyclic GMP). Plasma cyclic AMP rose in response to infusions of the beta-adrenergic agent, isoproterenol, or in response to infusions of either epinephrine or norepinephrine alone or in combination with the alpha-adrenergic-blocking agent, phentolamine. Although urinary cyclic AMP also rose, the percentage increase was less than that observed in the plasma. These treatments caused no increase in plasma cyclic GMP. Plasma cyclic GMP rose in response to infusions of alpha-adrenergic agents, viz., epinephrine or norepinephrine infused together with the beta-blocking agent, propranolol. These treatments caused no increase in plasma cyclic AMP. These observations are consistent with the current concept that the actions of beta-adrenergic agents are mediated by increases in cyclic AMP formation in target tissues. Such a mediating role has not been established for cyclic GMP, but the data suggest the possibility that cyclic GMP metabolism is responsive either to alpha-adrenergic stimulation or to parasympathetic stimulation which occurs as a reflexive consequence of the pressor effect of alpha-adrenergic agents.

Deficient renal cyclic adenosine 3'-5' monophosphate production in nephrogenic diabetes insipidus.

Vasopressin (ADH) (10 mU/min) was infused for 2–4 hr in 6 water loaded normal subjects, 5 patients with primary diabetes insipidus, and 2 with nephrogenic diabetes insipidus. Cyclic AMP in hourly urine samples prior to and during ADH administration was measured by high pressure anion exchange chromatography. In normals, urinary cyclic AMP was 2.7 ± 0.5 μm/g Cr (1 sd) during H2O loads increasing to 4.8 ± 1.0 with ADH, and in diabetes insipidus, urinary cyclic AMP was 2.5 ± 0.3 on no therapy increasing to 3.9 ± 1.0 μm/g Cr with ADH as urine osmolality rose from less than 100 to more than 330 mOsm/kg. Urinary cyclic AMP was significantly (p < 0.001) greater, 1.7 ± 0.4 times control, with ADH. However, in 2 patients with nephrogenic diabetes insipidus, urinary cyclic AMP was 2.0 ± 0.1 and 2.7 ± 0.2 μm/g Cr prior to and remained less than or equal to control values during ADH infusion. Tolbutamide (1 g iv) increased urine osmolality from 101 to 579 mOsm/kg in a glucose loaded diabetes insipidus patient while urinary cyclic AMP rose to 1.6 times baseline; while in nephrogenic diabetes insipidus tolbutamide produced no increase in urine osmolality or urinary cyclic AMP. Parathyroid hormone (200 U iv) increased urinary cyclic AMP 71–121-fold in 6 normals, while urinary cyclic AMP increased only 10- and 30-fold in the 2 nephrogenic diabetes insipidus patients. Glucagon (1 mg iv) increased urinary cyclic AMP 7–25-fold in 6 normals, and 6 times in nephrogenic diabetes insipidus. These findings show that in nephrogenic diabetes insipidus, urinary cyclic AMP fails to rise with ADH or tolbutamide in contrast to normal and diabetes insipidus patients. Nephrogenic diabetes insipidus patients appear to have a defect in ADH and parathyroid hormone stimulated urinary cyclic AMP excretion.

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.

BABIES, HORMONES AND KIDNEYS—A NEW LOOK AT DEVELOPMENT

The role of cyclic AMP (adenosine 3’,5’-monophosphate) in hormone action is now quite firmly established. Abundant evidence now demonstrates that after release from an endocrine gland a hormone (first messenger) is transported to its effector cell (target) where it interacts with the adenyl cyclase system to release cyclic AMP (second messenger) which acts intracellularly to carry out the work of the hormone. In 1967, Chase and Aurbach demonstrated that urinary cyclic AMP, now known to be derived from both plasma and kidney, increased when parathormone (PTH) was administered to the rat and man. These workers also demonstrated a PTH-sensitive adenyl cyclase in the proximal tubules of the rat kidney and in fetal bone.

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.

Urinary cyclic AMP excretion in depression and mania. Effects of levodopa and lithium carbonate.

The 24 hour urinary excretion of adenosine 3',5'-cyclic monophosphate (cyclic AMP) was studied in a series of 40 patients with affective disorders and in ten normal controls. The depressed patients were divided into two groups, severely and moderately depressed. Manic patients excreted the most cyclic AMP; the severely depressed excreted the least; and the controls and moderately depressed patients showed intermediate values. In longitudinal studies of four depressed patients treated with levodopa, marked increases in urinary cyclic AMP excretion occurred. Patients treated with lithium carbonate showed changes in cyclic AMP excretion in the direction of clinical change, ie, as depression improved, cyclic AMP excretion increased and as mania improved it diminished. Factors which may influence the excretion of urinary cyclic AMP are presented.

Effects of parathyroid hormone on plasma and urinary adenosine 3',5'-monophosphate in man.

The effects of parathyroid hormone (PTH) on plasma and urinary adenosine 3',5'-monophosphate (cyclic AMP) levels were studied in normal subjects. Under basal conditions normal adults have plasma concentrations of cyclic AMP ranging from 10 to 25 nmoles/liter and excrete from 1.5 to 5 mumoles of cyclic AMP per g of urinary creatinine. About one-half to two-thirds of the cyclic AMP excreted in the urine is derived from the plasma by glomerular filtration, and the remainder is produced by the kidney. Renal production of cyclic AMP is partly under the control of PTH. It can be suppressed by infusions of calcium and stimulated by infusions of the calcium chelating agent, EDTA. Infusions of PTH in doses up to 10 mU/kg per min were associated with dose-related increases both in urinary cyclic AMP and phosphate. Infusions of PTH in doses ranging from 20 to 80 mU/kg per min did not lead to any further increase in phosphaturia but did lead to further marked increases in urinary cyclic AMP. A modest increase in plasma cyclic AMP was noted when PTH was infused at 40 mU/kg per min. Anephric patients failed to show appreciable increases in plasma cyclic AMP in response to large doses of PTH but did show expected increases in response to glucagon. Surgical removal of parathyroid adenomas from nine patients with primary hyperparathyroidism was invariably followed by a decrease in urinary cyclic AMP, PTH, in large doses, and calcium infusion produced up to 2-fold increases in the other known naturally occurring cyclic nucleotide, guanosine 3',5'-monophosphate (cyclic GMP).