Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the majority of patients one of the primary features of bronchial asthma is the occurrence of nocturnal symptoms. There are significant bioperiodicities for hormonal, neural, cellular and humoral factors and for mediators, which are all in favour of reducing bronchial patency during the night. In the morning hours between 2 and 6 a.m. the histamine concentration shows a peak, the adrenaline and cyclic AMP have their minimum, while the cortisol secretion with its delayed onset of action is already ascending. The kallikrein kinin system is activated by histamine. Circadian variations have also been found for the receptor density of beta-receptors, cAMP, adenylcyclase and phosphodiesterase. While circadian rhythms are not known for the platelet activating factor (PAF) at the present time, the known nocturnal peak of thromboxane A2 may influence PAF-liberation as well. The bronchodilating metabolite of the cyclooxygenase pathway, PGE2, was found to have depressed levels during the night. Total plasma, total protein as well as IgA, IgM, IgG and IgE have a minimum during the night, cellular elements like T11-, T4-, B-lymphocytes and Leu8 have a maximum. Slow release theophylline is today the most important drug for nocturnal asthma. Theophylline is known to interfere with histamine release from mast cells, mediator release of arachidonic acid metabolites, the cyclic AMP concentration and suppressor cell activity. Important work remains to be done to clarify the therapeutic and immunological role of theophylline in nocturnal asthma and to identify the subgroups of patients having the greatest benefit of theophylline treatment.
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PMID:Biochemical and cellular basis for circadian rhythms in obstructive lung disease and implications for theophylline therapy. 305 28

Zymosan, carrageenan, arachidonic acid and platelet activating factor (PAF) were used to induce inflammation (edema) in the paws of mice. Antiinflammatory drugs (e.g., BW 755C and indomethacin) as well as cyproheptadine (mediator antagonist), theophylline (phosphodiesterase inhibitor) and guanabenz (alpha adrenoceptor agonist) showed the greatest efficacy in the carrageenan and zymosan models. Nonsteroidal antiinflammatory (NSAIDs) agents showed greater activity in the arachidonic acid (AA) paw edema model than the dual 5-lipoxygenase (LO)/cyclooxygenase (CO) inhibitors. The PAF model was insensitive to NSAIDs but showed some activity with drugs possessing inhibitory 5-LO activity (e.g., phenidone, BW 755C) and the mediator antagonist, cyproheptadine. Suramin, a complement inhibitor, as expected, was active only against zymosan-induced edema. In conclusion, the inhibitory activities of dual 5-LO/CO inhibitors and NSAIDs were not different in the zymosan, carrageenan and AA edema models in the mouse; however, some selectivity for 5-LO inhibitors was observed in the PAF model.
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PMID:Effect of selected antiinflammatory agents and other drugs on zymosan, arachidonic acid, PAF and carrageenan induced paw edema in the mouse. 312 May 10

The levels of the stable degradation products of prostacyclin (PGI2) and thromboxane A2 (TXA2): 6-oxo-prostaglandin E1 alpha (6-oxo-PGE1 alpha) and thromboxane B2 (TXB2) respectively were determined in the effluent of the rabbit epigastric skin flap after infusion of exogenous arachidonic acid. The blood to the flap passes through the microcirculation and thus the changes in eicosanoid biosynthesis in this part of the vasculature were recorded. The aim was to use inhibitors of arachidonic acid metabolism to increase the PGI2/TXA2 ratio. This may be potentially beneficial to ischaemic skin flaps by reducing platelet aggregation associated with damaged microvascular endothelium, overcoming vasospasm and increasing microvascular blood flow. Increased PGI2/TXA2 ratios (up to 5-fold) were best achieved using TXA2 synthetase inhibitors such as dazoxiben hydrochloride. These were significantly more potent than the phosphodiesterase inhibitor dipyridamole, and the lipoxygenase inhibitor Bay g6575. No increase in blood flow was achieved. The cyclooxygenase inhibitor indomethacin did slow the blood flow at high concentrations (above 10(-5) M), and inhibited both PGI2 and TXA2 synthesis. Approximately 2-fold higher concentrations of dazoxiben hydrochloride and dipyridamole were required to produce the same TXA2 synthetase inhibition in the flap microvasculature in vivo compared with platelets in vitro.
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PMID:Regulation of microvascular prostacyclin and thromboxane with inhibitors of arachidonic acid metabolism. 355 71

We determined whether cyclooxygenase or phosphodiesterase inhibition would alter the vasomotor response to acetylcholine in the dog lung. Lower left lobes were removed and then cannulated, ventilated, and pump perfused with autogenous blood at constant flow [6.0 +/- 0.1 ml X min-1 X g-1 lower left lobe (LLL)]. LLLs were challenged with graded doses of acetylcholine (ACh) (100-1,000 nmol) into the arterial cannula before and after administration of either 40 microM indomethacin (n = 5), 1 mM aspirin (n = 4), or 1 mM theophylline (n = 5). ACh produced a dose-dependent increase in pulmonary arterial pressure (Pa) and a decrease in the upstream-to-down-stream resistance ratio (Rus/Rds). Pretreatment with either indomethacin or aspirin potentiated the Pa response to ACh while eliminating the ACh-associated decrease in Rus/Rds. Pretreatment with the phosphodiesterase inhibitor theophylline significantly antagonized the ACh pressor response and decrease in the Rus/Rds. The present study suggests that the pulmonary pressor response to ACh is enhanced with cyclooxygenase inhibition. Our results indicate that ACh stimulates pulmonary vascular muscarinic cholinoceptors to cause vasoconstriction. Additionally or as sequelae to this response, predominantly vasodilatory prostanoids appear to be released.
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PMID:Prostanoid inhibition potentiates vasoconstrictor response to acetylcholine in dog lung. 375 43

The effects of the stable endoperoxide analog U46619 (U) on the regulation of prostacyclin (PGI2) formation and cyclic adenosine monophosphate (cAMP) were investigated in cultured bovine aortic endothelial (BAE) cells. Incubation of U (0.3, 3.0 and 30 microM) with BAE cells for 5 min results in a dose-dependent increase in PGI2. Cyclic AMP levels were not changed at 0.3 and 3.0 microM but were stimulated at 30 microM U. When cells were exposed to U for a second and third 5 min period, PGI2 formation at 0.3 and 3.0 microM U remained stimulated while at 30 microM, PGI2 was not increased. Five min incubation of BAE cells with the cyclooxygenase inhibitor indomethacin blocked the stimulation of PGI2 at all concentrations of U and also prevented the increase of cAMP levels at 30 microM. In cells prelabeled with 3H-arachidonate, U stimulated release of labeled products at 0.3 and 3.0 microM but not at 30 microM U. In cells treated with bradykinin in the presence of U, PGI2 production was stimulated at 0.3 and 3.0 microM but not 30 microM U. When cells were exposed to U and stimulated with PGI2 (with and without phosphodiesterase inhibition), U caused significant increases in cAMP. We conclude that incubation of BAE cells with U results in an initial dose-dependent increase in PGI2 formation. Cyclic AMP levels are increased at high concentrations of U. This increase in cAMP is mediated by the initial stimulated PGI2 and results in decreased PGI2 on further exposure to U. Data suggest that U stimulates phospholipase activity and, at high concentrations, inhibits phosphodiesterase.
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PMID:Effect of the stable endoperoxide analog U-46619 on prostacyclin production and cyclic AMP levels in bovine endothelial cells. 608 72

Cultured renal tubular cells (MDCK) have many of the biological properties of renal medullary tubular epithelial cells, including the ability to synthesize prostaglandin E2 (PGE2) as the major arachidonate metabolite. The hypothesis that adenosine 3',5'-cyclic monophosphate (cAMP) regulates prostaglandin synthesis in these cells was investigated by using cAMP, two degradation-resistant cAMP analogues [8-bromo-cAMP (8-BrcAMP) and N6,O2'-dibutyryl cAMP (DBcAMP)], and a phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). These agents inhibited basal-, calcium ionophore (A23187)-, or bradykinin-stimulated PGE2 biosynthesis by MDCK cells. The observed inhibition was dose- and time-dependent and could be reversed after 30 min of incubation in the absence of inhibitor. IBMX dose-dependently increased intracellular and extracellular cAMP levels by severalfold, suggesting that it was inhibiting prostaglandin biosynthesis by increasing cellular cAMP levels. Vasopressin, which stimulated cAMP levels by less than two-fold, did not inhibit prostaglandin synthesis. 8-BrcAMP and N6,O2'-DBcAMP inhibited A23187- or bradykinin-stimulated release of [3H]arachidonate from prelabeled cells, suggesting that cAMP inhibited acylhydrolase activity. Moreover, 8-BrcAMP also inhibited the conversion of exogenous arachidonate to PGE2 in intact cells and in a subcellular fraction containing prostaglandin synthetase activity, suggesting that cAMP inhibited cyclooxygenase and/or PGE2 isomerase activity. cAMP thus appears to regulate prostaglandin biosynthesis in MDCK cells by modulating the activity of two or more of the enzymes involved in the biosynthetic process.
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PMID:Inhibition of prostaglandin biosynthesis in renal (MDCK) cells by cAMP. 618 5

The present study examined the involvement of prostaglandins (PGs) in the mechanisms of ACTH and beta-endorphin release from rat anterior pituitary quarters incubated in vitro. Various cyclooxygenase inhibitors (indomethacin, diclofenac, flurbiprofen) had no effect on basal release of ACTH-like or beta-endorphin-like immunoreactivity (beta-EI), but enhanced ACTH-immunoreactivity/beta-EI release upon stimulation by arginine-vasopressin (AVP) or synthetic ovine corticotropin-releasing factor [CRF-(1-41)]. The lowest effective concentration of indomethacin was just sufficient to prevent PG synthesis. Indomethacin was similarly active after blockade of the phosphodiesterase by 3-isobutyl-1-methylxanthine. When added to the incubation media in concentrations up to 1 microM, PGE2, D2, F2 alpha, or prostacyclin (PGI2) did not alter basal beta-EI release; however, with stimulation by AVP or CRF-(1-41), PGE2 but not PGD2, F2 alpha, or I2 inhibited beta-EI release by about 60%. The concentrations of PGE2 in the incubation media, as measured by RIA, were somewhat higher than those of any other cyclooxygenase product (PGD2, F2 alpha, 6-keto-PGF1 alpha, thromboxane B2). Upon stimulation by AVP or CRF-(1-41), the concentrations of PGE2 increased, whereas those of PGD2 or F2 alpha remained unchanged. The release of beta-EI stimulated by high potassium concentration was not enhanced by indomethacin, although this release was sensitive to inhibition by PGE2. We conclude that PGE2 is formed locally subsequent to binding of the neurohormones and may act as a negative feedback-modulator of vasopressin's and CRF-(1-41)'s activity in the anterior pituitary gland.
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PMID:Adrenocorticotropin and beta-endorphin release from rat adenohypophysis in vitro: inhibition by prostaglandin E2 formed locally in response to vasopressin and corticotropin-releasing factor. 620 54

LA 2851 (2-4-diamino-7-methyl-pyrazolo (1,5-a) 1,3,5-triazine), a bronchodilator and antiallergic compound, in type I hypersensitivity, has been tested orally for activity against carrageenan oedema and complement dependent, reverse passive Arthus (RPA) and zymosan oedema in rats. Pharmacokinetic determinations were also realized in order to correlate plasma blood levels and pharmacological activity. LA 2851 was found active in the first test but showed a more marked effect in the immunologically mediated RPA reaction and zymosan oedema. Among reference drugs tested, theophylline showed the same pattern in contrast with non-steroidal anti-inflammatory agents. LA 2851 and theophylline, using a superfused lung preparation, were found ineffective on the synthesis of cyclooxygenase products from arachidonic acid. LA 2851 as theophylline inhibited cAMP phosphodiesterase (PDE) but this inhibition does not seem to be involved in their anti-inflammatory activity since papaverine, a potent inhibitor of PDE, was totally inactive. The activity on RPA and zymosan inflammation was achieved at the drug plasma level in the range of those required to relax the trachea. The same antagonism was obtained with the 2 drugs at a lower plasma level with LA 2851 than with theophylline for the same dose administered (25 mg/kg). LA 2851 and theophylline did not inhibit all the components of the inflammatory process since maximum inhibition did not exceed 60% up to 200 mg/kg and 100 mg/kg respectively.
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PMID:Anti-inflammatory effect of LA 2851 and reference drugs on some models of inflammation. Investigation of the mechanism of action. 629 6

Intracerebroventricular administration of (D-ala2, N-Me-Phe4, Met-(O)5-ol)-enkephalin (FK 33-824) induced dose-related hyperthermia in rabbits and guinea-pigs. Prostaglandins (PG) and norepinephrine (NE) were not involved in the hyperthermia induced by FK 33-824 because a cyclooxygenase inhibitor, indomethacin, and an alpha-adrenoceptor antagonist, phenoxybenzamine, had no antagonistic effects. Likewise, cAMP was not required since a phosphodiesterase inhibitor, theophylline, did not accentuate the hyperthermia due to FK 33-824. It is suggested that mu receptors were involved in the induction of hyperthermia by FK 33-824 in rabbits and guinea-pigs since naloxone attenuated it. These results indicate that FK 33-824-induced hyperthermia is not mediated by PG, NE and cAMP, but rather that mu receptors are involved in the induction of hyperthermia by FK 33-824.
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PMID:Hyperthermic effects of centrally injected (D-ala2, N-Me-Phe4, Met-(O)5-ol)-enkephalin (FK 33-824) in rabbits and guinea-pigs. 631 91

It seems paradoxical that AGEPC induces a transient rise in cyclic AMP, yet the preincubation of neutrophils with agents that elevate cyclic AMP actually inhibits AGEPC-induced aggregation. However, similar transient elevations in cyclic AMP are observed using other stimulators of PMN function such as fmet-leu-phe, C5a (22), immune complexes (24), and phagocytosable particles (11). Elevations in cyclic AMP by PGE1, PGI2, dibutyryl cyclic AMP, and phosphodiesterase inhibitors, before the addition of an agonist, also blocked subsequent neutrophil activation in the above studies. Thus, these observations are not unique to AGEPC. However, the finding that the cyclooxygenase inhibitor indomethacin enhanced AGEPC-stimulated cyclic AMP accumulation is a novel observation and suggests that some oxygenated derivative of the 5-lipoxygenase pathway is responsible for the increase in cyclic AMP. The evidence for the association of the spike in cyclic AMP and the 5-lipoxygenase is strengthened by the observation that the 5-lipoxygenase inhibitor U-60257 attenuates the AGEPC-induced spike in cyclic AMP. It should be noted that U-60257 does not antagonize LTB4-stimulated cyclic AMP accumulation and has no direct influence on the neutrophil adenylate cyclase. The final correlation of the spike in cyclic AMP and the 5-lipoxygenase is made by the fact that LTB4 itself stimulates cyclic AMP levels in intact neutrophils as well as the adenylate cyclase in cell homogenates. As is the case with AGEPC, the transient spike in cyclic AMP induced by LTB4 is coincident with the onset of neutrophil aggregation. However, it is clear that the spike in neutrophil cyclic AMP induced by AGEPC can be dissociated from neutrophil aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acetylglycerylether phosphorylcholine-(AGEPC) and leukotriene B4-stimulated cyclic AMP levels in human polymorphonuclear leukocytes. 632 44


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