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PubMed1998

Cyclic AMP-dependent protein kinases and human trophoblast cell differentiation in vitro.

Human trophoblast cells offer a unique in vitro model for the study of aspects of the dynamic processes occurring during cell fusion and syncytium formation. In the human placenta, mononuclear cytotrophoblasts aggregate and fuse to form a multinucleated syncytiotrophoblast. In vitro, the addition of cyclic AMP analogs, 8-bromo-cyclic-AMP or Sp-8-bromo-cyclic AMPS, promotes syncytiotrophoblast formation, as shown by the disappearance of immunostained E-cadherin and desmoplakin, and increased numbers of nuclei per syncytium. An antagonist of cyclic AMP, Rp-8-bromo-cyclic AMPS, and an inhibitor of the cyclic AMP-dependent protein kinase catalytic subunit, H-89, impair cell fusion. This led us to study the pattern of expression and subcellular localization of cyclic-AMP-dependent protein kinase subunits during syncytium formation. Cytotrophoblasts expressed the RIalpha and RIIalpha regulatory subunits and the Calpha and Cbeta catalytic subunits. RIalpha was down-regulated during syncytium formation. No change in RIIalpha protein levels was observed, but there was a drastic subcellular redistribution. RIIalpha located in the Golgi-centrosomal area of cytotrophoblasts was scattered throughout the cytoplasm of the syncytiotrophoblast. Interestingly, an accumulation of RIIalpha was observed underneath the apical membrane of syncytiotrophoblast in vitro and in situ. This suggests a key role of cyclic AMP-dependent protein kinase type IIalpha during cell fusion and microvilli formation, both of which are essential for the secretory and transfer functions of the syncytiotrophoblast.

Cell Differentiation↗
PubMed1979

The effect of collagen on the cyclic AMP content of embryonic somites.

Previous studies have demonstrated that collagen substrates stimulate in vitro somite chondrogenesis, and that agents that elevate intracellular cyclic AMP levels in hibit the ability of somites to respond to the inductive influence of collagen. In the present investigation, radiommunoassay was utilized to compare the cyclic AMP content of somite explants cultured on purified Type I collagen substrates with control explants cultured on Millipore filters. During the period of culture, the cyclic AMP content of collagen-treated explants is significantly lower than the cyclic AMP content of control explants. The cyclic AMP content of collagen-treated explants is 66% of control values as early as one hour following the initiation of culture, and the cyclic AMP content of collagen-treated explants remains lower than controls throughout the 3-day cultured period. The greatest difference in the cyclic AMP content of collagen-treated and control explants is observed at the seventeenth hour of culture, at which time the cyclic AMP content of collagen-treated explants is 56% of controls. These results combined with previous studies provides support for the hypothesis that collagen elicits a reduction in the cyclic AMP content of embroyic somites and that this reduction is necessary to trigger chondrogenic differentiation.

Animals↗
PubMed1977

Human synovial fibroblasts: the relationships between cyclic AMP, bradykinin, and prostaglandins.

Human synovial fibroblasts in culture respond to bradykinin (8 X 10(-9) M) with an increment in intracellular cyclic AMP concentration. These bradykinin (BK) concentrations are comparable to levels of the nonapeptide found in pathological synovial effusions. The cyclic AMP response to BK is enhanced by a heat stable factor(s) in fetal calf serum (FCS) and by the addition of arachidonic acid (AA) to monolayer cultures incubated in serum-free media. Synovial fibroblasts initially treated with BK are refractory to rechallenge with this agent as measured by the absence of an increment in cyclic AMP. These BK refractory cells do respond with significant increment in cyclic AMP to challenge with prostaglandin E1 (PGE1). Cells that have become refractory to PGE1 stimulation respond to BK. this suggests that a receptor or activator system different from the one for PGE1 and PGE2 exists for BK. When both BK and PGE1 are incubated together with synovial fibroblasts, the cyclic AMP response elicited is more than additive as compared to the response of each hormone separately. Indomethacin (IM) inhibits the BK evoked cyclic AMP response unless cell cultures are pretreated with PGE1. The PGE1 analog, 7-oxa-13-prostynoic acid, is a better inhibitor of the cyclic AMP response induced by BK than by PGE1. BK does not elicit a cyclic AMP response solely by elaborating PGE1, yet the prostaglandin pathway and its products seem to have a role in the degree of the cyclic AMP response to BK challenge.

Arachidonic Acids↗
PubMed1979

Effect of in vitro cultivation and Mycoplasma pneumoniae infection on intracellular cyclic AMP levels in hamster tracheal organ cultures.

Exogenous cyclic AMP and dibutyryl cyclic AMP decreased the relative ciliary activity values of tracheal organ cultures. In contrast, theophylline and cholera toxin were not ciliostatic. The use of a radioimmunoassay for cyclic AMP indicated that all of the tested substances increased intracellular cyclic AMP levels to some extent (from 3-fold for cholera toxin to almost 40-fold for dibutyryl cyclic AMP). Physical inactivation of explants by either freeze-thaw or heat destroyed all ciliary activity and greatly decreased intracellular cyclic AMP levels. Cyclic AMP levels of explants remained relatively constant during in vitro cultivation. Three strains of Mycoplasma pneumoniae were found to contain extremely low amounts of cyclic AMP. Infection of tracheal explants produced a significant decrease in relative ciliary activity, but only a slight decline in organ-culture cyclic AMP levels.

Animals↗
PubMed2001

MaxiK channel-mediated relaxation of guinea-pig aorta following stimulation of IP receptor with beraprost via cyclic AMP-dependent and -independent mechanisms.

The present study was aimed to elucidate the cellular pathway(s) controlling vascular relaxation triggered by stimulation of prostaglandin I2 (PGI2, IP) receptor with a stable PGI2 analog, beraprost. Beraprost caused a concentration-dependent relaxation in de-endothelialized guinea-pig aorta contracted with prostaglandin F2alpha (PGF2alpha). Beraprost-induced relaxation was almost abolished in high-KCl-contracted tissue, indicating a major role of K+ conductances. In contrast to other PGI2 analogs (e.g. cicaprost and iloprost), beraprost-induced relaxation was practically abolished by a selective voltage and Ca2+-activated K+ (MaxiK, BK) channel blocker Iberiotoxin (10(-7) M) or by tetraethylammonium (2 x 10(-3) M). The relaxation induced by beraprost was not significantly affected by other K+ channel blockers glibenclamide (10(-6) M) or Ba2+ (10(-5) M), but was slightly attenuated by 4-aminopyridine (10(-4) M). Beraprost increased intracellular cyclic AMP levels, suggesting a role for cyclic AMP-dependent pathways. A selective inhibitor of cyclic AMP-specific phosphodiesterase, RO-20-1724 (10(-4) M), significantly potentiated beraprost-induced relaxation. Iberiotoxin (10(-7) M) completely counteracted this potentiation. Moreover, tension decrement due to forskolin (3 x 10(-7) M) or 8-bromo-cyclic AMP (10(-2) M) was thoroughly restored by Iberiotoxin (10(-7) M), confirming a role for a cyclic AMP-dependent mechanism. However, SQ 22,536 (10(-4) M), an adenylyl cyclase inhibitor, did not affect beraprost-induced relaxation though it almost totally inhibited the elevation of cyclic AMP contents induced by beraprost, suggesting the existence of an additional mechanism that is cyclic AMP-independent. Moreover, cholera toxin (CTX, 1 microg/ml for 6 h), which activates the stimulatory G protein of adenylyl cyclase (Gs), significantly suppressed PGF2alpha-induced contraction both in the absence and presence of SQ 22,536 (10(-4) M). Iberiotoxin (10(-7) M) was also capable of restoring the relaxation induced by CTX. These findings suggest that MaxiK channel plays a primary role in mediating smooth muscle relaxation following stimulation of IP receptor with beraprost in guinea-pig aorta. Both cyclic AMP-dependent and -independent pathways contribute to the MaxiK channel-mediated relaxation following IP receptor stimulation in this vascular tissue. Direct regulation of MaxiK channels by Gs may partly account for the cyclic AMP-independent relaxant mechanism.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2001

Interaction between the opposing functional effects of cyclic AMP and cyclic GMP in hypertrophic cardiac myocytes.

We tested the hypothesis that in isolated cardiac myocytes, the negative functional effects of cyclic GMP would be blunted when the level of cyclic AMP was increased and that this interaction would be altered in renal hypertensive (One-Kidney-One-Clip, 1K1C) cardiac hypertrophic rabbits. Using isolated control and 1K1C ventricular myocytes, cyclic AMP and cell shortening (%) data were collected: 1) at baseline, 2) after the addition of 8-Br-cGMP 10(-7), -6, -5 M, and 3) after forskolin (10(-6) M), an adenylate cyclase activator, followed by 8-Br-cGMP 10(-7), -6, -5 M. Basal levels of cyclic AMP were similar in control vs. 1K1C myocytes (10.2 +/- 1.6 vs. 11.3 +/- 2.6 pmol/10(5) myocytes). We found that 8-Br-cGMP decreased the percent shortening in a dose related manner in both control myocytes (5.1 +/- 0.6 to 3.2 +/- 0.4%) and hypertrophic myocytes (5.2 +/- 0.4 to 3.6 +/- 0.5). The level of cyclic AMP significantly increased after the addition of 8-Br-cGMP in control myocytes (14.1 +/- 2.1), but not in 1K1C myocytes. Forskolin increased the percent shortening in the control myocytes (3.8 +/- 0.1 to 4.8 +/- 0.4), but no significant increase was noted in the hypertrophic myocytes (3.6 +/- 0.3 to 3.7 +/- 0.3). The level of cyclic AMP significantly increased after the addition of forskolin in both control (13.9 +/- 2.0), and 1K1C cells (14.6 +/- 3.8). Forskolin attenuated the negative functional effects of 8-Br-cGMP in the control (4.8 +/- 0.4 to 3.2 +/- 0.1) and 1K1C myocytes (3.7 +/- 0.3 to 2.7 +/- 0.3). The addition of 8-Br-cGMP did not affect the level of cyclic AMP after forskolin in either control (13.9 +/- 2.0 to 14.8 +/- 2.5) or 1K1C myocytes (14.6 +/- 3.8 to 13.8 +/- 1.9). These data indicated that in hypertrophic cardiac myocytes the negative functional effects of 8-Br-cGMP were similar to control, but the positive functional effects of cyclic AMP were blunted. There was an increase in cyclic AMP levels after addition of 8-Br-cGMP in control but not 1K1C cells. We conclude that in control and hypertrophic myocytes, the effects of cyclic GMP were blunted after forskolin, but this did not seem to be related to cyclic AMP phosphodiesterase activity.

Animals↗
PubMed1985

Role of AMP deaminase reaction in the control of fructose 1,6-bisphosphatase activity in yeast.

The physiological role of the inhibition of AMP deaminase (EC 3.5.4.6) by Pi was analyzed using permeabilized yeast cells. (a) Fructose 1,6-bisphosphatase (EC 3.1.3.11) was inhibited only a little by AMP, which was readily degraded by AMP deaminase under the in situ conditions. (b) The addition of Pi, which showed no direct effect on fructose 1,6-bisphosphatase, effectively enhanced the inhibition of the enzyme by AMP increased through the inhibition of AMP deaminase. (c) Pi activated phosphofructokinase (EC 2.7.1.11) and inhibited AMP deaminase activity. AMP deaminase reaction can act as a control system of fructose 1,6-bisphosphatase activity and gluconeogenesis/glycolysis reaction through the change in the AMP level. Pi may contribute to the stimulation of glycolysis through the inhibition of fructose 1,6-bisphosphatase by the increase in AMP in addition to the direct activation of phosphofructokinase.

AMP Deaminase↗
PubMed1983

The relationship between cyclic AMP changes and histamine release from basophil-rich human leucocytes.

Histamine release and changes in cyclic AMP levels induced by a variety of stimuli have been measured in isolated human leucocytes from a patient with 40-70% basophilia. Adenosine and sodium fluoride induced early monophasic rises in cyclic AMP which peaked at 1 min, but they did not release histamine. 2',5'-Dideoxyadenosine (DDA) caused a transient fall in cyclic AMP levels. Anti-IgE, polylysine and calcium ionophore A23187 induced a slow release of histamine commencing 2-5 min after addition of secretagogue. With polylysine and A23187, release was still proceeding 45 min after challenge. In contrast, the chemotactic peptide formyl-methionyl-leucyl-phenylalanine (f-met-leu-phe) induced a rapid secretion of histamine which was complete within 2 min. Anti-IgE induced a rapid monophasic rise in cyclic AMP which reached a maximum at 45 sec and was inhibited by pretreatment with DDA. Cyclic AMP rises induced by polylysine and f-met-leu-phe were kinetically similar but smaller in magnitude. A23187 caused a later rise in cyclic AMP which peaked 3 min after challenge. A high concentration (50 microM) of compound 48/80 induced a slow cytotoxic release of histamine which was not accompanied by changes in cyclic AMP levels. The inconsistent quantitative and kinetic relationships of histamine release and cyclic AMP production suggest that changes in cyclic AMP levels may not play a key role in the biochemical events leading to mediator secretion from human basophil leucocytes.

Adenosine↗
PubMed1986

Comparative study of the effects of cyclic nucleotide phosphodiesterase inhibitors on bone resorption and cyclic AMP formation in vitro.

The relation between the level of cyclic AMP and bone resorption was studied in a bone organ culture system, using calvaria from newborn mice. Two methylxanthines, iso-butyl-methylxanthine and theophylline and two non-xanthine inhibitors of cyclic AMP phosphodiesterase, Ro 20-1724 and rolipram, stimulated the release of [45Ca] and [3H] from bones prelabelled in vivo with [45Ca]- and [3H]proline, respectively. The release occurred after a delay of more than 24 hr. In 120-hr cultures, theophylline, IBMX, rolipram and Ro 20-1724, all stimulated the release of stable calcium, inorganic phosphate and the lysosomal enzymes, beta-glucuronidase and beta-N-acetylglucosaminidase from mouse calvarial bones. In addition, all four phosphodiesterase inhibitors decreased the amount of hydroxyproline in the bones at the end of the culture period. The release of minerals and the decrease of hydroxyproline was abolished by indomethacin. In short-term cultures (24 hr), rolipram and Ro 20-1724 did not reduce PTH-stimulated mineral mobilization, whereas the two methylxanthines, and dibutyryl cyclic AMP and 8-bromo cyclic AMP, did cause a reduction of PTH-stimulated mineral release during the first 24 hr. All four phosphodiesterase inhibitors increased the accumulation of cyclic AMP in the calvaria and inhibited cyclic AMP hydrolysis in extracts of calvarial bone. There was a correlation between the magnitude of the initial rise in cyclic AMP and the delayed stimulation of bone resorption. However, much lower concentrations of the PDE inhibitors were sufficient to produce a delayed increase in bone resorption than to block phosphodiesterase and significantly raise cyclic AMP levels. It is suggested that the elevation of cyclic AMP in a subset of bone cells results in an acute reduction of bone mobilization and the cAMP elevation in another subset to a delayed rise in bone resorption.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Differential effects of phosphodiesterase inhibitors on accumulation of cyclic AMP in isolated ventricular cardiomyocytes.

The intracellular actions of phosphodiesterase (PDE) inhibitors on the accumulation of cyclic nucleotides were studied in isolated ventricular cardiomyocytes from adult Sprague-Dawley rats. Elevated levels of cyclic AMP, due to the effects of selective PDE inhibitors, were detected only when the levels of cyclic nucleotide were enhanced with forskolin (10 microM). The time course for the elevation of cyclic AMP levels was similar for all the PDE inhibitors tested, following the pattern of an initial rise in the first 2-4 min, proceeded by a steady state at 67 +/- 6% of the maximum stimulation. HN-10200 (2-[3-methoxy-5-methylsulfinyl-2-thienyl]-1H-imidazo-[4,5-c]- pyridine hydrochloride), a new imidazopyridine derivative, had a similar concentration-dependent profile to the structurally related compound, sulmazole (AR-L 115 BS, 2-[2-methoxy-4-methylsulfinyl)phenyl]-1H- imidazo-[4,5-b]-pyridine). Both the non-selective inhibitor, 3-isobutyl-1-methylxanthine (IBMX), and the selective PDE IV inhibitor, Ro 20-1724 (4-[(3-butoxy-4-methoxyphenyl)methyl]-2- imidazolidinone), potentiated the forskolin-stimulated levels of cyclic AMP with a much greater efficacy than sulmazole or HN-10200. The concentrations of forskolin required by IBMX, sulmazole and HN-10200 (10(-3) M) to increase levels of cyclic AMP by 4 pmol/mg protein were 3.2 x 10(-6) M, 1.32 x 10(-5) M and 1.46 x 10(-5) M, respectively. Enoximone failed to cause an increase in the levels of cyclic AMP, even when stimulated with maximal concentrations of forskolin. Furthermore, in the presence of forskolin, enoximone attenuated the response of Ro 20-1724 and IBMX in a concentration-dependent manner. Enoximone, similarly to HN-10200, sulmazole, Ro 20-1724 and IBMX did not produce any significant effect on levels of cyclic GMP under elevated conditions in the presence of sodium nitroprusside. The combined action of Ro 20-1724, with either HN-10200, sulmazole, or IBMX (10(-4) M), on intracellular levels of cyclic AMP, was not greater than the response to Ro 20-1724 alone. These data demonstrate the differential actions of PDE III and PDE IV inhibitors in rat ventricular cardiomyocytes. It is suggested that enoximone has a high selectivity for the PDE III isoenzyme so that hydrolysis of cyclic AMP by the PDE IV isoenzyme is not inhibited, in accordance with the lack of increase in cyclic AMP by enoximone in rat cardiomyocytes. HN-10200 and sulmazole, producing small increases in intracellular levels of cyclic AMP, are less selective PDE III inhibitors than enoximone.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1975

Comparison of the effects of biogenic amines on cyclic GMP and cycle AMP levels in mouse cerebellum in vitro.

Norepinephrine (NE) elevates levels of both 3',5'-guanosine monophosphate (cyclic GMP) and 3',5'-adenosine monophosphate (cyclic AMP) in incubated slices of mouse cerebellum. As little as 1 muM NE is capable of increasing the level of either cyclic nucleotide. Maximal elevations of cyclic AMP and cyclic GMP levels produced by NE are 15- to 40-fold and 2- to 4-fold, respectively. Dopamine, serotonin and histamine, other biogenic amines considered to be neurotransmitters in CNS, have no effect on mouse cerebellum cyclic nucleotide levels except at relatively high (1 mM) concentrations. NE-induced accumulation of cyclic GMP, but not cyclic AMP, is blocked by omission of Ca2+ from the incubation media. Theophylline does not alter the effect of this catecholamine on either cyclic nucleotide. In tissue slices incubated in buffered sucrose or in choline-Krebs buffer, NE is still capable of increasing both cyclic GMP and cyclic AMP levels; however, these elevations are less than those observed in brain slices incubated in Krebs-Ringer buffer. NE, in combination with glutamate, produces supra-additive elevations of both cyclic GMP and cyclic AMP levels. However, NE in combination with adenosine or high levels of K+ only has a synergistic effect on cyclic AMP and not on cyclic AMP and not on cyclic GMP combination. The elevation of cyclic AMP levels produced by NE appears to be mediated via both alpha- and beta-adrenergic receptor sites. In contrast, the receptor site(s) mediating cyclic AMP accumulation do not appear to be either typical alpha- or beta-adrenergic receptors.

Adenosine↗
PubMed1991

Deoxyadenosine- and cyclic AMP-induced cell cycle arrest and cytotoxicity.

We compared deoxyadenosine (AdR)- and cyclic AMP (cAMP)-induced cell cycle arrest and cytotoxicity in wild type and mutant S49 cells to determine whether they resulted from the same or different mechanisms. Cyclic AMP and deoxyadenosine are synergistic rather than additive in cytotoxicity assays, suggesting different mechanisms of toxicity. Although cyclic AMP causes cell death after 72 h, in concentrations sufficient to result in cell cycle arrest it is reversible with virtually no cytotoxicity for at least 24 h, whereas AdR-induced cell cycle arrest is lethal and irreversible. AdR-induced G1 cell cycle arrest results in diminished ribonucleotide reductase activity but the kinetics of this inhibition differ from cyclic AMP-induced cell cycle arrest. Cyclic AMP arrest and cytotoxicity depend on cyclic AMP-dependent protein kinase (PKA) activity, whereas AdR toxicity does not differ between cell lines with or without PKA activity. Furthermore, deoxycytidine prevents AdR cell cycle arrest and cytotoxicity but has no effect on cyclic AMP G1 arrest. Finally, comparison of cytofluorographic patterns of G1-arrested cells suggests that the AdR block is later in G1 than cyclic AMP-induced cell cycle arrest. In summary, these data show that while the mechanisms of cell cycle arrest and cytotoxicity of cyclic AMP and deoxyadenosine are uncertain, they do appear to involve different pathways.

Cell Cycle↗
PubMed1985

The adenylate cyclase-cyclic AMP-protein kinase system in different cell populations of the guinea pig gastric mucosa.

In isolated guinea pig gastric mucous and enriched parietal cells it was tested whether or not cyclic AMP in response to histamine stimulation might reach concentrations sufficiently high to activate an intracellular cyclic AMP-dependent protein kinase and thereby mediate the acid response. Although histamine stimulated parietal cell adenylate cyclase to a greater extent than mucous cell adenylate cyclase, cyclic AMP levels in response to maximal histamine stimulation reached higher levels in mucous than in parietal cells. This had to be attributed to a five times higher phosphodiesterase activity in parietal cell than in mucous cell populations. In the absence of the phosphodiesterase inhibitor isobutylmethylxanthine exposure of the cells to histamine only in mucous cells produced an increase in cyclic AMP-dependent protein kinase activity ratio, but not in parietal cells. Dibutyryl-cyclic AMP induced cyclic AMP accumulation in parietal cell populations was compared to dibutyryl-cyclic AMP induced H+ secretion, as measured by 14C-aminopyrine uptake. A maximal acid response was associated with an intracellular cyclic AMP level of approximately 300 pmol/10(6) cells, which was never reached by maximal histamine stimulation even not in the presence of the phosphodiesterase inhibitor. It is concluded that activation of the parietal cell cyclic AMP-dependent protein kinase is one way for stimulating H+ secretion, but that the acid response elicited by histamine requires another intracellular pathway.

Adenylyl Cyclases↗
PubMed1990

Interactions between cyclic AMP and inositol phosphate transduction systems in astrocytes in primary culture.

Astroglial cells in primary culture possess receptors with cyclic AMP and inositol phosphates (IP) as second messengers. The beta-receptor agonist, isoproterenol induces an increase in the accumulation of cyclic AMP, the alpha 2-receptor agonist clonidine inhibits the isoproterenol-induced accumulation of cyclic AMP, while the alpha 1-receptor agonist phenylephrine acts only on the inositol phosphate system. 5-Hydroxytryptamine (5-HT) stimulates, the formation of inositol phosphate, while isoproterenol and clonidine per se do not affect the inositol phosphate system. In the present paper the possibility of interactions between the cyclic AMP and the inositol phosphate transduction systems were investigated. In the presence of 10(-5) M 5-HT, in itself ineffective on the formation of cyclic AMP, isoproterenol stimulated the accumulation of cyclic AMP far more than in the absence of 5-HT. The potentiation was blocked by the 5-HT2 receptor antagonist ketanserin. On the other hand, there were no indications for a beta-receptor influence on the 5-HT-induced inositol phosphate formation. Stimulation of the alpha 2-receptor did not induce accumulation of inositol phosphate but significantly potentiated 5-HT2-receptor transduction, as measured by hydrolysis of phosphoinositide and formation of inositol phosphate. Stimulation by 5-HT also increased the formation of inositol phosphate after adrenergic stimulation and this effect was found to be synergistic at certain concentrations of adrenergic agonists. In addition, there was a statistically significant accumulation of cyclic AMP in the presence of both 5-HT and phenylephrine, none of which stimulated cyclic AMP alone. The results suggest specific interactions between the cyclic AMP and inositol phosphate systems on cultured astroglial cells.

Adenylyl Cyclases↗
PubMed1983

Fluoride-induced changes in renal papillary cyclic-AMP.

Studies were conducted which examined urinary excretion and papillary production of cyclic-AMP in the rat following vasopressin (ADH) stimulation in the presence or absence of inorganic fluoride ion (F). In one set of experiments, six anesthetized Fischer 344 rats were administered 5 munits arginine vasopressin during iv saline and sodium fluoride (NaF) infusions. Urinary cyclic-AMP concentration was unchanged by ADH but declined during NaF infusion, while urinary cyclic-AMP excretion rate was unchanged by ADH or ADH/NaF. In a second set of experiments, 30 rats were divided into six groups of 5 each, and renal papilla and cortex were analyzed for cyclic-AMP. Group I was decapitated and not otherwise surgically manipulated. A second group had iv saline for 90 min while a third group had iv saline and ADH. A fourth group had isotonic NaF iv for 90 min and a fifth group had NaF and ADH. The results indicate that papillary cyclic-AMP is significantly increased by both ADH and NaF doses which did not cause changes in urinary cyclic-AMP excretion rates. We conclude from these experiments that determination of urinary cyclic-AMP concentration is not the best measure of vasopressin action and that tubular sensitivity to the hormone in the presence of F was better demonstrated by changes in papillary cyclic-AMP concentration. Further, it appears that the site of the biochemical renal lesion caused by F is at a site beyond the generation of cyclic-AMP.

Animals↗
PubMed1992

Cyclic AMP selectively up-regulates calmodulin genes I and II in PC12 cells.

Calmodulin is encoded by three genes in rat tissues, which collectively transcribe five different mRNAs. We showed previously that the pheochromocytoma cell line, PC12, expresses all five of these mRNAs and that treating PC12 cells with nerve growth factor differentially induces the calmodulin mRNAs; the greatest increase was seen by 24 h in the 1.4 kb transcript from calmodulin gene II. In the present study we found that treating PC12 cells with dibutyryl cyclic AMP also differentially increased the levels of the calmodulin mRNAs. However, dibutyryl cyclic AMP produced increases as early as 3 to 6 h, with the greatest increase (about 3-fold) being seen in the level of the 1.7 kb mRNA transcribed from calmodulin gene I. The transcripts of 4.1 kb (calmodulin gene I) and 1.4 kb (calmodulin gene II) were also increased, but the 2.3 kb transcript from calmodulin gene III remained stable. Another cyclic AMP analogue, chlorophenylthio cyclic AMP, produced effects similar to those of dibutyryl cyclic AMP, but dibutyryl cyclic GMP did not. Pretreatment with cycloheximide blocked the increase in the 4.1 kb calmodulin mRNA induced by dibutyryl cyclic AMP, but only partially blocked the increase in the 1.4 kb and 1.7 kb transcripts. Phorbol 12-myristate 13-acetate, which can induce some cyclic AMP responsive genes, failed to significantly change the levels of any of the calmodulin mRNAs. These studies show that, like nerve growth factor, cyclic AMP can selectively up-regulate the transcripts from calmodulin genes in PC12 cells, but the time-course and type of transcripts induced by cyclic AMP are distinct. These results suggest that the mechanisms by which these two agents alter the calmodulin transcripts are different.

Animals↗
PubMed1996

The enhancement and the inhibition of noradrenaline-induced cyclic AMP accumulation in rat brain by stimulation of metabotropic glutamate receptors.

1. The actions of several metabotropic glutamate receptor and antagonists on noradrenaline (NA)-stimulated [3H]-cyclic AMP accumulation were investigated in rat cerebral cortical slices. 2. Quisqualate (QUIS), L-2-amino-3-phosphonopropionic acid (L-AP3) and glutamate (GLU) elicited concentration-dependent inhibition of (NA)-stimulated [3H]-cyclic AMP accumulation, with IC50 values of 105 +/- 29, 275 +/- 36 and 944 +/- 150 microM respectively. In contrast (Rs)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) (0.5 mM) and N-methyl-D-aspartic acid (NMDA) (0.5 mM) had no effect. 3. (2S,3S,4S)-alpha-(Carboxycyclopropyl)glycine (L-CCGI), 1-Aminocyclo-pentane-1S,3R-dicarbo-xylate (1S,3R-ACPD), ibotenate (IBO) and (RS)-4-carboxy-3-hydroxy-phenylglycine (CHPG)elicited a concentration-dependent enhancement of NA-stimulated [3H]-cyclic AMP accumulation, with EC50 values of 2.5 +/- 0.11, 42 +/- 1.3, 97.8 +/- 2.1 and 157 +/- 13.4 microM, respectively. 4. (S)-3-carboxy-4-hydroxyphenylglycine (3C4HPG) and (S)-4-carboxy-3-hydroxyphenyl-glycine (4C3HPG) produced a biphasic effect, at concentrations up to 100 and 500 microM, respectively, they significantly enhanced the action of NA (100 microM), at 1mM concentration both compounds as well as alpha-methyl-4-carboxyphenylglycine (MCPG) produced a significant inhibition of NA-stimulated cyclic AMP accumulation. 5. A putative mGluR antagonist-L-AP3, inhibited the 1S,3R-ACPD (100 microM) induced enhancement of the action of NA (100 microM) on [3H]-cyclic AMP accumulation in a biphasic manner with an IC50 of 4.5 microM for the high affinity site, which represented 65% of the total and an IC50 of 283 microM for the low affinity site. 6. beta-adrenoceptor antagonist propranolol inhibited the interaction between 1S,3R-ACPD (100 microM) and NA (100 microM) on [3H]-cyclic AMP accumulation by about 80%, with an IC50 of 0.52 +/- 0.011 microM, to the level observed after 1S,3R-ACPD alone. Prazosin, an alpha 1-adrenoceptor antagonist was more potent (IC50 of 0.091 +/- 0.012 microM) but less efficacious (60% inhibition) as an inhibitor of the interaction either between NA and 1S,3R-ACPD while yohimbine, na alpha 2-adrenoceptor antagonist (up to 1 microM) had no effect. 7. Neither the protein kinase C inhibitor - staurosporine (10 microM) nor thapsigargin (1 microM), which depletes IP3 sensitive calcium stores, inhibited significantly the 1S,3R-ACPD (100 microM)-induced enhancement of the action of NA (100 microM) on [3H]-cyclic AMP accumulation. 8. Adenosine deaminase (0.5 U/ml) abolished both the 1S,3R-ACPD (100 microM)-induced [3H]-cyclic AMP accumulation and the synergistic interaction of this compound with NA (100 microM). 9. These results indicate the existence of different subtypes of metabotropic glutamate receptors in rat brain which either inhibit or enhance the NA-stimulated [3H]-cyclic AMP accumulation. The enhancement in cerebral cortical slices is mediated via receptors which are blocked with high affinity by L-AP3 and occurs via interactions with endogenous adenosine; the inhibition is mediated by receptors sensitive to quisqualate, L-AP3 and glutamate and may represent a predominant interaction between NA and excitatory amino acids (EAA), which in cerebral cortical slices is masked by excitatory effects.

Adrenergic Agonists↗
PubMed1983

Dissociation of E prostaglandin effects on liver glycogenolysis and cyclic AMP levels.

Some metabolic effects of prostaglandins have been related to their alteration of adenosine-3',5'-monophosphate (cyclic AMP) metabolism in different tissues. Prostaglandins E1 and E2 stimulate liver adenylate cyclase in vitro, but conflicting reports have been made about metabolic changes caused by E prostaglandins in hepatic tissue. We have attempted to resolve these issues by comparing the effects of PGE1 with those of glucagon using broken-cell homogenates, intact hepatocytes, liver slices and perfused liver. Prostaglandin E1 (PGE1) increased cyclic AMP in liver slices and in perfused liver without increasing glycogenolysis, but PGE1 had no discernible effect on carbohydrate or cyclic AMP metabolism in isolated hepatocytes. Glucagon caused predictable increases in cyclic AMP and glycogenolysis using hepatocytes, liver slices or perfused liver. These data can be explained by the absence of PGE effects on cyclic AMP metabolism in hepatocytes. The concentration of E prostaglandins (PGEs) increased 1.75-fold during incubations (37 degrees C) of hepatocyte suspensions, but cyclic AMP remained constant. Addition of exogenous arachidonate and indomethacin to cell suspensions increased and decreased PGEs, respectively, but cyclic AMP and glycogen metabolism were unchanged. Arachidonate and indomethacin likewise did not alter glucagon-stimulated glycogenolysis or cyclic AMP biosynthesis. The production of E prostaglandins and cyclic AMP appears to be unrelated in hepatocytes.

Adenylyl Cyclases↗