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At least 811 records · Page 45Linked to original sources
PubMed1979

Activation of cyclic AMP-dependent protein kinase and stimulation of protein phosphorylation in response to adenosine in C-1300 murine neuroblastoma.

DEAE-cellulose chromatography of the 20,000g supernatant fraction of homogenates of C-1300 murine neuroblastoma (clone N2a) yields one major and two minor peaks of cyclic AMP-dependent protein kinase activity. Assessment of the endogenous activation state of the enzyme(s) reveals that the enzyme is fully activated by the treatment of whole cells with adenosine (10 microM) in the presence of the phosphodiesterase inhibitor Ro 20 1724 (0.7 mM). This treatment produces a large elevation in the cyclic AMP content of the cells. The treatment of whole cells with adenosine alone (1-100 microM) or Ro 20 1724 alone (0.1-0.7 mM) produces minimal elevations in cyclic AMP but nevertheless causes significant activations of cyclic AMP-dependent protein kinase. The autophosphorylation of whole homogenates of treated and untreated cells was studied using [gamma-32P] ATP, sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography. Treatments which activate cyclic AMP-dependent protein kinase selectively stimulate the incorporation of 32P into several proteins. This stimulation is most prominent in the 15,000-dalton protein band. The addition of cyclic AMP to phosphorylation reactions containing homogenate of untreated cells stimulates the phosphorylation of the same protein bands. These results indicate that adenosine may have regulatory functions through its effect on the cyclic AMP:cyclic AMP-dependent protein kinase system.

4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
PubMed1986

Caffeine effects on cyclic AMP levels in the mouse embryonic limb and palate in vitro.

Caffeine is a teratogen that causes limb and palate malformations in rodents. Since the ability to raise cyclic nucleotide levels is a known biological action of caffeine, cyclic AMP levels were measured in CD-1 mouse embryonic forelimb from whole embryo culture and embryonic limb and palate cells grown in primary culture following treatment with various concentrations of caffeine (0, 1, 3, or 10 mM). In forelimb buds from whole embryo culture, a dose-dependent response was observed. Caffeine at 1 mM concentration stimulated cyclic AMP levels to 151% of control value at 60 min. Even greater stimulation of cyclic AMP occurred at higher caffeine concentrations. A dose-dependent response was seen in both limb and palate cell culture. In limb cell culture, all caffeine concentrations significantly stimulated cyclic AMP after 10 min compared to control. In palate cell culture, there was a twofold increase in cyclic AMP at the 1-mM caffeine concentration. At higher caffeine concentrations, cyclic AMP was significantly increased after 60 min. In addition, stimulation of cyclic AMP in cultured limb and palate cells by isoproterenol, a beta-adrenergic agonist, was used as a positive control. Isoproterenol stimulated a 2.5-fold greater response in the palate cells than in the limb bud cells at isoproterenol levels of 10(-5) or 10(-4) M. The increase of cyclic AMP may be influential in the process of abnormal limb or palate development.

Animals↗
PubMed1993

Stimulation of calcium influx and calcium cascade by cyclic AMP in cultured carrot cells.

Treatment of cultured carrot (Daucus carota L.) cells with activators of adenylate cyclase, forskolin, and cholera toxin induced the biosynthesis of an antifungal isocoumarin, 6-methoxymellein, in the cells. Addition of dibutyryl cyclic AMP to carrot cell culture also stimulated the accumulation of the compound. The cyclic AMP-evoked 6-methoxymellein production was significantly depressed in the presence of certain inhibitors of calcium cascade such as Ca2+ channel blockers and inhibitors of calmodulin-dependent processes. In dibutyryl cyclic AMP- and forskolin-treated carrot cells, increase in cytosolic Ca2+ concentration was observed as monitored by the fluorescent calcium indicator fluo-3. Cyclic AMP-dependent Ca2+ influx into carrot cells was also confirmed with Ca(2+)-loaded vesicles prepared from the plasma membrane-rich fraction of the cells. Transient increase in Ca(2+)- and Ca2+/calmodulin-dependent protein kinase activity but not cyclic AMP-dependent protein phosphorylation was detected in the cells of high cyclic AMP concentration. Results obtained in the present work suggest that the increase in cyclic AMP content in carrot cells induces Ca2+ influx across plasma membrane without activating cyclic AMP-dependent protein kinase which, then, stimulates calcium cascade in the cells.

Adenylyl Cyclases↗
PubMed1987

Dopamine D-2 receptors inhibit D-1 stimulated cyclic AMP accumulation in striatum but not limbic forebrain.

The effect of dopamine D-2 receptor activation on dopamine D-1 stimulated cyclic AMP accumulation was investigated in slices of rat striatum and limbic forebrain (nucleus accumbens and tuberculum olfactorium). In striatal slices the dose-dependent increase in cyclic AMP accumulation due to dopamine (3-100 mumol/l) was enhanced by selective D-2 receptor blockade using (-)-sulpiride (30 mumol/l). In limbic slices the increase in cyclic AMP due to dopamine (3-50 mumol/l) was unaffected by selective D-2 receptor blockade. The enhancement of cyclic AMP accumulation due to the selective D-1 agonist SKF 38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; 1 mumol/l) in striatal slices was attenuated in the presence of the selective D-2 receptor agonist LY 171555 (quinpirole hydrochloride; 10 mumol/l). This attenuation was in turn blocked by (-)-sulpiride (10 mumol/l). In limbic slices LY 171555 (10 mumol/l) had no effect on SKF 38393 (1 mumol/l) stimulated cyclic AMP accumulation. Conversely muscarine receptor activation, using carbachol (10 mumol/l), attenuated D-1 stimulated cyclic AMP accumulation in both striatum and limbic forebrain. Dopamine D-2 or muscarine receptor stimulation in either striatal or limbic slices did not attenuate cyclic AMP accumulation due to VIP (vasoactive intestinal polypeptide; 0.5 mumol/l), isoprenaline (10 mumol/l) or 2-chloroadenosine (100 mumol/l). This suggests that in striatal slices, D-2 receptors mediate a selective inhibition of D-1 stimulated cyclic AMP accumulation, but that in the limbic forebrain D-2 receptors are unlikely to be coupled to D-1 receptor-linked adenylate cyclase. These data indicate a fundamental difference in the properties of D-2 receptor-effector coupling in these brain regions.

1-Methyl-3-isobutylxanthine↗
PubMed2000

Cyclic GMP attenuates cyclic AMP-stimulated inotropy and oxygen consumption in control and hypertrophic hearts.

We tested the hypothesis that increasing myocardial cyclic GMP would attenuate cyclic AMP induced positive inotropy and O2 consumption, in part, through changes in cyclic AMP and that renal hypertension-induced cardiac hypertrophy (HYP) would alter this relationship. Anesthetized, open chest rabbits (N = 48) were divided into four groups of control (CON) and HYP animals which received vehicle (VEH), isoproterenol 10(-6)M (ISO), 3-morpholinosyndnonimine 10(-4)M, (SIN-1), or a combination of ISO+SIN-1. Coronary blood flow (microspheres) and O2 extraction (microspectrophotometry) were used to determine O2 consumption in both subepicardium (EPI) and subendocardium (ENDO). Left ventricular change in wall thickness (%) was increased significantly by ISO in both CON (16 +/- 4 to 31 +/- 6) and HYP (17 +/- 2 to 24 +/- 3). Percent change in wall thickness was similar in the CON, SIN-1, and ISO+SIN-1 groups. Myocardial O2 consumption (ml O2/min/100 g) was increased by ISO in CON (10.3 +/- 1.0 to 13.6 +/- 2.0 EPI; 10.9 +/- 1.0 17.1 +/- 1.7 ENDO) and HYP (8.2 +/- 1.4 to 12.3 +/- 2.2 EPI; 6.6 +/- 1.4 to 14.8 +/- 1.8 ENDO). Oxygen consumption was unaffected by SIN-1 in CON and HYP animals. ISO+SIN-1 caused attenuated ISO-induced increases in O2 consumption in CON in EPI and ENDO, and in EPI in HYP. Cyclic GMP (pmol/g) was unchanged by ISO in CON and HYP, and increased by SIN-1 in CON (8.1 +/- 1.3 to 19.2 +/- 2.3 EPI) and HYP (9.1 +/- 1.5 to 12.8 +/- 2.0 EPI). Cyclic GMP remained elevated with ISO+SIN-1 in both groups. Cyclic AMP (pmol/g) was increased significantly by ISO in CON (496 +/- 43 to 725 +/- 106 EPI; 534 +/- 44 to 756 +/- 148 ENDO) and insignificantly in HYP (435 +/- 50 to 566 +/- 35 EPI; 497 +/- 51 to 583 +/- 47 ENDO). Cyclic AMP levels were unaffected by SIN-1 in either group. Isoproterenol induced increases in cyclic AMP were blunted by ISO+SIN-1 in CON (496 +/- 43 to 537 +/- 59 EPI) and not affected in HYP. The current study demonstrated attenuation of cyclic AMP mediated increased inotropy and O2 consumption by increasing cyclic GMP, which appeared, in part, related to cyclic GMP-induced reduction in cyclic AMP. This effect of cyclic GMP on cyclic AMP was not observed in myocardial hypertrophy.

Animals↗
PubMed1981

Membrane localization of myocardial type II cyclic AMP-dependent protein kinase activity.

Crude cardiac membrane vesicles were separated into subfractions of sarcolemma and sarcoplasmic reticulum. The subfractions were used to determine the origin and type of cyclic AMP-dependent protein kinase activity present in myocardial membranes. A cyclic AMP-binding protein of molecular weight 55,000 was covalently labeled with the photoaffinity probe 8-azido adenosine 3',5'-mono[32P]phosphate, and found to copurify with the (Na+ + K+)-ATPase activity of sarcolemma, and away from the (Ca2+ + K+)-ATPase activity of sarcoplasmic reticulum. Endogenous cyclic AMP-dependent protein kinase activity also copurified with sarcolemma. Protein substrates phosphorylated by cyclic AMP-dependent protein kinase activity had apparent molecular weights of 21,000 and 8000 and were present in both sarcolemma and sarcoplasmic reticulum. However, while addition of cyclic AMP alone resulted in phosphorylation of sarcolemma proteins, both cyclic AMP and exogenous, soluble cyclic AMP-dependent kinase were required for phosphorylation of sarcoplasmic reticulum proteins. Addition of the calcium-binding protein, calmodulin, to either sarcolemma or sarcoplasmic reticulum resulted in phosphorylation of the 21,000 and 8000-dalton proteins, as well. The results suggest that cardiac sarcolemma contains an intrinsic type II cyclic AMP-dependent protein kinase activity that is not present in sarcoplasmic reticulum. On the other hand, Ca2+- and calmodulin-dependent protein kinase activity is present in both sarcolemma and sarcoplasmic reticulum.

Adenosine Triphosphatases↗
PubMed1978

Protein activator of cyclic AMP phosphodiesterase and cyclic nucleotide phosphodiesterase in bovine retina and bovine lens. Activity, subcellular distribution and kinetic parameters.

We have examined the activity of cyclic AMP phosphodiesterase, cyclic GMP phosphodiesterase and the protein activator of cyclic AMP phosphodiesterase in various anatomic and subcellular fractions of the bovine eye. Cyclic GMP hydrolysis was 1.6--12 times faster than hydrolysis of cyclic AMP in the subcellular fractions of the retina and in the precipitate of the rod outer segment. An opposite pattern was seen in the bovine lens, where the hyrolysis of cyclic AMP occurred 17 and 169 times faster than that of cyclic GMP in the supernatant and precipitate of lens, respectively. The activity of cyclic AMP phosphodiesterase was not affected by ethylene-glycol bis(beta-aminoethylether)-N,N'-tetraacetic acid in any fractions except in the retinal supernatant, suggesting that the phosphodiesterase exists primarily as a Ca2+-independent, activator-independent form. However, the protein activator of cyclic AMP phosphodiesterase existed in all fractions examine. A complex kinetic patternwas observed for both cyclic AMP and cyllic GMP hydrolysis by the 105000 times g lens supernatant. The Michaelis constants for both cyclic AMP (1.3-10(-6) and 9.I-10(-6) M) and cyclic GMP (1.04-10(6) AND 1.22 10(-5) M) appeared to be similar.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1979

Negative homotropic cooperativity in rat muscle AMP deaminase. A kinetic study on the inhibition of the enzyme by ATP.

1. Rat skeletal muscle AMP deaminase (AMP aminohydrolase, EC 3.5.4.6) at optimal KCl concentrations shows a biphasic response to increasing levels of the allosteric inhibitor ATP. 2. Up to 10 micrometer, ATP appears to convert the enzyme to a form exhibiting sigmoidal kinetics while at higher concentrations its inhibitory effect is manifested by an alteration of AMP binding to AMP deaminase indicative of negative homotropic cooperativity at about 50% saturation. 3. AMP deaminase is inactivated by incubation with the periodate oxidation product of ATP. The (oxidized ATP)--AMP deaminase complex stabilized by NaBH4 reduction shows kinetic properties similar to those of the native enzyme in the presence of high ATP concentrations. 4. A plausible explanation of the observed cooperativity is that ATP induces different conformational state of AMP deaminase subunits, causing the substrate to follow a sequential mechanism of binding to enzyme. 5. Binding of the radioactive oxidized ATP shows that 3.2 mol of this reagent bind per mol AMP deaminase.

AMP Deaminase↗
PubMed1982

Differential effects of various phosphodiesterase inhibitors, pyrimidine and purine compounds, and inorganic phosphates on cyclic CMP, cyclic AMP and cyclic GMP phosphodiesterases.

The effects of various compounds on homogeneous cyclic CMP phosphodiesterase (cyclic CMP-PDE) from pig liver were compared with the effects on cyclic AMP phosphodiesterase (cyclic AMP-PDE) and cyclic GMP phosphodiesterase (cyclic GMP-PDE). Of the conventional inhibitors for AMP-PDE and cyclic GMP-PDE, only Sch 15280 was found to inhibit cyclic CMP-PDE. Nucleoside monophosphates, orthophosphate, and 2':3'-cyclic nucleotides were rather specific and were more effective in inhibiting cyclic CMP-PDE, compared to their effects on cyclic AMP-PDE and cyclic GMP-PDE. On the other hand, nucleoside di-and triphosphates and pyrophosphate (PPi) were less effective in inhibiting cyclic CMP-PDE and were without marked effect on cyclic AMP-PDE and cyclic GMP-PDE. Orthophosphate (Pi) was more potent than CMP, CDP and CTP in inhibiting cyclic CMP-PDE, with a rank order of inhibitory potency of Pi greater than CMP greater than CDP greater than CTP. Of the 3' :5'-cyclic nucleotides examined, cyclic UMP was more specific in inhibiting cyclic CMP-PDE compared to its effect on cyclic AMP-PDE and cyclic GMP-PDE. In all experiments similar results were obtained when either cyclic CMP or cyclic AMP was used as a substrate for this multifunctional cyclic CMP-PDE, supporting the contention that a single catalytic site on the enzyme is responsible for the hydrolysis of both cyclic CMP and cyclic AMP. The present studies further support our original suggestion that cyclic CMP-PDE is a unique enzyme that is distinguishable from the conventional enzymes for purine cyclic nucleotides.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗
PubMed1988

The role of cyclic-AMP in the regulation of steroid metabolism in isolated rat hepatocytes.

In vivo experiments have shown that hepatic steroid metabolism is under hormonal control but the intracellular mechanism of action of the hormones has been little studied. One pathway of hormone action known to be active in the liver is the alteration of cyclic-AMP levels. To investigate the role played by cyclic-AMP in the control of hepatic steroid metabolism, we raised intracellular cyclic-AMP by a number of methods and studied the resultant changes in the metabolism of androst-4-ene-3,17-dione after various periods of time. Results indicate that cyclic-AMP levels are raised to their maximal levels (2-20-fold stimulation) 2-20 min following the additions but that the effects on steroid metabolism were seen later and depended on the initial change in cyclic-AMP levels. At lower rises in cyclic-AMP (up to 5-fold stimulation), a marked inhibition of steroid metabolism is seen at 1/2-1 hr post-treatment, whereas at higher stimulations of cyclic-AMP (greater than 10-fold stimulation), a significant stimulation of steroid metabolism is observed at later time periods (after 1 hr), sometimes following a slight inhibition at 1/2 hr. This indicates that acute rises in intracellular cyclic-AMP produced by hormonal stimulation may play a role in regulating steroid metabolism in the rat liver both in an inhibitory and a stimulatory direction.

1-Methyl-3-isobutylxanthine↗
PubMed1985

Differential effects of selective and non-selective neuroleptics on intracellular and extracellular cyclic AMP accumulation in rat striatal slices.

Cyclic AMP was measured in both striatal slices and in the incubation medium after exposure to dopamine and dopamine antagonist. Dopamine increased cyclic AMP in both tissue and medium. The effect of dopamine was enhanced by sulpiride and domperidone, and to a lesser extent by haloperidol, but alpha-fluphenthixol had only an inhibitory effect. The enhancement by sulpiride was stereoselective and totally suppressed by the D1 antagonist SCH 23390. Cyclic AMP in the medium provided the more sensitive measure of drug effect and increased linearly for up to 20 min., whereas the nucleotide in tissue remained stable or declined after 10 min. It is concluded that: the increase in dopamine-stimulated cyclic AMP efflux caused by D2 antagonists reflects increased intracellular cyclic AMP accumulation rather than an effect on the efflux mechanism; dopamine enhances cyclic AMP accumulation via a D1 receptor, and simultaneously inhibits it through a D2 receptor; and changes in D1 receptor-stimulated cyclic AMP formation in striatum may not be related to the clinical actions of neuroleptics. It remains possible that D2 receptor-mediated inhibition of cyclic AMP accumulation stimulated by a different agonist system may underlie some of the therapeutic actions of dopamine agonists and antagonists.

Animals↗
PubMed1996

Local exposure to salbutamol or Bt2 cyclic AMP inhibits pleural exudation and leukocyte influx caused by antigen in rats.

The local effect of salbutamol and N6,2'-O-dibutyryl adenosine 3':5'-cyclic monophosphate (Bt2 cyclic AMP) on the rat pleural inflammation caused by allergen was investigated. Antigen (ovalbumin, 12 micrograms/cavity) intrathoracically administered to immunized rats led to a marked pleural protein extravasation and leukocyte infiltration, as attested by the quantification of protein and enumeration of leukocytes recovered from the pleural cavity. Salbutamol (10-40 micrograms/cavity) and the cell-permeable cyclic AMP analogue, Bt2 cyclic AMP (20-160 micrograms/cavity), injected 1 h and 5 min before the antigen, respectively, inhibited the exudation occurring within 30 min, and neutrophil and eosinophil accumulation occurring 4 and 24 h, respectively. The late eosinophilia was also markedly attenuated by salbutamol administered 10 min post-challenge, when mast cells had already been degranulated. Pretreatment with the beta-adrenoceptor antagonist propranolol (1 mg/kg, i.v.) failed to modify the inhibitory effect of Bt2 cyclic AMP, but abolished the blockade caused by salbutamol of leukocyte infiltration under conditions where the salbutamol anti-exudatory activity was impaired to about 80%. In another set of experiments, salbutamol (20 and 40 micrograms/cavity) markedly inhibited the exudation caused by histamine and 5-hydroxytryptamine (5-HT) which, though to a lesser extent, was also sensitive to Bt2 cyclic AMP (80 micrograms/cavity). As observed with allergic pleurisy, propranolol impaired the inhibition by salbutamol of histamine- and 5-HT-induced exudation, whereas the Bt2 cyclic AMP inhibition was not affected. We conclude that salbutamol and Bt2 cyclic AMP share the ability to inhibit pleural exudation and leukocyte recruitment caused by allergen in immunized rats, suggesting that the anti-inflammatory effect of salbutamol may be mediated by a cyclic AMP signaling pathway, probably via beta 2-adrenoceptor activation.

Adrenergic beta-Agonists↗
PubMed1976

Mechanism of inhibition of organic acid transport in rabbit renal cortex by cyclic AMP.

The mechanism by which isoproterenol and cyclic AMP inhibit organic acid transport was examined. Accumulation of 131I-Hippuran (S/M) was used as an index of organic acid transport. Propranolol, an antagonist of isoproterenol's beta-adrenergic response, not only inhibited accumulation of Hippuran but, when combined with isoproterenol, caused further inhibition. PTH elicited larger increases than isoproterenol in cortical-slice cyclic AMP content but did not inhibit accumulation of Hippuran. This lack of correlation between a positive effect on the adenylate-cyclase-cyclic AMP system and inhibition of transport was also seen when other agents were tested. Cyclic GMP, which has been postulated to work in opposition to cyclic AMP, was as potent as cyclic AMP in decreasing S/M. The decreasing of S/M by adenine and uric acid could not be related to any known effect of these agents on tissue cyclic AMP content. Similarly, although 0.1 mM theophylline significantly decreased S/M, cortical cyclic-AMP content was not increased until a 100-fold greater concentration of theophylline was employed. The data suggest that the inhibitory effect of these agents was attributable to their molecular configurations, which interact directly with the organic acid transport system rather than indirectly via the adenylate-cyclase-cyclic AMP system.

Adenine↗
PubMed1985

Effect of alkaline cations on cyclic 3' 5'-AMP stimulated lipolysis in rat adipocytes.

In Krebs-Ringer phosphate medium, cyclic AMP had little effect on production of free fatty acids by fat cells in vitro, whereas dibutyryl cyclic AMP or epinephrine stimulated the production of free fatty acids. On the other hand, although under non-physiological condition, cyclic AMP was found to stimulate the lipolysis in simple KCl-Tris medium. The stimulation level was similar to that elicited by dibutyryl cyclic AMP. Cyclic AMP also stimulated lipolysis in LiCl-Tris or RbCl-Tris medium, but not in NaCl-Tris medium. In KCl-Tris medium, addition of divalent alkaline cations (Mg2+, Ca2+ and Sr2+, at 40 mM) completely inhibited the stimulation by cyclic AMP, but not those by dibutyryl cyclic AMP and epinephrine. No cyclic AMP-induced lipolysis was observed in homogenized or freeze-thawed cells.

Adipose Tissue↗
PubMed1977

Disruption of multicellular organization in the cellular slime molds by cyclic AMP.

Addition of cyclic AMP causes disorder in the multicellular stage of a number of species of cellular slime molds. In those which produce fruits with cellular stalks, the addition of cyclic AMP stimulates prestalk cells to differentiate into mature stalk cells. Prespore cells do not differentiate into spores under the influence of cyclic AMP, most degenerate and seem to die. I hypothesize that the normal course of differentiation from vegetative cells is one leading to spores, but that cyclic AMP can divert this course to one leading to the stalk cell. Dibutyryl cyclic AMP, cyclic GMP and cyclic AMP disrupt slugs of Polysphondylium pallidum, while species of Dictyostelium are disrupted by only cyclic AMP. The multicellular stage of P. violaceum is unaffected by high concentrations of exogenous cyclic nucleotides. Cell organization of Acytostelium ellipticum, a species with an acellular stalk, was disrupted by cyclic AMP, but no stalk cells were formed; only spores.

Adenine Nucleotides↗
PubMed1977

Cyclic AMP and platelet prostaglandin synthesis.

The present study has investigated the influence of agents which elevate intracellular levels of endogenous platelet adenosine 3'5'-cyclic monophosphate (cyclic AMP), and the effect of the exogenous cyclic AMP analog, dibutyryl cyclic AMP, on the conversion of 14C-arachidonic acid by washed platelets. Prostaglandin E1 (PGE1), PGE1 with theophylline, or dibutyryl cyclic AMP incubated with washed platelets prevented arachidonic acid induced platelet aggregation, but had no effect on the conversion of arachidonic acid to 12L-hydroxy-5,8,10, 14-eicosatetraenoic acid (HETE), 12L-hydroxy-5,8,10 heptadecatrienoic acid (HHT), or thromboxane B2. Ultrastructural studies of the platelet response revealed that agents acting directly or indirectly to increase the level of cyclic AMP inhibited the action of arachidonic acid on washed platelets and prevented internal platelet contraction as well as aggregation. The influence of PGE1 with theophylline, and dibutyryl cyclic AMP on the thrombin induced release of 14C-arachidonic acid from platelet membrane phospholipids was also investigated. These agents were found to be potent inhibitors of the thrombin stimulated release of arachidonic acid from platelet phospholipids, due most likely to an inhibition of platelet phospholipase A activity. The results show that dibutyryl cyclic AMP and agents which elevate intracellular cyclic AMP levels act to inhibit platelet activation at two steps 1) internal contraction and 2) release of arachidonic acid from platelet phospholipids.

Arachidonic Acids↗
PubMed1992

Stimulatory effect of vasoactive intestinal peptide (VIP) on cyclic AMP production in rat peritoneal macrophages.

Vasoactive intestinal peptide (VIP) stimulated cyclic AMP production in rat peritoneal macrophages. The stimulatory effect of VIP was dependent on time, temperature and cell concentration, and was potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). At 15 degrees C, the response occurred in the 0.1-1000 nM range of VIP concentrations. Half maximal stimulation of cellular cyclic AMP (ED50) was obtained at 1.2 +/- 0.5 nM VIP, and maximal stimulation (about 3-fold basal level) was obtained between 100-1000 nM. The cyclic AMP system of rat peritoneal macrophages showed a high specificity for VIP. The order of potency observed in inducing cyclic AMP production was VIP greater than rGRF greater than hGRF greater than PHI greater than secretin. Glucagon, insulin, pancreastatin and octapeptide of cholecystokinin did not modify cyclic AMP levels at concentrations as high as 1 microM. The beta-adrenergic agonist isoproterenol increased the cyclic AMP production and show additive effect with VIP. Somatostatin inhibits the accumulation of cyclic AMP in the presence of both vasoactive intestinal peptide and isoproterenol. The finding of a VIP-stimulated cyclic AMP system in rat peritoneal macrophages, together with the previous characterization of high-affinity receptors for VIP in the same cell preparation, strongly suggest that VIP may be involved in the regulation of macrophage function.

1-Methyl-3-isobutylxanthine↗
PubMed1988

Evidence of cyclic AMP-independent action of glucagon on calcium mobilization in rat hepatocytes.

Glucagon increases the cytoplasmic free calcium concentration as measured by aequorin bioluminescence. It has been proposed by Wakelam et al. (Nature 323 (1986) 68-71) that low concentrations of glucagon mobilize calcium from an intracellular pool by causing polyphosphoinositide breakdown. To identify whether cyclic AMP mediates changes in the cytoplasmic free calcium concentration ([Ca2+]c) induced by glucagon, the effects of forskolin and exogenous cyclic AMP on [Ca2+]c were compared with that of glucagon in aequorin-loaded hepatocytes. Although the magnitudes of the [Ca2+]c responses to 250 microM forskolin and 1 mM 8-bromo cyclic AMP were identical to that of 5 nM glucagon, these two agents induced a more prolonged elevation of [Ca2+]c. Glucagon-induced elevation of [Ca2+]c was accompanied by a smaller increase in cyclic AMP than that induced by forskolin. When the cyclic AMP response to glucagon was potentiated by an inhibitor of phosphodiesterase, 3-isobutyl-1-methylxanthine, the glucagon-induced increase in [Ca2+]c was not affected. Conversely, when the cyclic AMP response to glucagon was reduced by pretreatment of the cells with angiotensin II, glucagon-induced changes in [Ca2+]c were rather enhanced. Furthermore, vasopressin potentiated glucagon-induced changes in [Ca2+]c despite the reduction of the cyclic AMP response to glucagon. In the presence of 1 microM extracellular calcium, angiotensin II did not enhance glucagon-induced changes in [Ca2+]c. These results suggest that at least part of the action of 5 nM glucagon on calcium mobilization is independent of cyclic AMP.

1-Methyl-3-isobutylxanthine↗