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PubMed1990

Expression of beta 2-adrenoceptors mediating cyclic AMP accumulation in astroglial and neuronal cell lines derived from the rat CNS.

The effect of isoprenaline on cyclic AMP accumulation has been investigated in the rat neuronal cell line B50 and the rat astrocytoma cell line C6. Noradrenaline and isoprenaline stimulated cyclic AMP accumulation in both cell lines. Isoprenaline (0.5 microM; EC50 = 0.1 microM) produced a rapid (T1/2 = 1.3 min) increase in [3H]cyclic AMP accumulation in B50 cells while the response to isoprenaline (0.1 microM; EC50 = 0.01 microM) in C6 cells was somewhat slower (T1/2 = 7.5 min). The response to 0.5 microM isoprenaline was antagonized by both propranolol (IC50 = 8.4 +/- 1.6 nM; N = 3) and the beta 2-selective antagonist ICI 118551 (IC50 = 2.1 +/- 0.2 nM; N = 6). However, no attenuation of the response to isoprenaline (0.5 microM) was observed at concentrations of the beta 1-adrenoceptor antagonist atenolol up to 10 microM (N = 3). In contrast, in C6 cells, which have previously been shown to possess beta 1-adrenoceptors, atenolol inhibited isoprenaline-induced (0.1 microM) cyclic AMP accumulation (IC50 = 2.0 +/- 0.5 microM; N = 6). Furthermore, the beta 2-selective antagonist ICI 118551 was much less potent in the C6 cell line (IC50 = 0.2 +/- 0.05 microM; N = 3) than in the B50 cells. In conclusion, the present data suggest that isoprenaline mediates cyclic AMP accumulation in the neuronal cell line via activation of beta 2-adrenoceptors, while in the astrocytoma cell line the cyclic AMP response is mediated by beta 1-adrenoceptors.

Animals↗
PubMed1991

Alpha- and beta-adrenoceptor regulation of cyclic AMP accumulation in cultured rat astrocytes. A comparison of primary protoplasmic and mixed fibrous/protoplasmic astroglial cultures.

The effect of noradrenaline and isoprenaline on cyclic AMP accumulation has been investigated in primary rat astrocytes which contain either (a) protoplasmic astrocytes alone or (b) both fibrous and protoplasmic astrocytes. Isoprenaline and noradrenaline stimulated cyclic AMP formation in both astrocyte culture preparations. Combinations of noradrenaline (1 microM) and isoprenaline (1 microM) produced a cyclic AMP response which was 58% and 26% of that produced by isoprenaline alone in protoplasmic and mixed fibrous/protoplasmic cultures, respectively. In both preparations this inhibitory effect of noradrenaline was antagonized by the alpha 2-adrenoceptor antagonist yohimbine (1 microM). A striking feature of the concentration-response curve for isoprenaline (EC50 = 0.8 microM) in mixed fibrous/protoplasmic cultures was that the cyclic AMP response decreased sharply at concentrations above 1 microM. This phenomenon was not seen in cultures containing protoplasmic astroglia alone. The fall in the isoprenaline concentration-response curve was not observed in the presence of the alpha-adrenoceptor antagonist phentolamine (1 microM), the dihydropyridine calcium antagonist isradipine (10 microM), the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (0.1 mM) or in nominally calcium-free medium. The effect of phentolamine was mimicked by the alpha 1-adrenoceptor antagonist prazosin (1 microM) but not by the alpha 2-antagonist yohimbine (1 microM). In conclusion, the data from this study suggest that two different populations of astrocytes in in vitro culture are able to raise intracellular cyclic AMP levels via beta-adrenoceptor activation and that there are differences in the extent of alpha-adrenoceptor (both alpha 1- and alpha 2-) mediated inhibition of cyclic AMP accumulation between the two primary astroglial cell preparations.

Adrenergic Antagonists↗
PubMed1993

Reduction by arachidonic acid of prostaglandin I2-induced cyclic AMP formation. Involvement of prostaglandins E2 and F2 alpha.

Arachidonic acid reverses the increase in cyclic AMP levels of washed human platelets exposed to prostaglandin (PG)I2, under conditions where the PGH2 analogue U46619 is ineffective. This effect of arachidonic acid was inhibited by aspirin, a cyclooxygenase inhibitor, but not by the thromboxane (Tx) synthase inhibitor Ridogrel, which induces, by inhibiting the conversion of PGH2 into TxA2, an overproduction of PGE2, PGD2 and PGF2 alpha. Addition of PGE2 or PGF2 alpha, which share a receptor with PGI2, to washed human platelets also induced a decrease in cyclic AMP levels, but PGD2, which interacts with a different receptor, had no effect. Thus neither PGD2, PGG2, PGH2, TxA2 nor TxB2 formed from arachidonic acid via the cyclooxygenase pathway is involved in the decrease in cyclic AMP levels. These findings were confirmed using forskolin, a diterpene from the labdane family, which enhanced the formation of cyclic AMP synergistically with the PGs. Also, arachidonic acid, unlike U46619, is able to reverse the inhibition of platelet aggregation by PGI2 after a lag phase of about 4 min. Our data indicate that arachidonic acid decreased cyclic AMP levels through its cyclooxygenase metabolites PGE2 and PGF2 alpha probably interacting competitively with the receptor of PGI2. In addition, intracellular cyclic AMP levels and the degree of aggregation of platelets by arachidonic acid seem to be inversely correlated.

Arachidonic Acid↗
PubMed1977

Cyclic AMP-stimulated phosphorylation of a high molecular weight endogenous protein substrate in sub-cellular fractions of molluscan nervous system.

Cyclic AMP stimulated the incorporation of radioactive phosphate from ATP into endogenous phosphoproteins in a 20,000 X g supernatant, as well as in a 150,000 X g supernatant, prepared from Helix nervous system homogenates. No effect of cyclic AMP was observed in the respective pellet fractions. A part (but not all) of the cyclic AMP-stimulated activity in both supernatants was due to phosphorylation of an endogenous protein substrate, of apparent molecular weight 120,000 daltons as determined from its mobility in polyacrylamide gels. Little phosphorylation of 120,000 dalton material was observed in the particulate fractions, both in the presence and absence of cyclic AMP. When the 20,000 X g pellet was incubated with radioactive ATP and an exogenous calf ovary protein kinase, cyclic AMP stimulated the phosphorylation of the 120,000 dalton material. The results suggest that both membranes and cytosol from Helix nervous system contain 120,000 dalton substrates for cyclic AMP-dependent protein kinase. However, no kinase catalyzing phosphorylation of these substrates is recovered in membrane fractions following homogenization of the tissue.

Adenosine Triphosphate↗
PubMed1986

Identified octopaminergic neurons modulate contractions of locust visceral muscle via adenosine 3',5'-monophosphate (cyclic AMP).

D,L-Octopamine elevates the cyclic AMP content of the lateral oviduct of the locust, Locusta migratoria, in a dose-dependent manner with a threshold of about 10(-8) M. The effect of octopamine is potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). The response is specific for octopamine and synephrine with an order of potency being octopamine = synephrine greater than metanephrine greater than tyramine greater than norepinephrine = dopamine = 5-hydroxytryptamine and the effect of octopamine is inhibited by the alpha-adrenergic receptor antagonist phentolamine. The diterpene adenylate cyclase activator forskolin also elevates cyclic AMP levels and IBMX potentiates the action of forskolin. Stimulation of the two identified octopaminergic neurons which project to the lateral oviducts results in an elevation in cyclic AMP and again this effect is blocked by phentolamine. Elevation of cyclic AMP levels in the lateral oviducts by means of IBMX, forskolin or dibutyryl cyclic AMP mimics the physiological effects of octopamine on this preparation. The results indicate that the octopaminergic control of this insect's visceral muscle is mediated via cyclic AMP.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Alpha 2-adrenergic receptors mediate inhibition of cyclic AMP production in neurons in primary culture.

The actions of adrenergic agents on the intracellular production of cyclic adenosine monophosphate (AMP) was examined in intact cortical and striatal neurons in primary culture, generated from the fetal mouse brain. Exposure of striatal neurons to the beta-adrenergic agonist isoproterenol (10 microM) resulted in a 5-fold increase in intraneuronal cyclic AMP; norepinephrine (100 microM), alone or in combination with isoproterenol, produced only a 3-fold increase in cyclic AMP levels. However, in the presence of yohimbine (10 microM), cyclic AMP productions due to norepinephrine or isoproterenol plus norepinephrine were identical to isoproterenol alone. When striatal or cortical neurons were exposed to pertussis toxin (100 ng/ml) overnight, there was no detectable difference between isoproterenol- and norepinephrine-stimulated cyclic AMP production. These data suggest that alpha 2-adrenergic receptors mediate the attenuation of cyclic AMP production in neurons and do so via the inhibitory guanine nucleotide regulatory protein of adenylate cyclase.

Adenylate Cyclase Toxin↗
PubMed1990

Control of potassium currents and cyclic AMP levels by autoactive neuropeptides in Aplysia neurons.

The bag cell neurons of Aplysia are capable of generating an afterdischarge, which, in vivo, triggers egg-laying behavior. Pharmacologic elevation of cyclic AMP levels in isolated bag cell neurons has been shown to initiate repetitive firming similar to that seen during an afterdischarge, and to decrease outward currents measured under voltage-clamp. We have now examined the effects of three autoactive neuropeptides, alpha-, beta-, and gamma-bag cell peptide (BCP), on cyclic AMP levels and voltage-dependent potassium currents in these neurons. Previous work has shown that alpha-BCP lowers cyclic AMP levels in intact clusters of bag cell neurons. We have found that beta-BCP elevates cyclic AMP levels, whereas gamma-BCP, like alpha-BCP, lowers cyclic AMP levels. We used whole cell patch clamp technique to determine the effects of the peptides on the delayed voltage-dependent potassium currents in isolated bag cell neurons. As one would predict from their effects on cyclic AMP levels, beta-BCP decreased the amplitude of the delayed potassium currents whereas both alpha- and gamma-BCP increased the amplitude of these currents. In contrast, no consistent effects of these peptides on the transient voltage-dependent potassium current (A-current) were seen in these cells. Our results suggest that these three autoactive peptides may contribute to changes in second messengers and ionic currents during a bag cell afterdischarge.

Amino Acid Sequence↗
PubMed1978

Negative chronotropic action of cyclic AMP on the fetal rat heart in organ culture.

Dibutyryl cyclic AMP and cyclic AMP in a DMSO medium were administered to the fetal rat heart in organ culture. Changes in heart rate were observed. Dibutyryl cyclic AMP in concentrations of 5 X 10(-5) M and 1 X 10(-4) M produced significant negative chronotropism. At a concentration of 1 X 10(-3) M, cyclic AMP in a 3% or 0.5% DMSO medium produced significant negative chronotropism. These data were compared with other studies. The negative chronotropic action of cyclic AMP and its dibutyryl derivative are evidence against the involvement of cyclic AMP in positive cardiac chronotropism.

Animals↗
PubMed1984

Effects of forskolin and isoproterenol on cyclic AMP and tension in the myometrium.

The effects of forskolin and isoproterenol on total cyclic AMP accumulation and relaxation were compared in uterine segments from estrogen-treated rabbits and term-pregnant rats. In the rabbit, forskolin (0.2-5.0 microM) inhibited spontaneous and acetylcholine-induced contractions and increased cyclic AMP levels. At lower doses forskolin significantly inhibited contractions but had little effect on cyclic AMP (cAMP) levels. Isoproterenol (0.005-0.5 microM), doses equi-effective to those of forskolin for inhibition of contractions, did not alter cyclic AMP levels. In the rat, forskolin (0.5 microM) and isoproterenol (0.05 microM) inhibited spontaneous and potassium-induced contractions by 80%. This reduction was accompanied by an increase in cyclic AMP levels, but the increase was significantly greater with forskolin than with isoproterenol. We conclude that: (1) cAMP may mediate relaxation under certain conditions but it is not an obligatory mediator, (2) some form of compartmentalization of cyclic AMP might exist in the myometrium.

Acetylcholine↗
PubMed1986

Different types of relationship between beta-adrenergic relaxation and activation of cyclic AMP-dependent protein kinase in canine saphenous and portal veins.

We examined the relationships between the relaxation mediated by beta-adrenoceptor and either the associated cyclic AMP production or the activation of cyclic AMP-dependent protein kinase (A-PK) in canine saphenous and portal veins. In the saphenous vein constricted with methoxamine, isoproterenol caused concentration-dependent relaxation (maximum relaxation 92.7%), and concomitant increases in cyclic AMP and A-PK activity ratio (from 52.8 to 73.5%). The portal vein was only slightly relaxed by isoproterenol (14.7% in the longitudinal strips) after constriction with methoxamine, while cyclic AMP and A-PK activation increased significantly. Isoproterenol markedly activated A-PK of the portal vein after KCl constriction (from 52.6 to 74.6%) but the maximum relaxation was only slight (13.3%). The portal vein also showed a smaller relaxation response to either forskolin or dibutyryl cyclic AMP than the saphenous vein. These results indicated that the relationship between the relaxation response to isoproterenol and either cyclic AMP production or A-PK activation was different in the saphenous and portal veins.

Animals↗
PubMed1989

Human endothelial cells inhibit platelet aggregation by separately stimulating platelet cyclic AMP and cyclic GMP.

Thrombin-induced platelet aggregation was monitored in a mixture of washed human platelets and cultured human endothelial cells on microcarrier beads. Endothelial cells completely inhibited platelet aggregation and enhanced the content of both cyclic AMP and cyclic GMP in the platelets. Inhibition of endothelial prostacyclin synthesis with indomethacin abolished the cyclic AMP increase in the platelets, whereas the cyclic GMP increase was unimpaired. A significant component of the endothelial anti-aggregatory effect persisted in the presence of indomethacin. This anti-aggregatory component and the elevation of cyclic GMP were blocked by the inhibitors of endothelium-derived relaxing factor (EDRF), gossypol, haemoglobin and methylene blue. These inhibitors did not affect the endothelium-induced increases in cyclic AMP or the cyclic AMP-mediated anti-aggregatory effects. Exogenous prostacyclin stimulated only platelet cyclic AMP, whereas sodium nitroprusside selectively enhanced cyclic GMP. These data suggest that the endothelium can inhibit platelet aggregation by two completely separate mechanisms, one mediated by prostacyclin and cyclic AMP, and the other by EDRF and cyclic GMP.

Biological Factors↗
PubMed1990

Inhibition of cyclic AMP accumulation by alpha 2-adrenoceptors in the rat cerebral cortex.

The effects of alpha 2-adrenoceptor agonist and antagonists on the accumulation of cyclic AMP were examined in rat cerebral cortex slices. Norepinephrine (10(-4) M) caused a 123 +/- 11% increase in the cyclic AMP concentration in the cortical slices, which was greater than the increase (89 +/- 7% increase) caused by isoproterenol (10(-4) M) alone. However, the cyclic AMP response to norepinephrine was completely inhibited by propranolol (10(-4) M), a beta-adrenoceptor antagonist. Yohimbine (10(-7)-10(-5) M), an alpha 2-adrenoceptor antagonist, intensified the cyclic AMP response to norepinephrine by 30%, whereas, clonidine, an alpha 2-adrenoceptor agonist, decreased the response. Treatment with reserpine (3.0 mg/kg) reduced the density of [3H]p-aminoclonidine binding sites (Bmax, 93.8 +/- 18.4 fmol/mg protein) compared to the density in non-treated rats (154.4 +/- 33.5 fmol/mg protein). The potentiating effect of yohimbine and the inhibitory effect of clonidine on the cyclic AMP response to norepinephrine were also reduced. These results suggest that alpha 2-adrenoceptors regulate the accumulation of cyclic AMP in the rat cerebral cortex in an inhibitory fashion. The results also suggest that the accumulation is mediated through beta-adrenoceptors and that this response is intensified by alpha 1-adrenoceptor stimulation.

Adenylyl Cyclases↗
PubMed1993

Inhibitory actions of cyclic AMP on neurogenic plasma extravasation in rat airways.

To determine whether neurogenic inflammation can be inhibited by cyclic AMP, which is suggested to have an inhibitory effect on neuropeptide release from airway sensory nerves, we examined plasma extravasation in the airways of anesthetized rats in vivo with Evans blue dye as a marker. Neurogenic inflammation was produced by antidromic electrical stimulation of the right vagus nerve (4 Hz, 1 ms, 4 V for 1 min). Electrical stimulation significantly increased leakage of dye in the trachea and right bronchus. Forskolin (from 0.01 to 100 pM/kg), dibutyryl cyclic AMP (db cyclic AMP; from 10 pM/kg to 100 nM/kg) and fenoterol (from 100 to 1 nM/kg) dose dependently inhibited the leakage of dye induced by electrical stimulation in the trachea and right bronchus. Substance P (1 microgram/kg) increased Evans blue dye extravasation in the same way as the leakage induced by electrical stimulation. Forskolin (from 0.1 to 1 pM/kg), db cyclic AMP (1 nM/kg) and fenoterol (10 nM/kg) failed to inhibit substance P-induced leakage, but showed significant inhibitory effects on the leakage induced by electrical stimulation in the trachea and right bronchus. However, further increases in the concentrations of forskolin, db cyclic AMP and fenoterol significantly inhibited substance P-induced leakage of dye in both tissues. These results suggest that cyclic AMP inhibits neurogenic plasma leakage by presynaptic inhibition of the release of neuropeptides from sensory nerves as well as by postsynaptic effects on the vascular endothelium.

Anesthesia↗
PubMed1996

Adenosine A1 receptor-mediated inhibition of cyclic AMP accumulation in type-2 but not type-1 rat astrocytes.

The effects of adenosine receptor-selective ligands on [3H]cyclic AMP accumulation have been investigated in type-1 and type-2 astrocyte-enriched cultures derived from neonatal rat forebrains. In type-1 astrocytes, 5'-N-ethylcarboxamidoadenosine (NECA) caused a concentration-dependent increase in [3H]cyclic AMP accumulation (EC50 = 1.2 microM) which was antagonised by pretreatment with either xanthine amine congener (8-[4-[[[[(2-aminoethyl)amino]carbonyl]methyl]oxy]-phenyl]- 1,3-dipropylxanthine, apparent Kd = 9 nM) or PD115,199 (N-[2-(dimethylamino)ethyl]-N-methyl-4-(1,3-dipropylxanthine) benzene sulphonamide, apparent Kd = 122 nM). In these cultures, N6-cyclopentyladenosine (CPA), did not affect forskolin- or isoprenaline-mediated elevations of [3H]cyclic AMP accumulation. These data indicate that type-1 astrocytes possess adenosine A2B but not adenosine A1 receptors coupled to adenylyl cyclase. In type-2 astrocyte-enriched cultures, 10 microM NECA caused significant elevations of [3H]cyclic AMP accumulation which were similarly inhibited by either 1 microM xanthine amine congener or 10 microM PD115,199 suggesting that they were primarily due to adenosine A2B receptor stimulation. However, CGS 21680 ((2-[[4-(2-carboxyethyl) phenethyl]-amino]adenosine-5'-N-ethylcarboxamide, 10 microM), also significantly increased [3H]cyclic AMP accumulation in type-2 astrocytes suggesting the additional presence of adenosine A2A receptors. Forskolin-mediated elevations of [3H]cyclic AMP accumulation in type-2 astrocytes were inhibited in a concentration-dependent manner by CPA. This effect was reversed by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 0.1 microM), confirming the presence of adenosine A1 receptors negatively coupled to adenylyl cyclase in type-2 astrocytes.

Adenosine↗
PubMed1985

Cyclic AMP and c-myc gene expression in PY815 mouse mastocytoma cells.

The possibility was examined that inhibition of growth of PY815 mouse mastocytoma cells by N6,O2'-dibutyryladenosine 3',5'-cyclic monophosphate (DB cyclic AMP) results from inhibition of c-myc gene expression. Temporary increases in c-myc RNA which occurred soon after DB cyclic AMP treatment and upon removal of the drug were not consistent with direct inhibition of c-myc gene expression by DB cyclic AMP. The increases in c-myc RNA coincided with the passage through, or accumulation of cells in late G1-early S phase. It is proposed that cyclic AMP may stimulate c-myc gene expression which normally occurs only in late G1-early S phase in PY815 cells and that cyclic AMP prevents c-myc expression in cells at other phases of the cell cycle by inhibiting their progression past a cyclic AMP-sensitive restriction point in early G1 phase.

Animals↗
PubMed1986

Role of calcium in luteinizing hormone-induced progesterone and cyclic AMP production in granulosa cells of the hen (Gallus domesticus).

The effects of calcium on steroidogenesis and cyclic AMP production in chicken granulosa cells were examined. For the expression of full steroidogenic effects by LH, forskolin, and 8-bromo cyclic AMP the presence of calcium in the incubation medium was essential, the optimal concentration being 1 mM. Moreover, calcium antagonists (verapamil, TMB-8) significantly suppressed steroidogenesis in response to all three agonists. The metabolism of 25-hydroxycholesterol and the conversion of pregnenolone to progesterone, however, were not affected by the lack of calcium or by coincubation with calcium antagonists. LH-stimulated cyclic AMP production was also suppressed in calcium-deficient medium and in the presence of the putative calcium channel blocker, verapamil. However, TMB-8 did not affect LH-induced cyclic AMP production. Moreover, neither forskolin- nor IBMX-induced cyclic AMP accumulation was significantly affected by lack of calcium or verapamil. These results are interpreted to indicate that the continuous presence of extracellular calcium is essential for hormonal regulation of steroidogenesis and is important for events both proximal and distal to cyclic AMP generation up to pregnenolone synthesis.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Glucagon and insulin regulate in vitro hepatic glycogenolysis in the axolotl Ambystoma mexicanum via changes in tissue cyclic AMP concentration.

Glucagon increases the rate of glycogenolysis in in vitro cultures of hepatic tissue from the axolotl Ambystoma mexicanum. The hormone causes an increase in the concentration of cyclic AMP in the tissue which is followed by activation of glycogen phosphorylase and subsequent breakdown of glycogen and release of glucose from the tissue. Insulin counteracts the glycogenolytic effect of glucagon by inhibiting the increase in tissue cyclic AMP concentration brought about by glucagon. This inhibitory effect of insulin is not seen in the presence of the phosphodiesterase inhibitor IBMX and so it appears that the initial action of insulin is a stimulation of cyclic AMP phosphodiesterase activity which lowers the tissue concentration of cyclic AMP and so counters the actions of hormones that act by raising the tissue concentration of cyclic AMP. This model for the mode of action of insulin is supported by the finding that insulin also interferes with the glycogenolytic actions of adrenaline, a second hormone which acts by raising tissue cyclic AMP concentrations.

1-Methyl-3-isobutylxanthine↗
PubMed1984

Cyclic AMP and steroidogenesis in superovulated rat ovaries.

During the gonadotropin stimulated differentiation of ovarian follicles into corpora lutea, the concentrations of total cyclic AMP and protein bound cyclic AMP increased only marginally. In contrast, there was a 10 fold increase in progesterone production. After acute stimulation of luteinized ovaries with choriogonadotropin total cyclic AMP levels increase more than 6 times while bound cyclic AMP and plasma progesterone rose by 80 and 60% respectively. Our results question the role of cyclic AMP in the basal production of progesterone by the ovary, and suggest a relationship between bound cyclic AMP and progesterone synthesis only exists after acute gonadotropin stimulation.

Animals↗