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.     

Seasonal variation in urinary excretion of cyclic AMP in healthy people

In a group of healthy young men and women the daily urinary excretion of cyclic adenosine 3', 5'-monophosphate (cAMP), calcium, hydroxyproline and the renal threshold phosphate concentration were evaluated at monthly intervals during 1 yr. A significant seasonal variation in cAMP urinary excretion was demonstrated, with a maximum occurring in spring and a minimum in winter. A clear annual rhythm was also observed when the other above parameters were considered. These findings are of importance in the interpretation of urinary cAMP values in clinical situations, and in the study of bone metabolism.     

Somatostatin inhibits multireceptor stimulation of cyclic AMP formation and corticotropin secretion in mouse pituitary tumor cells.

The AtT-20/D16-16 mouse pituitary tumor cell secretes corticotropin (ACTH) in response to corticotropin-releasing factor (CRF), (-)-isoproterenol, and vasoactive intestinal peptide (VIP). These responses are associated with a rapid increase in cyclic AMP formation. Somatostatin (SRIF) markedly decreases the stimulatory effect of CRF, (-)-isoproterenol, and VIP on both cyclic AMP formation and immunoreactive ACTH secretion. Forskolin and cholera toxin, adenylate cyclase activators, also stimulate cyclic AMP formation and ACTH secretion in AtT-20 cells and these responses are all inhibited by SRIF. The ACTH secretory responses to melittin and to the calcium ionophore A23187, neither of which increases cyclic AMP in AtT-20 cells, were not inhibited by SRIF. SRIF did not affect the binding of a tritiated beta-adrenergic receptor antagonist to AtT-20 membranes nor did it decrease basal cyclic AMP formation even in the presence of excess phosphodiesterase inhibitor, indicating that the reduction of cyclic AMP levels by SRIF did not involve either an interference with beta-adrenergic agonist binding to receptors or stimulation of cyclic AMP degradation. These results indicate that the inhibition of CRF-, (-)-isoproterenol-, and VIP-stimulated ACTH secretion by SRIF may be regulated by its inhibitory action on adenylate cyclase.     

Changes in nephrogenous cyclic AMP excretion and plasma cyclic AMP following treatment of hyperthyroidism

Plasma cyclic AMP (PcAMP) concentration and the excretion of cyclic AMP/dl GF were estimated in 11 thyrotoxic patients before and after medical treatment. PcAMP concentrations were significantly higher during hyperthyroidism (2.30 +/- 0.69 vs 1.88 +/- 0.71 nmol/dl; P less than 0.05), and total urinary cyclic AMP (TcAMP) excretion showed no significant changes (3.24 +/- 0.64 vs 3.44 +/- 1.77 nmol/dl GF). Nephrogenous (NcAMP) excretion rose significantly (1.00 +/- 0.82 vs 1.68 +/- 1.31 mmol/dl GF; P less than 0.025). The increase in NcAMP excretion correlated significantly with the decrease in serum T3 levels (r = -0.46; P less than 0.05). Serum iPTH levels showed no significant change. Both the serum Ca, corrected for serum total protein and TmPO4/GFR declined after treatment (respectively 2.44 +/- 0.13 vs 2.33 +/- 0.08 mmol/l; P less than 0.05 and 1.18 +/- 0.29 vs 1.05 +/- 0.22 mmol/l; P less than 0.05). It is concluded that the rise in NcAMP excretion corroborates the concept of increasing parathyroid activity following the treatment of hyperthyroidism.     

氯沙坦对实验性糖尿病大鼠尿白蛋白排泄的影响

目的 观察血管紧张素受体拮抗剂氯沙坦（ｌｏｓａｒｔａｎ）对糖尿病大鼠白蛋白排泄的影响。方法 雄性ＳＤ大鼠分为正常对照组（ＮＣ）、糖尿病对照组（ＤＣ）、糖尿病氯沙坦治疗组（ＤＬ）和糖尿病培哚普利治疗组（ＤＰ）。检测各组第４、８、１２、１６周尿白蛋白排泄变化。结果 ＤＬ组较ＤＣ组尿白蛋白排泄显著下降（Ｐ〈０．０１）,和ＤＰ组比较无显著性差异。结论 血管紧张素受体拮抗剂氯沙坦能有效降低糖尿病大鼠尿白蛋白的排泄。     

Epinephrine-induced alterations in urinary cyclic AMP in hyper- and hypothyroidism.

Although ratios of urinary cyclic AMP (cAMP) to creatinine were found in this study to be elevated in hyperthyroidism, as previously reported, this elevation appears to result primarily from a decrease in the rate of urinary creatinine excretion associated with the hyperthyroid state and not to be due to an increase in the urinary cAMP production rate. Indeed, there was no significant alteration observed in the urinary cAMP excretion found in 15 hyper-, 12 eu-, and 5 hypothyroid subjects. However, a slight, but significant increase in the 24-hour urinary cAMP excretion was noted in ambulating hyperthyroid subjects (8.5 +/- 2.4 muMol/day; normal 5.2 +/- 1.6 muMol/day; P less than .05). In contrast, the effect of the infusion of 0.05 mug/kg/min of epinephrine over a 2-hour period, resulted in a significantly greater rise in urinary cAMP excretion in hyperthyroid patients (0.83 +/- 0.07 muMol/h) compared to euthyroid subjects (0.53 +/- 0.4 muMol/h; P less than .005). Furthermore, hypothyroid subjects had no significant rise in urinary cAMP excretion after epinephrine infusion (P less than .001). Cardiovascular end-organ response to the epinephrine infusion was also greater in the hyperthyroid subjects and virtually absent in the hypothyroid group. These results suggest that there may be a significant alteration in the cAMP generating systems in states of thyroid hormone excess or insufficiency, and that provocative stimuli, such as epinephrine, may have its end-organ response modified by thyroid hormone effects on adenylate cyclase-cyclic AMP generating systems.     

Effect of insulin and adrenaline on cyclic AMP in the diaphragm of normal and diabetic rats.

The effects of insulin and adrenaline on cyclic AMP (cAMP) levels in diaphragms of normal, streptozotocin-diabetic and insulin-treated diabetic rats were studied. Adrenaline caused a biphasic rise in cAMP with peak values of cAMP within the first few minutes. Diaphragms of diabetic rats showed an increased responsiveness to adrenaline. Injection of insulin to diabetic rats normalized the rise in cAMP after addition of adrenaline. There was no difference in basal levels of cAMP between diaphragms of normal, diabetic or insulin-treated diabetic rats. Insulin in vitro did not affect basal cAMP-levels or the release of cAMP from the tissue but significantly decreased adrenaline-induced peak levels of cAMP. This effect of insulin was abolished by theophylline. The results of the present study suggest that experimental diabetes is associated with changes of the adenylate cyclase and/or phosphodiesterase enzyme activities in skeletal muscle resulting in an increased responsiveness to adrenaline. Since insulin in vitro depressed the adrenaline-induced elevation of cAMP the increased responsiveness in diaphragms of diabetic rats might be attributed to the specific lack of insulin.     

Interferon inhibits agonist-induced cyclic AMP accumulation in human lymphocytes

Wheezing episodes often accompany viral respiratory infections. Viral pathogens are also known to induce interferon production. Cyclic AMP (cAMP) levels affect bronchial reactivity; therefore, we analyzed cAMP accumulation in human lymphocytes as a model to determine if interferon might influence the accumulation of this important intracellular mediator. After an overnight exposure to interferon in whole blood, a reduction in agonist-stimulated cAMP accumulation was demonstrated. Basal cAMP concentrations were equivalent in control and interferon-exposed lymphocytes from the same donor, but the response to isoproterenol and prostaglandin E1 was significantly reduced by 61 and 30%, respectively. The decreased responsiveness persisted in the presence of RO 20-1724, a phosphodiesterase inhibitor, indicating that the effect was in part due to a decrease in cAMP synthesis in intact cells. These results suggest that interferon may play a role in inducing or potentiating bronchospasm.     

Effects of sodium depletion on plasma renin activity and on the urinary excretion of cyclic AMP and aldosterone in hypoparathyroid patients.

The effect of sodium depletion on plasma renin activity (PRA), urinary cyclic AMP and urinary aldosterone excretion was studied in hypoparathyroid patients whose basal urinary cylic AMP excretion (urinary cAMP) was less than 50% of that observed in normal subjects. During 7 days of sodium depletion, PRA, urinary aldosterone and urinary cAMP each rose significantly. Administration of the beta-blocker propranolol, 160 mg/day, during 5 further days of sodium depletion produced a fall in PRA and urinary cAMP, but no change in urinary aldosterone excretion. The dissociation in these effects suggests that the increase in aldosterone secretion during sodium depletion may be mediated by pathways other than the renin-angiotensin and adenyl cyclase systems. There was a high degree of correlation between PRA and urinary cAMP (P less than 0.001) during the period of sodium depletion, but not significant relationship between these parameters was found during control and propranolol phases, or in control studies in normal subjects. These findings suggest that beta-adrenergic receptors have a role in mediating the effects of sodium depletion upon renin secretion and adenyl cyclase activity.     

Endothelin inhibits histamine-induced cyclic AMP accumulation in bovine brain vessels

We have studied whether endothelin isopeptides have any effects on histamine-induced cyclic AMP in [(3)H]adenine-prelabeled brain vessels isolated from bovine brain. Basal levels of [(3)H]cyclic AMP were enhanced by histamine in a concentration-dependent manner (EC(50) = 1.1 +/- 0.3 microM). Endothelin-1 inhibited histamine-elicited [(3)H]cyclic AMP generation with an IC(50) value of 3 +/- 2.5 nM. Sarafotoxin 6c, an ET-B receptor agonist, had no effect. ET-1 inhibition of histamine-induced [(3)H]cyclic AMP was reversed by the ET-A receptor antagonist BQ-123 while the ET-B receptor antagonist BQ-788 had no effect. The levels of [(3)H]cyclic AMP induced by isoprenaline were not altered by endothelin-1. Taken together, these results show that endothelins modulate the actions of histamine on the blood-brain barrier, probably by type A endothelin receptors.     

Increased urinary nitrate excretion in rats with adjuvant arthritis.

OBJECTIVES--In rats with adjuvant arthritis measurements were taken of the urinary excretion of nitrate, reflecting endogenous nitric oxide (NO) formation, and cyclic guanosine monophosphate (cGMP). METHODS--Urinary nitrate was determined by gas chromatography, cGMP by radioimmunoassay. RESULTS--A significant (p < 0.001), more than three fold increase of urinary nitrate excretion was found in rats 20 days after induction of adjuvant arthritis compared with non-arthritic rats. There was no significant difference in urinary cGMP excretion between arthritic rats and control animals. CONCLUSION--The data suggest that the dramatic increase of urinary nitrate excretion is due to increase of NO synthesis by the inducible form of NO synthase.     

Circadian rhythms in the urinary excretion of cyclic 3',5'-adenosine monophosphate (cyclic AMP) and cyclic 3',5'-guanosine monophosphate (cyclic GMP) in human subjects.

Significant circadian rhythns in urinary excretion of cyclic AMP, cyclic GMP, creatinine, 17-hydroxycorticosteroids and inorganic phosphorus were demonstrated in three normal subjects (two males and one post-menopausal female) who collected serial 4-h specimens for periods of 33, 22, and 14 days, respectively. Peak excretion of the above substances occurred, respectively, at approximately 1500-1700, 2300-0200, 1700-1800, 1100-1300, and 1800-2200 h. The estimated amplitudes of the rhythms expressed as a percentage of the mean 4-h excretion rate were 12-13%, 9-13%, 9-15%, 30-78% and 22-26%, respectively. With the possible exception of cyclic GMP, all of the observed rhythms appeared to be sinusoidal, with normal periods of 24 h. The rhythms in both cyclic AMP and creatinine excretion, but not in the remaining substances may be explained largely in terms of the known rhythm in glomerular filtration rate. The factors responsible for the rhythm in cyclic GMP excretion are unknown.     

Somatostatin: an endogenous peptide in the toad urinary bladder inhibits vasopressin-stimulated water flow.

Somatostatin (somatotropin release-inhibiting factor; SRIF) is a tetradecapeptide present in brain, pancreas, gastrointestinal tract, and thyroid that inhibits the secretion or action of several hormones in these tissues. We observed that the toad urinary bladder contains concentrations of endogenous somatostatin (8.0 pg/micrograms of protein) comparable to those found in the mammalian pancreas and gastrointestinal tract. To determine if somatostatin directly alter the action of vasopressinn we studied the effects of this polypeptide on vasopressin-stimulated transport processes in the toad urinary bladder in vitro. Somatostatin produced a dose-dependent, reversible inhibition of vasopressin-stimulated osmotic water flow; it inhibited theophylline-stimulated osmotic water flow but not the water flow stimulated by 8-p-chlorophenylthioadenosine 3',5'-cyclic monophosphate. These data are consistent with an inhibition of both basal and hormone-stimulated adenylate cyclase. Vasopressin-stimulated short circuit current was not inhibited by somatostatin. These studies provide direct evidence for an effect of somatostatin on hormone-modulated epithelial transport in tissues other than the gastrointestinal tract. We propose that endogenous somatostatin may function as a local regulator of the cellular action of vasopressin on osmotic water flow.     

Increased urinary prostaglandin excretion in galactose-fed rats

Increased renal production of prostaglandins (PG) may contribute to the hyperfiltration that accompanies early diabetes. It was postulated that a putative metabolic abnormality of diabetes, ie, increased flux through the polyol pathway, stimulates renal PG production and that this phenomenon can be prevented by aldose-reductase inhibition. To test this hypothesis, the effects of polyol accumulation on urinary excretion rates (UER) of PGE2 and 6-keto-PGF1 alpha were studied, using the galactose-fed rat model. UER of PGE2 and 6-keto-PGF1 alpha were measured in three groups of weanling Wistar male rats. Group 1 was maintained on normal chow (n = 6), group 2 was fed chow supplemented with 30% galactose (n = 6), and group 3 received chow supplemented with 30% galactose and 0.7% sorbinil (n = 6). Ten 24-hour urine samples were obtained from each group between 151 and 240 days on the respective diets. UER of PGE2 (P less than .001) and 6-keto-PGF1 alpha (P less than .01) were higher in group 2 than in group 1. UER of PGE2 (NS) and 6-keto-PGF1 alpha (NS), respectively, were similar in groups 1 and 3. These data indicate that flux through the polyol pathway modulates the UER of PGE2 and 6-keto-PGF1 alpha. This phenomenon may contribute to the glomerular hyperfiltration of early diabetes.     

Urinary cyclic AMP excretion in birds: dependence on parathyroid hormone activity

The cyclic AMP response of avian kidney to parathyroid activity has been evaluated both in vitro and in vivo. The production of cyclic AMP by dispersed avian kidney cells was stimulated by bovine parathyroid hormone or by an extract of avian parathyroid glands. Intravenous infusion of bovine parathyroid hormone resulted in increased urinary excretion and plasma concentration of cyclic AMP, as well as increased plasma calcium and urinary phosphorus excretion. The increases in plasma and urinary cyclic AMP preceded those of plasma calcium and of phosphorus excretion. EDTA infusion resulted in a decrease in plasma calcium and an increase in urinary cyclic AMP excretion. After 10 days on a low-calcium diet, chickens exhibited a 4.5-fold increase in urinary cyclic AMP excretion. The results suggest that urinary cyclic AMP in chickens reflects PTH activity similar to some mammalian species.     

Dibutyryl cyclic AMP inhibits acute hypoxic pulmonary vasoconstriction in conscious sheep

We examined the effects of cell-permeable dibutyryl cyclic AMP (DBcAMP) on acute hypoxic pulmonary vasoconstriction (HPV) in conscious sheep. Mean left and right atrial, pulmonary, and systemic pressures (Pla, Pra, Ppa, and Psa, mm Hg), cardiac output (CO, L/min), and heart rate were measured continuously. Systemic (SVR) and pulmonary vascular resistances (PVR) were calculated by (Psa-Pra)/CO and (Ppa-Pla)/CO, respectively. Five groups of experiments were performed using the same sheep (n = 6). After a 30-min baseline period, sheep inhaled a hypoxic gas mixture (O2:N2 = 1:9) for 40 min. Pretreatment with DBcAMP (200 micrograms/kg/min) inhibited HPV (Ppa, 12.0 +/- 2.3 to 20.0 +/- 2.3 versus 13.2 +/- 2.5 to 14.3 +/- 1.4 mm Hg, p less than 0.01; PVR, 2.61 +/- 0.81 to 4.15 +/- 1.14 versus 2.30 +/- 0.87 to 2.52 +/- 0.59 mm Hg/L/min, p less than 0.01). DBcAMP treatment (200 micrograms/kg/min) after induction of HPV also significantly attenuated hypoxic pulmonary response (Ppa, 19.0 +/- 1.7 to 14.2 +/- 2.3 mm Hg, p less than 0.01; PVR, 3.92 +/- 0.39 to 2.34 +/- 0.34 mm Hg/L/min, p less than 0.01) without significant decreases in Psa and SVR. Pretreatment with DBcAMP (200 micrograms/kg/min) did not significantly alter pulmonary pressor responses to bolus injections of prostaglandin F2 alpha (PGF2 alpha) (10 micrograms/kg) and norepinephrine (4 micrograms/kg). These results may suggest that intracellular augmentation of cyclic AMP plays a crucial role in modulating HPV.     

Somatostatin: lack of effect of cyclic AMP release and amino acid transport in isolated rat hepatocytes.

The aim of the present study was to determine whether or not somatostatin can directly affect amino acid transport and cyclic AMP (cAMP) release in isolated rat hepatocytes. Somatostatin at 1.5 microgram/ml (1mumol/l) had no effect on basal uptake of alpha-aminoisobutyric acid (AIB). Similarly, the peptide was without effect on basal cAMP release. Somatostatin exerted a slight but statistically not significant inhibitory effect on glucagon-stimulated AIB uptake and cAMP release. These observations do not support the possibility that somatostatin might directly interfere with hepatic glucose metabolism by altering the entry of amino acids into the liver and--or--by affecting the level of endogenous cAMP.     

Studies on gluconeogenesis,protein synthesis and cyclic AMP levels in isolated hepatocytes from alloxan diabetic rats

Alloxan diabetic rats maintained on protamine zinc insulin for two weeks were used for these studies. Hepatocytes were isolated from these rats at various time intervals after withdrawal of insulin (0, 48, 72 and 96 hr). Gluconeogenesis with various concentrations of lactate and fructose was studied. Both lactate and fructose stimulated gluconeogenesis and showed progressive increases in glucose production up to 72 hr after the insulin withdrawal. Glucose production decreased at 96 hr. Protein synthesis in isolated hepatocytes from diabetic liver cells, as measured by the incorporation of radioactive isoleucine, valine and phenylalanine into protein, showed a decrease (5- to 6-fold) with time after insulin withdrawal. Glucagon (10(-6)M) alone increased cyclic AMP levels 10-fold in liver cells, in isolated cells from rats maintained on insulin (0 hr) or from rats withdrawn from insulin for 48 hr. The ability of glucagon to elevate cyclic AMP levels in isolated diabetic liver cells decreases 72 hr following insulin withdrawal.