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PubMed1983

Comparison of the effects of forskolin and isoproterenol on cyclic AMP levels and tension in bovine coronary artery.

The effects of isoproterenol and forskolin on cyclic AMP levels and tension were compared in helical strips of bovine coronary artery. Both compounds produced time- and dose-dependent increases in cyclic AMP levels and both compounds relaxed potassium-contracted arteries. However, in contrast to the results with isoproterenol, cyclic AMP elevation and relaxation were not well correlated at lower concentrations of forskolin. For example, 0.1 microM forskolin increased cyclic AMP levels in the arteries by approximately 5.5-fold but did not relax the muscles. A smaller elevation of cyclic AMP produced by 1.0 microM isoproterenol, on the other hand, was accompanied by an almost complete relaxation of the arteries. These results suggest that either cyclic AMP is not responsible for the relaxation caused by these agents, or some form of functional compartmentalization of cyclic AMP exists in this tissue.

Animals↗
PubMed1992

AMP deaminase binding in contracting rat skeletal muscle.

AMP deaminase, which hydrolyses AMP to inosine 5'-monophosphate (IMP) and NH3 at high rates during excessive energy demands in skeletal muscle, is activated when bound to myosin in vitro. We evaluated AMP deaminase binding in vivo during muscle contractions to assess whether binding 1) is inherent to deamination and found only with high rates of IMP production or simply coincident with the contractile process and 2) requires cellular acidosis. AMP deaminase activity (mumol.min-1.g-1) was measured in the supernatant (free) and 10(4)-g pellet (bound) homogenate fractions of muscle of anesthetized rats after in situ contractions to determine the percent bound. In resting muscle, nearly all (approximately 90%) AMP deaminase is free (cytosolic). During contractions when energy balance was well maintained, binding did not significantly differ from resting values. However, during intense contraction conditions that lead to increased IMP concentration, binding increased to approximately 60% (P less than 0.001) in fast-twitch and approximately 50% in slow-twitch muscle. Binding increased in an apparent first-order manner and preceded initiation of IMP formation. Further, binding rapidly declined within 1 min after cessation of intense stimulation, even though the cell remained extremely acidotic. Extensive binding during contractions was also evident without cellular acidosis (iodoacetic acid-treated muscle). Thus the in vivo AMP deaminase-myosin complex association/dissociation is not coupled to changes in cellular acidosis. Interestingly, binding remained elevated after contractions, if energy recovery was limited by ischemia. Our results are consistent with myosin binding having a role in AMP deaminase activation and subsequent IMP formation in contracting muscle.

AMP Deaminase↗
PubMed1998

Alterations in AMP deaminase activity and kinetics in skeletal muscle of creatine kinase-deficient mice.

Alterations in the competency of the creatine kinase system elicit numerous structural and metabolic compensations, including changes in purine nucleotide metabolism. We evaluated molecular and kinetic changes in AMP deaminase from skeletal muscles of mice deficient in either cytosolic creatine kinase alone (M-CK-/-) or also deficient in mitochondrial creatine kinase (CK-/-) compared with wild type. We found that predominantly fast-twitch muscle, but not slow-twitch muscle, from both M-CK-/- and CK-/- mice had much lower AMP deaminase; the quantity of AMP deaminase detected by Western blot was correspondingly lower, whereas AMP deaminase-1 (AMPD1) gene expression was unchanged. Kinetic analysis of AMP deaminase from mixed muscle revealed negative cooperativity that was significantly greater in creatine kinase deficiencies. Treatment of AMP deaminase with acid phosphatase abolished negative cooperative behavior, indicating that a phosphorylation-dephosphorylation cycle may be important in the regulation of AMP deaminase.

AMP Deaminase↗
PubMed1975

Evidence for disordered cyclic amp metabolism in patients with cerebral infarction.

Systemic blood cyclic AMP levels were elevated but urinary excretion was unaltered in patients with recent cerebral infarction. Cerebral venous levels for cyclic AMP were significantly higher than arterial levels. CSF cyclic AMP levels were also elevated. After intravenous 10% glycerol, CSF cyclic AMP levels decreased and cerebral A-V differences were reduced. Elevation of cyclic AMP levels in plasma may be due to alteration of neuroendocrinal function after cerebral infraction and contributed to in part by release from infarcted brain. Cyclic AMP release into cerebral venous blood and CSF suggests (1) blood brain barrier damage and (2) extracellular cyclic AMP accumulation in infarcted brain secondary to abnormal neurotransmitter release and/or impaired cellular function which appears to be partially reversed by glycerol.

Cyclic AMP↗
PubMed1976

Effect of exogenous cyclic AMP and other adenine nucleotides on neutrophil chemotaxis and motility.

Cyclic AMP placed in the bottom of the modified Boyden chemotaxis chamber is weakly chemotactic for rabbit peritoneal neutrophils. Dibutyryl-cyclic AMP under similar conditions gives a biphasic response, being weakly chemotactic at low concentrations and inhibiting cell movement at higher concentrations. When mixed with the cells in the upper compartment of the chemotaxis chamber, cyclic AMP and dibutyryl-cyclic AMP enhance neutrophil spontaneous motility; on the other hand, dibutyryl-cyclic AMP mixed with the cells in the upper compartment consistently inhibits neutrophil chemotactic responsiveness, while cyclic AMP has a variable effect on chemotaxis. The effect of ADP and ATP was to inhibit chemotaxis and spontaneous motility. AMP is totally without effect.

Adenine Nucleotides↗
PubMed1980

Postnatal development of jejunal sucrase: independence from cyclic AMP.

It has previously been shown that jejunal sucrase activity becomes increasingly responsive to glucocorticoids between the postnatal ages of 4 and 15 days. This study examines the possibility that cyclic AMP is the mediator of the increasing responsiveness. When dibutyryl cyclic AMP was administered concomitantly with glucocorticoid to rat pups aged 6 days, there was no enhancement of sucrase activity in pups sacrificed either 30 or 54 h later. To check for short-lived effects of cyclic AMP, pups aged 5 days were pretreated with glucocorticoid for 2 days to elicit sucrase activity, then received dibutyryl cyclic AMP by injection and were sacrificed 1, 3 and 6 h later. Once again there was no effect of cyclic AMP on sucrase activity. The final approach was to use cholera enterotoxin to stimulate epithelial adenylyl cyclase in jejunal segments in vivo. Under these conditions the stimulation of fluid secretion served as positive evidence that intracellular concentrations of cyclic AMP were elevated. However, once again there was no stimulation of sucrase activity. It is concluded that cyclic AMP does not mediate the increasing responsiveness of the developing intestine to glucocorticoids.

Animals↗
PubMed1980

Plasma c-AMP during the normal menstrual cycle and under different hormonal treatment.

There is a highly significant difference between the plasma c-AMP value of the first and the second half of the normal menstrual cycle (days 1-12: 10.5 +/- 2.0 pmol, x +/- SEM; days 13-16: 21.9 +/- 4.5; days 17-28: 19.9 +/- 2.0; p less than 0.001). In amenorrheic patients plasma c-AMP levels were nearly the same as in normal women during the first half of the menstrual cycle (11.1 +/- 2.5). Plasma c-AMP of amenorrheic women was significantly higher under HMG treatment (16.7 +/- 2.5; p less than 0.01). Under oral contraception with estrogens (alone) or with low doses of gestagens the plasma c-AMP values were comparable to those of the amenorrheic women, but there was a dose-dependent increase of plasma c-AMP under gestagen application. It is concluded that the midcyclic plasma c-AMP increase is mainly caused by the gonadotropin effect, and is followed by the progesterone effect during the second half of the menstrual cycle. Therefore, plasma c-AMP levels are in accordance to the stages of the menstrual cycle reflecting their different endocrine pattern.

Contraceptives, Oral↗
PubMed1981

Role of cyclic AMP in regulation of chloride secretion by canine tracheal mucosa.

Cyclic adenosine monophosphate (cyclic AMP) mediates the action of many hormones, and it affects ion transport in several different epithelia. The effect of the analogue dibutyryl cyclic AMP was tested in canine tracheal epithelium in vitro under short-circuit conditions. This agent raised short-circuit current and electrical conductance. Dibutyryl cyclic AMP at 1 mM concentration added to the submucosal bath increased net Cl secretion from 1.74 +/- 0.40 to 2.72 +/- 0.34 mu eq/cm2 . h (mean +/- SE, n = 6). Net Na absorption was slightly reduced. Dibutyryl cyclic AMP and theophylline decreased mannitol flux, suggesting that cyclic AMP acts on Cl transport by increasing its flow through cellular rather than through paracellular pathways. Epinephrine, which also stimulates Cl secretion, causes significant elevation in cyclic AMP in epithelial cells scraped from tracheal mucosa. Data suggest that cellular concentrations of cyclic AMP play an important role in the regulation of Cl transport by tracheal mucosa.

Animals↗
PubMed1974

Effects of acetazolamide on the urinary excretion of cyclic AMP and on the activity of renal adenyl cyclase.

Acetazolamide, an inhibitor of the enzyme carbonic anhydrase, increased the urinary excretion of cyclic AMP in normal and parathyroidectomized rats. The increase was greater in rats with intact parathyroid glands than in parathyroidectomized rats. This rise in the urinary excretion of cyclic AMP was not due to an increase in urine flow or a change in urine pH. Furosemide caused an increase in urine flow, but did not affect the excretion of cyclic AMP or phosphate. Alkalinization of the urine with bicarbonate did not increase the urinary excretion of phosphate or cyclic AMP. Acetazolamide increased the productionof cyclic AMP by rat renal cortical slices in vitro. This effect was dose-dependent. Acetazolamide also stimulated the activity of renal cortical adenyl cyclase in a dose-dependent manner but had no effect on the activity of cyclic nucleotide phosphodiesterase. The pattern of urinary excretion of cyclic AMP and phosphate after administration of acetazolamide was similar to that observed in rats given parathyroid hormone. It is suggested that acetazolamide stimulates the renal production of cyclic AMP by activating adenyl cyclase and that this may be the mechanism by which this inhibitor of carbonic anhydrase produces phosphaturia.

Acetazolamide↗
PubMed1976

Insulin release and cyclic AMP accumulation in response to glucose in pancreatic islets of fed and starved rats.

The dose as well as the time kinetics of insulin and adenosine-3', 5' -monophosphate (cyclic AMP) responses to glucose were compared in pancreatic islets of fed and starved rats. There was a preferential impairment of the early phase of glucose-induced insulin release in perifused islets of rats starved for 16 and 48 h. Similarly, the accumulation of 3H cyclic AMP in islets prelabeled with 3H-2-adenine was less in islets of 48 h starved than fed rats, during the first 10-min of stimulation with 26.7 mM glucose in the presence of 0.1 mM of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, whereas at 30 and 60 min 3H cyclic AMP responses to glucose were similar in fed and starved islets. Also, in 10-min incubations with glucose 3.3, 6.7, 10.0, 13.3, and 26.7 mM without and with 0.1 mM and 1.0 mM 3-isobutyl-1-methylxanthine, insulin release correlated strongly with the accumulation of 3H cyclic AMP in the islets of fed as well as starved rats. The thresholds for glucose-induced insulin and 3H cyclic AMP responses were higher and the maximal responses were lower in starved than fed islets. Preincubation of islets of 48-h starved rats with 16.7 mM glucose for 60 min corrected the impaired insulin and 3H cyclic AMP responses to glucose. Starvation-induced impairment of insulin secretory responses to glucose, and their restoration by preincubation with glucose in vitro, may represent acute regulatory effects of glucose on the adenylate cyclase-cyclic AMP system in the pancreatic beta cell.

Animals↗
PubMed1977

In vivo effect of indomethacin to potentiate the renal medullary cyclic AMP response to vasopressin.

In a previous study we demonstrated that indomethacin potentiated the hydro-osmotic action of vasopressin in vivo. It was hypothesized that this action of indomethacin was due to its ability to suppress renal medullary prostaglandin synthesis, since in vitro studies have suggested that prostaglandins interfere with the ability of vasopressin to stimulate production of its intracellular mediator, cyclic AMP. In the present study this hypothesis was tested in vivo. Anesthetized rats undergoing a water diuresis were studied. In a control group, bolus injections of 200 muU of vasopressin caused a rise in urinary osmolality (Uosm) from 124 +/- 6 to 253 +/- 20 mosmol/kg H2O (P less than 0.005). In a group treated with 2 mg/kg of indomethacin the same dose of vasopressin caused a significantly greater (P less than 0.001) rise in Uosm from 124 +/- 7 to 428 +/- 19 mosmol/kg H2O. Medullary tissue cyclic AMP rose from 9.4 +/- 0.9 to 13.4 +/- 1.7 (P less than 0.05) pmol/mg tissue protein after vasopressin administration in animals receiving no indomethacin, while in indomethacin-treated animals there was a significantly greater rise (P less than 0.001) in medullary cyclic AMP from 10.4 +/- 0.9 to 21.6 +/- 2.1 pmol/mg tissue protein in response to the vasopressin injections. In neither control animals nor indomethacin-treated animals were there significant changes in renal hemodynamics, as measured by clearance techniques. Indomethacin, when given alone, had no effect on Uosm or medullary tissue cyclic AMP. Indomethacin did, however, reduce medullary prostaglandin E content from 84.7 +/- 15.0 to 15.6 +/- 4.3 pg/mg tissue. This study has shown that indomethacin, in a dose which suppresses medullary prostaglandin content, potentiates the ability of vasopressin to increase the tissue content of its intracellular mediator, cyclic AMP. Indomethacin caused no demonstrable inhibition of cyclic AMP phosphodiesterase. Therefore, it seems likely that indomethacin enhanced the ability of vasopressin to increase medullary cyclic AMP levels by causing an increased production rather than decreased destruction of the nucleotide. We conclude that this action of indomethacin contributes to its ability to potentiate the hydro-osmotic action of vasopressin in vivo. A corollary to this conclusion is that endogenous medullary prostaglandin E's may be significant physiological modulators of the renal response to vasopressin.

Animals↗
PubMed1975

Calcium transport in isolated bone cells. III. Effects of parathyroid hormone and cyclic 3',5'-AMP.

The effects of parathyroid hormone (PTH) and cyclic 3',5'-AMP (cyclic AMP) on calcium transport were studied in isolated bone cells. Bone cells were isolated by collagenase digestion of 20-21 day old fetal rat calvaria. Calcium transport was measured with 45Ca. PTH (0.2 mug/ml) increased calcium uptake 30--40% over control values at 37 C. At 4 C, the effects were magnified and 70--170% increases in calcium uptake were observed. The effects were present 1--10 minutes after the simultaneous addition of hormone and 45Ca. PTH had no effect on calcium efflux. Neither dibutyryl cyclic AMP (10(-4)-10(-3)M) nor cyclic AMP (10(-7)-3 X 10(-6)M) had any effect on calcium uptake or efflux. Methylisobutylxanthine (0.1 mM) caused no change in calcium uptake although increase in cyclic AMP were noted. The characteristic PTH-induced increase in cyclic AMP seen at 37 C was not observed at 4 C. It is postulated that PTH increases the permeability of bone cell membranes to calcium. At 4 C the membrane is relatively impermeable so the PTH effect is magnified. The PTH-induced increase does not appear to be mediated through cyclic AMP.

Animals↗
PubMed1976

Comparison of prostaglandin E1 and TSH stimulation of cyclic AMP synthesis in thyroid tissues from euthyroid subjects and thyrotoxic patients.

Possible differences of the mode of action of TSH and prostaglandin E1 (PGE) on the synthesis of cyclic AMP were studied in normal human thyroids (normal thyroid) and thyroids from thyrotoxic patients (toxic thyroid). TSH was less effective in toxic thyroids than in normal thyroids; whereas PGE1 was equally effective in normal thyroids and toxic thyroids. Since the basal level of cyclic AMP was the same in normal and toxic thyroids, this lower sensitivity of toxic thyroids to TSH was not due to the fact that toxic thyroids were already overactive in terms of cyclic AMP synthesis. The measurement of adenylate cyclase and phosphodiesterase activities in the plasma membranes or homogenates failed to explain this lower sensitivity of toxic thyroids to TSH. Small and large doses of T4 and T3 failed to suppress an increase of cyclic AMP produced by PGE1, in the slices and plasma membranes of normal and toxic thyroids; whereas large doses of T3 depressed an increase of cyclic AMP in response to TSH in the thyroid plasma membrane of toxic thyroids. When both TSH and PGE1 were administered simultaneously, an additive increase of cyclic AMP was found in normal thyroids and in toxic thyroids. From the data accumulated, we suggest that, although TSH and PGE1 stimulate cyclic AMP synthesis in normal and toxic thyroids, the site of action and/or mode of action of these two stimulators may possibly be different, at least in human thyroids.

Adenylyl Cyclases↗
PubMed1982

Effects of cyclic AMP on contact formation and differentiation in Dictyostelium discoideum.

It has been shown previously that Dictyostelium discoideum NC4 cells dissociated at the early aggregation stage form cell clumps and differentiate into prespore cells in a shaking culture containing glucose, albumin, EDTA and cyclic AMP. In this culture system, we found that the cells neither differentiate nor form cell clumps in the absence of cyclic AMP. Wheat-germ agglutinin (WGA) completely inhibited the cyclic AMP-induced formation of cell contact and the inhibition was nullified by the addition of N-acetyl-D-glucosamine. When the cells were prevented from forming contact by either rapid shaking or the addition of WGA, they were unable to differentiate even in the presence of cyclic AMP, indicating that contact formation is a prerequisite for prespore differentiation. Cells dissociated from migrating slugs formed cell clumps in shaking culture, with or without cyclic AMP, and the cell contact was sensitive to WGA. In the absence of cyclic AMP, prespore cells lost their differentiated state, even though the cells were in contact. This indicates that cyclic AMP has a second effect, that of pomoting differentiation, in addition to the effect of inducing contact formation. Both effects were required for prespore differentiation of strain NC4 cells.

Cell Adhesion↗
PubMed1987

Adaptation to chemotactic cyclic AMP signals in Dictyostelium involves the G-protein.

Amoebae of Dictyostelium discoideum show adaptation towards a chemotactic cyclic AMP signal. Within a few seconds of receipt of the signal they are inhibited for a period of 1-2 min from further chemotactic responses to subsequent cyclic AMP signals of similar or smaller magnitude. The site of this adaptation mechanism in the chemotactic transduction pathway was investigated by addition of components of the transduction chain (GTP analogues, myo-inositol-1,4,5-trisphosphate (InsP3) and Ca2+) to permeabilized cells followed by determination of the amount of cyclic GMP formed as a measure of the chemotactic response. This approach was made possible by finding that permeabilization of amoebae with saponin did not uncouple the cell surface cyclic AMP receptors from stimulation of cyclic GMP formation. It was found that InsP3 and Ca2+ were 'downstream' from the adaptation mechanism: they could trigger a cyclic GMP response in cyclic AMP-adapted amoebae but could not themselves induce adaptation. In contrast, GTP gamma S was unable to trigger a cyclic GMP response in cyclic AMP-adapted cells, although it could trigger multiple cyclic GMP responses in non-adapted cells. We deduce that the site of adaptation to cyclic AMP stimulation is at the G-protein involved in this signalling pathway. Moreover, as GTP gamma S was found to be unable to induce adaptation, we conclude that the mechanism of adaptation involves an action of the cyclic AMP receptor on the G-protein that is distinct from its commonly reported action of stimulating G-protein binding of GTP.

Adaptation, Physiological↗
PubMed1984

Involvement of cyclic AMP in the positive inotropic effect of OPC-8212, a new cardiotonic agent, on the canine ventricular muscle.

OPC-8212 is a new positive inotropic drug which scarcely produces an increase in heart rate and vasodilatation. The positive inotropic effect of OPC-8212 was investigated in relation to cyclic AMP metabolism in canine isolated ventricular muscle. The positive inotropic effect of OPC-8212 was accompanied by accumulation of cyclic AMP in the tissue: the cyclic AMP level was elevated before the increase in force of contraction and elevated in a concentration-dependent manner in the presence of a beta-adrenoceptor antagonist, atenolol (10(-6) M). The OPC-8212-induced increases in force of contraction and cyclic AMP level were abolished by carbachol (3 X 10(-6) M). The relationship between the force of contraction and cyclic AMP level in the presence of OPC-8212 was changed by neither carbachol nor isoproterenol. OPC-8212 enhanced the positive inotropic effect of isoproterenol as cyclic AMP phosphodiesterase inhibitors did. OPC-8212 shortened the time to peak tension and had a tendency to shorten the relaxation time of single contractions. These results altogether suggest that change in cyclic AMP metabolism is involved at least in the positive inotropic effect of OPC-8212 on canine ventricular muscle.

Animals↗
PubMed1990

Effects of a new cardiotonic agent 1,2-dihydro-6-methyl-2-oxo-5-[imidazo (1,2-a) pyridin-6-yl]-3-pyridine carbonitrile hydrochloride monohydrate (E-1020) on contractile force and cyclic AMP metabolism in canine ventricular muscle.

E-1020, a newly synthesized imidazopyridinylpyridine or imidazopyridine derivative (structurally closely related to the bipyridine derivative milrinone) increased the force of contraction and cyclic AMP levels in a concentration-dependent manner in the isolated canine ventricular trabeculae electrically driven at 0.5 Hz at 37 degrees C. The concentration-response curve for the increase in force of contraction by E-1020 was biphasic. The maximal positive inotropic effect (PIE) of E-1020 is comparable to that of milrinone, and its potency is 3-fold less than that of milrinone, but 10-fold higher than that of amrinone. The time course of increases in force of contraction induced by E-1020 was coincident with that of cyclic AMP accumulation. The concentration-response curve for the PIE of E-1020 was superimposable to that of cyclic AMP accumulation. A beta-adrenoceptor antagonist, (+/-)-bupranolol (3 X 10(-7) mol/l), did not affect the PIE of E-1020. The increase in the force of contraction and accumulation of cyclic AMP produced by E-1020 were inhibited by a muscarinic receptor agonist, carbachol. The relationship between the force of contraction and cyclic AMP levels in the presence of E-1020 was not modified by addition of carbachol or isoproterenol. E-1020 shifted the concentration-response curve for isoproterenol to the left. E-1020 shortened the total duration of contraction and relaxation time of isometric contractions. These findings indicate that cyclic AMP is essentially involved in the PIE of E-1020 on the canine ventricular muscle, although the possible involvement of a cyclic AMP-independent mechanism can not be excluded.

Amrinone↗
PubMed2000

Correlation between adenine nucleotide-induced cyclic AMP elevation and extracellular adenosine formation in NG108-15 cells.

We previously demonstrated that extracellular adenine nucleotides induced cyclic AMP elevation in NG108-15 cells. This response was resistant to adenosine deaminase (ADA) and the ecto-5'-nucleotidase (CD73) inhibitor alpha,beta-methylene ADP (alpha,beta-MeADP), but was inhibited by both P1- and P2-receptor antagonists. In the present study, we investigated the relationship between adenine nucleotide-induced cyclic AMP elevation and extracellular adenosine formation. ATP, AMP and beta,gamma-methylene ATP (beta,gamma-MeATP) were time-dependently metabolized to adenosine in NG108-15 cells. Adenosine formations from ATP, AMP and beta,gamma-MeATP were not affected by alpha,beta-MeADP, but suppressed by the P2-receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS). A close correlation between extracellular adenosine formation and cyclic AMP increasing effects were obtained with several adenine nucleotide agonists in NG108-15 cells as well as their parent cell line C6Bu-1 and N18TG-2 cells, all of which possess functional adenosine A2 receptors. When NG108-15 cells were incubated with [3H]ATP or [3H]AMP in the presence of ADA, [3H]adenosine was found to distribute dominantly on the cell surface. NG108-15 cells expressed mRNA for the ecto-ATPase and nucleotide pyrophosphatase, but not for CD73. These results suggest that local adenosine formation by an ecto-enzyme distinct from CD73 is involved in adenine nucleotide-induced cyclic AMP formation in NG108-15 cells.

Adenine Nucleotides↗