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PubMed1984

Differential effects of prostaglandin E2 and cyclic AMP on release of arachidonic acid metabolites from resting and lipopolysaccharide-stimulated macrophages.

The present study investigated the effect of cyclic adenosine 3',5'-monophosphate (cyclic AMP) and prostaglandin E2 (PGE2) on arachidonic acid metabolism in rat peritoneal macrophages. Dibutyryl cyclic AMP (db-cyclic AMP) caused differential effects on the synthesis of PGE2 and thromboxane. Although db cyclic AMP enhanced the release of PGE2, it inhibited the release of thromboxane. This suggests that cyclic AMP may regulate cellular functions via induction of a shift in the proportion of arachidonic acid metabolites. PGE2, at low concentrations, markedly inhibited thromboxane release in nontreated macrophages, but it had virtually no effect on thromboxane release in cells treated with lipopolysaccharide (LPS). By contrast, db-cyclic AMP inhibited thromboxane release also in LPS-stimulated cells. The interrelationships between PGE2, thromboxane and cyclic AMP, and possible interference of LPS in these interactions are discussed.

Animals↗
PubMed1985

The mechanism of the inhibitory action of adrenaline on transmitter release in bullfrog sympathetic ganglia: independence of cyclic AMP and calcium ions.

The effects of adrenaline and dibutyryl adenosine 3':5' - cyclic monophosphate (db cyclic AMP) on nicotinic transmission in bullfrog sympathetic ganglia were compared by use of an intracellular recording technique. The evoked release of transmitter, acetylcholine (ACh), was decreased in the presence of adrenaline (10-100 microM), while the postsynaptic sensitivity to ACh was unchanged (10 microM adrenaline) or slightly reduced (100 microM). Transmitter release was similarly inhibited by dopamine (10 microM), but not by isoprenaline (10 microM). The inhibitory action of adrenaline on transmitter release was blocked by phenoxybenzamine but not by propranolol. The inhibition of transmitter release was independent of the external calcium concentration. The evoked release of transmitter and the electrical properties of the postsynaptic membrane were unchanged during exposure to db cyclic AMP (1-4 mM), while the postsynaptic sensitivity to ACh was slightly but significantly depressed. The spontaneous release of transmitter in a high K+ (10 mM) solution was decreased in the presence of adrenaline (100-300 microM), but unchanged with db cyclic AMP (4 mM). In contrast to the effects during exposure, both the evoked and spontaneous release of transmitter were enhanced after the removal of adrenaline or db cyclic AMP. Neither adrenaline (100 microM) nor db cyclic AMP (4 mM) affected the presynaptic spike and synaptic delay. It is concluded that adrenaline mainly inhibits the release of ACh from the presynaptic terminals through its alpha-action, while db cyclic AMP reduces slightly the postsynaptic sensitivity to ACh and that both agents facilitate transmitter release when they are removed from the presynaptic terminals. It is further suggested that the inhibitory action of adrenaline is independent of endogenous cyclic AMP and calcium ions.

Acetylcholine↗
PubMed1990

Effects of selective phosphodiesterase inhibition on cyclic AMP hydrolysis in rat cerebral cortical slices.

1. The effects of selective inhibition of phosphodiesterase activities on the concentration and rate of hydrolysis of adenosine 3':5' cyclic-monophosphate (cyclic AMP) in rat cerebral cortical slices has been studied. 2. Isoprenaline caused a rapid, concentration-dependent increase in cyclic AMP concentration to new steady-state levels (basal: 7.1 +/- 0.7; 10 microM isoprenaline: 14.3 +/- 1.4 pmol mg-1 protein). Addition of a beta-adrenoceptor antagonist to isoprenaline-stimulated cerebral cortical slices caused a rapid decrease in cyclic AMP concentration to basal levels (t1/2: 58 +/- 18 s). 3. Preincubation of slices for 30 min with the phosphodiesterase inhibitors 1-methyl-3-isobutylxanthine, denbufylline, rolipram or Ro20,1724 caused concentration-dependent increases in basal and isoprenaline-stimulated cyclic AMP concentrations and decreased the rate of cyclic AMP hydrolysis measured after addition of a beta-adrenoceptor antagonist. However, SKF 94120 and zaprinast had none of these effects. 4. The results are discussed with respect to previous studies of phosphodiesterase isozymic activities isolated from cerebrum and it is suggested that the Ca2+/calmodulin-independent, low Km cyclic AMP phosphodiesterase isozyme, which is selectively inhibited by denbufylline, rolipram and Ro20,1724, and is present in cerebrum is of critical importance to the regulation of cyclic AMP concentration in this tissue.

Animals↗
PubMed1992

Effect of adenosine and adenosine analogues on cyclic AMP accumulation in cultured mesangial cells and isolated glomeruli of the rat.

1. Changes in intracellular levels of adenosine 3':5'-cyclic monophosphate (cyclic AMP) were studied in rat isolated glomeruli and cultured glomerular mesangial cells exposed to adenosine and to the preferential A1 receptor agonist N6-R-1-methyl-2-phenylethyl adenosine (R-PIA), or the potent A2 adenosine receptor agonist 5-(N-ethylcarboxamide)adenosine (NECA). 2. Whereas NECA and adenosine triggered a dose-dependent increase in cyclic AMP values with EC50 values of approximately 10(-6) M and 3 x 10(-5) M respectively, R-PIA lowered cyclic AMP levels at concentrations of 10(-6) M or less and increased them at higher concentrations. 3. The time-course of the increase induced by 10(-6) M NECA was slower than that induced by 10(-4) M adenosine. Adenosine produced a maximal stimulation within the first minute, whereas the effect of NECA in both glomeruli and mesangial cells was noticeable only from the second minute of incubation. 4. The effects of the agonists R-PIA and NECA on the cyclic AMP system were blocked respectively by the A1 adenosine receptor antagonist, 8-cyclopentyl-1, 3-dipropylxanthihe (DPCPX) at 10(-6) M and the A2 antagonist N-(2-dimethylaminoethyl)-N-methyl-4-(2, 3, 6, 7-tetrahydro-2,b-dioxo-1, 3-dipropyl-1H-purin-8-yl) benzene sulphonamide (PD115,199) at 10(-6) M. Theophylline, a known antagonist of adenosine receptors, inhibited the action of adenosine on cyclic AMP in mesangial cells. Dipyridamole, an inhibitor of the uptake of adenosine by the cells, enhanced the response to adenosine.5. These results suggest the existence of Al and A2 adenosine receptors with opposite actions on intracellular levels of cyclic AMP in both glomeruli and mesangial cells. Adenosine seems to increase cyclic AMP through the activation of a surface adenosine receptor with pharmacological properties distinct from those exhibited by the A2 adenosine receptor.

Adenosine↗
PubMed1993

Salmeterol, a long-acting beta 2-adrenoceptor agonist mediating cyclic AMP accumulation in a neuronal cell line.

1. The accumulation of cyclic AMP stimulated by salmeterol, a long-acting beta 2-adrenoceptor agonist and by isoprenaline, a non-selective beta-adrenoceptor agonist have been compared in the B50 neuroblastoma cell line. 2. Salmeterol produced a concentration-dependent increase in the accumulation of total [3H]-cyclic AMP in B50 cells yielding an EC50 value of 37 nM which was lower than that obtained with isoprenaline (294 nM). The maximum response to salmeterol was only 46% of that obtained with isoprenaline. 3. The beta 2-adrenoceptor antagonist, ICI 118551, inhibited the responses to both salmeterol (apparent KD 2.2 nM) and isoprenaline (apparent KD 1.6 nM). However, the beta 1-adrenoceptor antagonist, atenolol, produced no significant effect at concentrations up to 100 microM. 4. Salmeterol (1 microM) changed the concentration-response curve of isoprenaline in the manner of a partial agonist interacting with a full agonist. The KD of salmeterol obtained from the interaction was 55.6 nM. 5. Whereas salmeterol has a slow onset of action in airway smooth muscle compared to other beta 2-adrenoceptor agonists, in B50 monolayers both salmeterol and isoprenaline produced a rapid increase in cyclic AMP accumulation (t1/2 1.1 min and 0.4 min respectively). 6. Despite the existence of cyclic AMP efflux mechanisms that exist in this cell line it was possible to investigate the duration of agonist action by measuring intracellular levels of the second messenger. Replacement of drug-containing medium with fresh buffer led to a rapid reduction in intracellular levels of cyclic AMP in isoprenaline-stimulated cells whereas cyclic AMP accumulation was sustained for much longer periods in salmeterol-stimulated cells. However, the persistent action of salmeterol could be reversed by the addition of a beta2-selective antagonist.7. These results confirm that salmeterol has a high affinity, but low efficacy (relative to isoprenaline) for beta2-adrenoceptors coupled to cyclic AMP accumulation and that the drug persists at its site of action for long periods in the B50 neuronal cell line.

Adrenergic beta-Agonists↗
PubMed1994

Induction of nitric oxide synthase in cultured vascular smooth muscle cells: the role of cyclic AMP.

1. Interleukin-1 beta (IL-1 beta) is a potent stimulant of inducible nitric oxide synthase (iNOS) mRNA and nitric oxide (NO) production in vascular smooth muscle (VSM) cells in culture. These studies investigate the role of adenosine 3':5'-cyclic monophosphate (cyclic AMP) in this process. 2. Dibutyryl cyclic AMP (db cyclic AMP, 0.1-1 mM), forskolin (1-10 microM) and the phosphodiesterase inhibitor, Ro 20-1724 (1-10 microM), all of which increase intracellular cyclic AMP, had no effect on NO production when added alone but markedly enhanced NO production by IL-1 beta-stimulated VSM cells in a dose-dependent manner. Consistent with a cyclic AMP-mediated action, isoprenaline (1-10 microM) increased NO production from IL-1 beta-stimulated cells. Dibutyryl cyclic GMP (db cyclic GMP) had no effect at concentrations up to 1 mM. 3. Pursuing these observations, iNOS protein levels were examined by Western blot analysis and iNOS mRNA levels were measured by reverse transcription and amplification of the resultant cDNA using the polymerase chain reaction. In addition to enhancing NO production, db cyclic AMP increased iNOS protein and mRNA above that produced by IL-1 beta alone. 4. These data demonstrate a major effect of cyclic AMP on cytokine-induced NOS activity in VSM cells, mediated at least in part by regulating synthesis of iNOS, and has implications for the pathogenesis and management of septic shock.

Amino Acid Oxidoreductases↗
PubMed1996

Modulation of agonist-induced phosphoinositide metabolism, Ca2+ signalling and contraction of airway smooth muscle by cyclic AMP-dependent mechanisms.

1. The effects of increased cellular cyclic AMP levels induced by isoprenaline, forskolin and 8-bromoadenosine 3':5'-cyclic monophosphate (8-Br-cyclic AMP) on phosphoinositide metabolism and changes in intracellular Ca2+ elicited by methacholine and histamine were examined in bovine isolated tracheal smooth muscle (BTSM) cells. 2. Isoprenaline (pD2 (-log10 EC50) = 6.32 +/- 0.24) and forskolin (pD2 = 5.6 +/- 0.05) enhanced cyclic AMP levels in a concentration-dependent fashion in these cells, while methacholine (pD2 = 5.64 +/- 0.12) and histamine (pD2 = 4.90 +/- 0.04) caused a concentration-related increase in [3H]-inositol phosphates (IP) accumulation in the presence of 10 mM LiCl. 3. Preincubation of the cells (5 min, 37 degrees C) with isoprenaline (1 microM), forskolin (10 microM) and 8-Br-cyclic AMP (1 mM) did not affect the IP accumulation induced by methacholine, but significantly reduced the maximal IP production by histamine (1 mM). However, the effect of isoprenaline was small (15.0 +/- 0.6% inhibition) and insignificant at histamine concentrations between 0.1 and 100 microM. 4. Both methacholine and histamine induced a fast (max. in 0.5-2 s) and transient increase of intracellular Ca2+ concentration ([Ca2+]i) followed by a sustained phase lasting several minutes. EGTA (5 mM) attenuated the sustained phase, indicating that this phase depends on extracellular Ca2+. 5. Preincubation of the cells (5 min, 37 degrees C) with isoprenaline (1 microM), forskolin (10 microM) and 8-Br-cyclic AMP (1 microM) significantly attenuated both the Ca(2+)-transient and the sustained phase generated at equipotent IP producing concentrations of 1 microM methacholine and 100 microM histamine (approx. 40% of maximal methacholine-induced IP response), but did not affect changes in [Ca2+]i induced by 100 microM methacholine (95.2 +/- 3.5% of maximal methacholine-induced IP response). 6. Significant correlations were found between the isoprenaline-induced inhibition of BTSM contraction and inhibition of Ca2+ mobilization or influx induced by methacholine and histamine, that were similar for each contractile agonist. 7. These data indicate that (a) cyclic AMP-dependent inhibition of Ca2+ mobilization in BTSM cells is not primarily caused by attenuation of IP production, suggesting that cyclic AMP induced protein kinase A (PKA) activation is effective at a different level in the [Ca2+]i homeostasis, (b) that attenuation of intracellular Ca2+ concentration plays a major role in beta-adrenoceptor-mediated relaxation of methacholine- and histamine-induced airway smooth muscle contraction, and (c) that the relative resistance of the muscarinic agonist-induced contraction to beta-adrenoceptor agonists, especially at (supra) maximal contractile concentrations is largely determined by its higher potency in inducing intracellular Ca2+ changes.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1979

Anticonvulsant drug actions on in vitro and in vivo levels of cyclic AMP in the mouse brain.

Injections of pentylenetetrazol to mice produced a rise in steady state levels of cyclic AMP in the cerebrum and cerebellum subsequent to sacrifice by focused microwave irradiation. One hour pretreatment with anticonvulsant drugs--phenytoin, phenobarbital, carbamazepine, clonazepam, and diazepam--prevented this pentylenetetrazol-induced rise in cyclic AMP. Anticonvulsant agents which alone depressed steady state levels of cyclic AMP were phenytoin and carbamazepine in the cerebral cortex and carbamazepine in the cerebellum while elevations in the cyclic nucleotide were evoked by clonazepam in the cerebrum and cerebellum or diazepam and phenytoin in the cerebellum. Under in vitro conditions, in which incubated tissue slices of mouse cerebral cortex were used, the stimulation of cyclic AMP by norepinephrine was blocked by carbamazepine greater than phenobarbital greater than phenytoin. Inhibition of adenosine-induced accumulation of cyclic AMP was observed with phenobarbital greater than carbamazepine greater than phenytoin. Clonazepam enhanced this response to adenosine. Ouabain stimulation of cyclic AMP was prevented by carbamazepine, phenytoin greater than clonazepam greater than phenobarbital greater than diazepam. Only the highest concentrations (0.5 mM) of phenytoin, phenobarbital, and carbamazepine reduced the action of KCl on cyclic AMP elevation. Clonazepam and diazepam elevated the basal levels of the cyclic nucleotide.

Adenosine↗
PubMed1990

Human leukocyte beta-adrenergic stimulated cyclic AMP in ethanol intoxication and withdrawal.

The effects of ethanol were examined on cyclic AMP production in intact human leukocytes in vitro. In leukocytes isolated from alcohol abstinent subjects, ethanol enhances isoproterenol-stimulated and prostaglandin E1-stimulated cyclic AMP formation. Without agonist, ethanol is able to stimulate cyclic AMP production at concentrations of 160 mM and above. Leukocytes isolated from subjects undergoing alcohol detoxification showed increases in basal levels of leukocyte cyclic AMP, in isoproterenol-stimulated cyclic AMP, and in ethanol-stimulated cyclic AMP on the 2nd or 3rd day of withdrawal in comparison to the first day of withdrawal and in comparison to abstinent subjects. The data suggest that increased beta-adrenergic activity seen in alcohol withdrawal may be in part due to an increased responsiveness of beta-adrenergic stimulated cyclic AMP in tissues.

Adrenergic beta-Agonists↗
PubMed1990

c-AMP and ANP levels in VVI and DDD pacing with different AV delays during daily activity and exercise.

Nine patients (three males) mean age 68 +/- 8 years, having complete heart block, and paced in the DDD mode were examined in VVI and DDD pacing with 100 and 150 ms atrioventricular delays (AVD) during rest and exercise. Plasma atrial natriuretic peptide (ANP) and cyclic AMP (c-AMP) were measured at rest and at peak exercise test. ANP plasma levels at rest were significantly higher in VVI pacing compared to 150 AVD (P less than 0.03). On exercise, ANP release was statistically increased only in DDD with 150 ms AVD, while in VVI it remained in high levels at exercise but no significant change was found (p:ns). c-AMP during rest was unchanged in any pacing mode or AVD, but on exercise DDD pacing with short AVD (100 ms) released lower c-AMP plasma levels, than at rest (p:ns). DDD pacing with long AVD (150 ms) during exercise produced statistically higher c-AMP plasma levels (P less than 0.05) than at rest. Also in VVI pacing the c-AMP plasma levels were statistically higher than at rest (P less than 0.02). Adrenergic activity seems to be lower during exercise in DDD pacing with shorter AVD (100 ms) than in DDD with 150 ms AVD or VVI pacing. No difference was found in c-AMP plasma levels at rest. ANP release was also found to be lower at exercise in DDD pacing with short AVD (100 ms) than in DDD with 150 ms AVD. ANP plasma levels at rest were statistically higher in VVI pacing.

Aged↗
PubMed1982

Effects of beta-adrenergic stimulation on calcium movements in rabbit aortic smooth muscle: relationship with cyclic AMP.

1. The effects of isoprenaline (10(-6) M) on relaxation, unidirectional as well as net Ca(2+) fluxes, and cyclic AMP levels were investigated in rabbit aorta under the condition of high-K(+) depolarization in the presence of phentolamine (10(-5) M).2. Isoprenaline (10(-6) M) caused significant inhibition of Ca(2+) influx stimulated by 145 mM-K(+) (0 Na(+)) solution. The time courses of Ca(2+) influx inhibition and relaxation by isoprenaline were parallel. Isoprenaline also caused a significant inhibition of high-K(+)-induced gain in net Ca(2+) content.3. Ro 20-1724 (1 mM), a phosphodiesterase inhibitor, also caused relaxation and Ca(2+) influx inhibition in high-K(+)-depolarized rabbit aorta. Pre-treatment with Ro 20-1724 potentiated isoprenaline-induced Ca(2+) influx inhibition and relaxation.4. Isoprenaline and Ro 20-1724 each alone increased cyclic AMP levels. Furthermore pre-treatment with Ro 20-1724 caused potentiation of isoprenaline-induced increases in cyclic AMP levels.5. At submaximal concentration, D600 (10(-7) M) caused partial inhibition of high-K(+)-stimulated Ca(2+) influx and produced relaxation. However, unlike Ro 20-1724, it did not potentiate isoprenaline-induced Ca(2+) influx inhibition and relaxation. D600 does not increase cyclic AMP levels in smooth muscle.6. Dibutyryl cyclic AMP (1 mM), a lipid-soluble analogue of cyclic AMP, caused relaxation and inhibited high-K(+)-stimulated Ca(2+) influx.7. Isoprenaline failed to cause stimulation of Ca(2+) efflux in high-K(+)-depolarized rabbit aorta.8. It is concluded that the inhibition of Ca(2+) influx may be one of the mechanisms by which beta-receptor stimulation can reduce intracellular free Ca(2+) to promote relaxation of smooth muscle. The data support the involvement of cyclic AMP in this action of the beta-agonist.9. Since the experiments were conducted in 145 mM-K(+) (0 Na(+)) depolarizing conditions, the role of hyperpolarization or of a Na(+)-Ca(2+) exchange mechanism in isoprenaline-induced Ca(2+) influx inhibition and/or relaxation can be excluded.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1991

Ca2+ channel currents in rat sensory neurones: interaction between guanine nucleotides, cyclic AMP and Ca2+ channel ligands.

1. The characteristics have been examined of the high threshold calcium channel current in cultured rat dorsal root ganglion (DRG) neurones recorded in the presence of guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S; 200 microM in the patch pipette). This current, termed IBa, GTP gamma S, was slowly activating and showed little inactivation over 100 ms. 2. External application of forskolin (10 microM) to elevate internal cyclic AMP levels increased the amplitude of IBa, GTP gamma S whereas it had no effect on the control IBa. This cyclic AMP-dependent protein kinase (PKI; 25 microM). 3. The cyclic AMP-dependent phosphorylation induced enhancement of IBa, GTP gamma S was voltage dependent and either did not occur or was observed only transiently at a holding potential (VH) of -30 mV. The forskolin-stimulated enhancement seen at VH -80 mV was lost with a t1/2 of about 1 min when VH was depolarized to -30 mV. Cholera toxin pre-treatment also increased the amplitude of IBa, GTP gamma S at VH -80 mV but not at VH -30 mV. 4. The calcium channel antagonist (-)-202-791 (5 microM) increased the amplitude of IBa, GTP gamma S when applied at VH -80 mV, but either not, or only transiently, at VH -30 mV, as previously observed. This 'agonist' effect of (-)-202-791 was prevented by PKI and was occluded by prior enhancement of IBa, GTP gamma S with forskolin. (-)-202-791 did not increase cyclic AMP levels in DRG neurones. 5. The 'agonist' response of IBa, GTP gamma S to D600 (10 microM) was also occluded by application of forskolin (10 microM) in the patch pipette. Forskolin alone, applied in this manner, increased IBa, GTP gamma S to a similar extent to D600 applied alone. 6. The agonist effect of (+)-202-791 (5 microM) on IBa, GTP gamma S was not prevented by prior enhancement with forskolin, nor was it prevented by PKI. 7. In conclusion, internal GTP gamma S activates G proteins which may interact directly with calcium channels to influence the kinetics of activation and to reduce steady-state inactivation of the channels. There is also an indirect effect on the generation of second messengers such as cyclic AMP. It is likely that forskolin enhances IBa, GTP gamma S by increasing activated Gs coupling to adenylyl cyclase and increasing cyclic AMP generation. The mechanism of action of (-)-202-791 to enhance IBa, GTP gamma S also involves cyclic AMP-dependent phosphorylation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Cyclic AMP-and beta-agonist-activated chloride conductance of a toad skin epithelium.

1. The control by intracellular cyclic AMP and beta-adrenergic stimulation of chloride conductance was studied in toad skin epithelium mounted in a chamber on the stage of an upright microscope. Impalement of identified principal cells from the serosal side with single-barrelled conventional or double-barrelled Cl(-)-sensitive microelectrodes was performed at x500 magnification. For blocking the active sodium current 50 microM-amiloride was present in the mucosal bath. 2. When clamped at transepithelial potential difference V = 0 mV, the preparations generated clamping currents of 0.9 +/- 1 microA/cm2 (mean +/- S.E.M.; number of observations n = 55). The intracellular potential of principal cells (Vb) was -96 +/- 2 mV with a fractional resistance of the basolateral membrane (fRb) of 0.016 +/- 0.003 (n = 54), and an intracellular Cl- activity of 40 +/- 2 mM (n = 24). 3. At V = 0 mV, serosal application of a cyclic AMP analogue, dibutyryl cyclic AMP (500 microM) or a beta-adrenergic agonist, isoprenaline (5 microM) resulted in a sixfold increase in transepithelial Cl- conductance identified by standard 36Cl- tracer technique. 4. The clamping current at V = 0 mV was unaffected by cyclic AMP (short-circuit current Isc = 0.1 +/- 0.3 microA/cm2, n = 16) indicating that subepidermal Cl(-)-secreting glands are not functioning in our preparations obtained by collagenase treatment. 5. Cyclic AMP- or isoprenaline-induced chloride conductance (Gcl) activation (V = 0 mV) was not reflected in membrane potential and intracellular Cl- activity in principal cells. Intracellular chloride activity was constant at approximately 40 mM at membrane potentials between -90 and -100 mV. Therefore, it can be concluded that the principal cells are not contributing to activated Cl- currents. 6. At V = -100 mV where the voltage-dependent chloride conductance of mitochondria-rich (MR) cells was already fully activated, GCl was unaffected by cyclic AMP or isoprenaline. The major effect of these treatments was a rightward displacement of the MR cell-generated GCl-V relationship along the V axis. 7. Our results indicate that the beta-adrenergically controlled cyclic AMP-mediated chloride conductance is localized to the mitochondria-rich cells.

Animals↗
PubMed1993

Cyclic AMP mediates inhibition of the Na(+)-K+ electrogenic pump by serotonin in tactile sensory neurones of the leech.

1. Serotonin (5-HT) reduced the after-hyperpolarization (AHP) amplitude in tactile sensory neurones (T) but not in pressor (P) or nociceptive (N) cells of the leech. 2. Adenylate cyclase activators, phosphodiesterase inhibitors and membrane permeant analogues of cyclic adenosine monophosphate (cyclic AMP) mimicked the effect of 5-HT in reducing the AHP amplitude in T neurones. 3. Ionophoretic injection of cyclic AMP in T cells reduced the AHP amplitude, while cyclic guanosine monophosphate (cyclic GMP) or adenosine-5'-monophosphate (AMP) were without effect. 4. Inhibition of adenylate cyclase by the drug RMI 12330A (also known as MDL 12330A) suggested that 5-HT reduced the AHP amplitude through cyclic AMP. 5. 8-Bromoadenosine-3'-5'-cyclic monophosphate (8-Br-cyclic AMP) was still able to reduce the AHP amplitude after blocking the Ca(2+)-activated K+ conductance with CdCl2 and converted the normal hyperpolarization which follows the intracellular injection of Na+ into a depolarization. In addition, the cyclic AMP analogue slowed down and reduced the repolarization usually induced by CsCl after perfusion with K(+)-free solution. It is proposed that, in T sensory neurones, cyclic AMP mediates the inhibition of the Na(+)-K+ electrogenic pump induced by 5-HT application.

1-Methyl-3-isobutylxanthine↗
PubMed2003

Ecto-AMP deaminase blunts the ATP-derived adenosine A2A receptor facilitation of acetylcholine release at rat motor nerve endings.

At synapses, ATP is released and metabolised through ecto-nucleotidases forming adenosine, which modulates neurotransmitter release through inhibitory A1 or facilitatory A2A receptors, according to the amounts of extracellular adenosine. Neuromuscular junctions possess an ecto-AMP deaminase that can dissociate extracellular ATP catabolism from adenosine formation. In this study we have investigated the pattern of ATP release and its conversion into adenosine, to probe the role of ecto-AMP deaminase in controlling acetylcholine release from rat phrenic nerve terminals. Nerve-evoked ATP release was 28 +/- 12 pmol (mg tissue)-1 at 1 Hz, 54 +/- 3 pmol (mg tissue)-1 at 5 Hz and disproportionally higher at 50 Hz (324 +/- 23 pmol (mg tissue)-1). Extracellular ATP (30 microM) was metabolised with a half time of 8 +/- 2 min, being converted into ADP then into AMP. AMP was either dephosphorylated into adenosine by ecto-5'-nucleotidase (inhibited by ATP and blocked by 200 microM alpha,beta-methylene ADP) or deaminated into IMP by ecto-AMP deaminase (inhibited by 200 microM deoxycoformycin, which increased adenosine formation). Dephosphorylation and deamination pathways also catabolised endogenously released adenine nucleotides, since the nerve-evoked extracellular AMP accumulation was increased by either alpha,beta-methylene ADP (200 microM) or deoxycoformycin (200 microM). In the presence of nitrobenzylthioinosine (30 microM) to inhibit adenosine transport, deoxycoformycin (200 microM) facilitated nerve-evoked [3H]acetylcholine release by 77 +/- 9 %, an effect prevented by the A2A receptor antagonist, ZM 241385 (10 nM). It is concluded that, while ecto-5'-nucleotidase is inhibited by released ATP, ecto-AMP deaminase activity transiently blunts adenosine formation, which would otherwise reach levels high enough to activate facilitatory A2A receptors on motor nerve terminals.

AMP Deaminase↗
PubMed1982

Cellular levels, excretion, and synthesis rates of cyclic AMP in Escherichia coli grown in continuous culture.

Changes in dilution rate did not elicit large and systematic changes in cellular cyclic AMP levels in Escherichia coli grown in a chemostat under carbon or phosphate limitation. However, the technical difficulties of measuring low levels of cellular cyclic AMP in the presence of a large background of extracellular cyclic AMP precluded firm conclusions in this point. The net rate of cyclic AMP synthesis increased exponentially with increasing dilution rate through either the entire range of dilution rates examined (phosphate limitation) or a substantial part of the range (lactose and glucose limitations). Thus, it is probable that growth rate regulates the synthesis of adenylate cyclase. The maximum rate of net cyclic AMP synthesis was greater under lactose than under glucose limitation, which is consistent with the notion that the uptake of phosphotransferase sugars is more inhibitory to adenylate cyclase than the uptake of other carbon substrates. Phosphate-limited cultures exhibited the lowest rate of net cyclic AMP synthesis, which could be due to the role of phosphorylated metabolites in the regulation of adenylate cyclase activity. Under all growth conditions examined, greater than 99.9% of the cyclic AMP synthesized was found in the culture medium. The function of this excretion, which consumed up to 9% of the total energy available to the cell and which evidently resulted from elaborate regulatory mechanisms, remains entirely unknown.

Adenosine Triphosphate↗
PubMed1988

mRNA decay rates in late-developing Dictyostelium discoideum cells are heterogeneous, and cyclic AMP does not act directly to stabilize cell-type-specific mRNAs.

We reevaluated the use of 32PO4 pulse-chases for analyzing mRNA decay rates in late-developing Dictyostelium cells. We found that completely effective PO4 chases could not be obtained in developing cells and that, as a consequence, the decay rates exhibited by some mRNAs were influenced by the rates at which they were transcribed. In developing cells disaggregated in the presence of cyclic AMP, the poly(A)+ mRNA population turned over with an apparent half-life of 4 h, individual mRNA decay rates were heterogeneous, and some prestalk and prespore mRNAs appeared to decay with biphasic kinetics. In cells disaggregated in the absence of cyclic AMP, all prestalk and prespore mRNAs decayed with biphasic kinetics. During the first 1 to 1.5 h after disaggregation in the absence of cyclic AMP, the cell-type-specific mRNAs were selectively degraded, decaying with half-lives of 20 to 30 min; thereafter, the residual prestalk and prespore mRNA molecules decayed at rates that were similar to those measured in the presence of cyclic AMP. This short-term labilization of cell-type-specific mRNAs was observed even for those species not requiring cyclic AMP for their accumulation in developing cells. The observation that cell-type specific mRNAs can decay at similar rates in disaggregated cells with or without cyclic AMP indicates that this compound does not act directly to stabilize prestalk and prespore mRNAs during development and that its primary role in the maintenance of cyclic-AMP-dependent mRNAs is likely to be transcriptional.

Cell Aggregation↗
PubMed1977

Nonshivering thermogenesis in the rat. I. The relation between drug-induced changes in thermogenesis and changes in the concentration of plasma cyclic AMP.

Barbital-sedated, cold-acclimated (CA) or warm-acclimated (WA) rats were given different doses and combinations of noradrenaline, theophylline, and the adrenergic-blocking agents propranolol and phentolamine, to stimulate or inhibit calorigenesis in various ways. To see whether the effects of these drugs on calorigenesis could be ascribed to effects on the adenylate cyclase (EC 4.6.1.1) - cyclic AMP system, and to try to assess thereby the significance of this system in the regulation of nonshivering thermogenesis (NST), changes in the concentration of plasma cyclic AMP were measured as an index (Broadus, A.E., Hardman, J.G., Kaminsky, N. I., Ball, J. H., Sutherland, E.W., and Liddle, G. W.: 1971. Ann. N.Y. Acad. Sci. 185, 50-60) of changes in tissue levels of cyclic AMP. In CA rats, which have a severalfold greater capacity for NST than WA rats, calorigenic responses to noradrenaline, theophylline, noradrenaline plus theophylline, or phentolamine plus theophylline were as much as four times larger than in WA rats, However, the changes in level of plasma cyclic AMP produced by each of these and other treatments were virtually the same for both groups. It would appear, therefore, that the difference between WA and CA rats in ability to produce heat by NST is not a function of the amplitude of changes in tissue levels of cyclic AMP. Nevertheless, it was also observed, and was particularly striking in CA rats, that when a drug or combination of drugs had a stimulatory, inhibitory, or synergistic effect on calorigenesis, it had a similar effect with respect to elevation of plasma cyclic AMP. Altogether, the results indicate that adenylate cyclase and cyclic AMP are likely to be participants in the regulation of NST in the rat, but that they would be subservient in this regard to whatever factors are responsible for acclimation-related differences in capacity for NST.

Animals↗