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)

The ability of azelastine to influence antigen-induced contractile responses (Schultz-Dale phenomenon) in isolated tracheal segments of the guinea-pig was investigated and compared with selected antiallergic drugs and inhibitors of arachidonic acid metabolism. Indomethacin produced a significant leftward shift of the antigen concentration-effect curve. The inhibitory activity of azelastine on anaphylactic responses in guinea-pig trachea was dependent on the duration of exposure (preincubation period). The relative order of potency (antianaphylactic activity) at calculated IC50 level was as follows: FPL 55712 (a leukotriene receptor antagonist) greater than nordihydroguaiaretic acid (a lipoxygenase inhibitor) greater than p-bromophenacyl bromide (a phospholipase A2 inhibitor) greater than BW 755c (a dual inhibitor of lipoxygenase and cyclo-oxygenase) greater than theophylline (a phosphodiesterase inhibitor) greater than azelastine greater than diphenhydramine (H1 histamine-receptor antagonist) greater than ketotifen greater than disodium cromoglycate. FPL 55712 (added 5 min before antigen challenge) was about 12 times as potent as azelastine (added 2 h before antigen challenge). The incubation of tracheal segments with azelastine and BW 755c for a period of 30 min was found to inhibit indomethacin-augmented anaphylactic responses. These observations seem to suggest that azelastine and BW 755c interfere with the synthesis/release of the products of lipoxygenase/leukotriene synthetase pathway (e.g., leukotrienes) in the mediation of allergic responses in airway smooth muscles.
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PMID:Modulation of in vitro anaphylaxis of guinea-pig isolated tracheal segments by azelastine, inhibitors of arachidonic acid metabolism and selected antiallergic drugs. 308 2

Platelet-derived growth factor (PDGF) stimulated up to 15-fold the production of prostaglandin E2 (PGE2) and bone resorption in neonatal mouse calvaria in organ culture. The action of PDGF on bone resorption occurred at low concentrations of the protein (ED50 = 10 ng/ml). All concentrations of PDGF which stimulated resorption also enhanced the production of PGE2 by bone; concentrations of PDGF which did not stimulate resorption did not enhance PGE2 production. PDGF-induced formation of PGE2 and bone resorption were inhibited completely by indomethacin (100 ng/ml) and hydrocortisone (1 microgram/ml). Indomethacin did not inhibit the bone resorption-stimulating activity of exogenous PGE2. In the continued presence of a maximum concentration of PDGF (100 ng/ml), an increase in bone resorption, as measured by an increase in medium calcium, was detected at 16 h (P less than 0.01), but not at 12 h; however, an increase in PGE2 production occurred within the first 2 h of treatment. A similar lag period for the onset of bone resorption was seen after the addition of exogenous PGE2 to the culture medium. On the other hand, exposure of bones to PDGF (50 ng/ml) for as brief a period as 5-15 min, followed by washout of PDGF, triggered bone resorption over the subsequent 48 h. PDGF increased cAMP production by bone within 30 min, and this effect of PDGF was blocked completely by indomethacin while the action of exogenous PGE2 on the production of cAMP was not blocked by indomethacin. The action of a low concentration of PDGF (1 ng/ml), which did not stimulate bone resorption alone, was potentiated by the phosphodiesterase inhibitor isobutylmethylxanthine (4 microM). We conclude that low concentrations of PDGF stimulate bone resorption via the enhanced local production of PGE2.
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PMID:Platelet-derived growth factor stimulates bone resorption via a prostaglandin-mediated mechanism. 617 24

Partially purified porcine PDGF or purified human PDGF in the presence of phosphodiesterase inhibitors caused marked accumulation of cAMP in Swiss 3T3 cells. The responses were time- and dose-dependent; half-maximal effect was obtained at 0.6 nM PDGF. Indomethacin prevented the increase of cAMP levels in a dose-dependent manner; half-maximal effect was obtained at about 10 nM. Addition of PDGF increased (at least 25-fold) the production of E-type prostaglandins; PGE reached a concentration in the medium of 26 ng/ml 1 hr after treatment with human PDGF. This concentration of PGE produced a similar level of cAMP to that found with PDGF, suggesting that the PDGF-induced increase in cAMP is mediated by E-type prostaglandins released in the culture medium. Increased cAMP levels promoted by PDGF acting through stimulation of E-type prostaglandin synthesis may contribute to signal the initiation of cell proliferation in 3T3 cells.
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PMID:Platelet-derived growth factor elicits cyclic AMP accumulation in Swiss 3T3 cells: role of prostaglandin production. 619 34

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

The guinea-pig lung parenchymal (GPLP) strip is sensitive to leukotrienes (LT) C4 and D4 (LTC4 and LTD4). These substances induce contractions during which thromboxane (TX) A2 (TxA2) is released. This event was measured both by bioassay of TxA2 and radioimmunoassay of thromboxane B2 (TxB2). Indomethacin partially inhibited the contractile response and completely abolished the release of TxA2. The proportional participation of TxA2 in the contractile response was calculated quantitatively, and appeared to be 70-90%. On basis of these results, it is concluded that only a small proportion of the contractions is due to the direct action of the leukotrienes and a major part to the formed thromboxane A2. The action of the phospholipase A2 (PLA2) inhibitor chloroquine and the phosphodiesterase inhibitor, 3-isobutyl-1-methyl-xanthine (IBMX), were measured both on the contraction and the TxA2 release. Chloroquine in a dose of 40 /micrograms/ml totally inhibited the TxA2 release induced by 50 ng LTD4. At higher doses, the contractions were also completely inhibited. IBMX in a dose of 22 /micrograms/ml inhibited both the contraction and the TxA2 release to a large extent. These effects are most probably due to an inhibition of the phospholipase A2 which is activated by the leukotrienes. It is supposed that chloroquine acts directly and that the action of IBMX is due to an increase in cyclic AMP, which also leads to an inhibition of the enzyme. After the incubation of lung strips with [1-14C] arachidonic acid (AA), mainly TxB2 and lipoxygenase products are formed.
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PMID:The effect of inhibitors on the LTD4-induced contractions and release of thromboxane A2 in the guinea pig lung parenchymal strip. 620

Intratesticular injection of prostaglandin E2 (PGE2) and F2 alpha (PGF2 alpha) caused stimulation of ornithine decarboxylase (ODC) activity in the testis of immature rats. PGE2 at a dose of 10 microgram per testis was maximally effective 2 hours after the injection. Dibutyryl cyclic AMP (cAMP) and 1 methyl, 3-isobutyl xanthine (MIX), a phosphodiesterase inhibitor, also stimulated ODC activity. Simultaneous injection of PGE2 and FSH or LH caused additional stimulation of ODC activity. Similarly injection of PGE2 in addition to cAMP or MIX also caused increased stimulation of ODC. Indomethacin (IM, 60 microgram/testis) inhibited LH, FSH or cAMP induced ODC activity. However, IM at the same dose inhibited the synthesis of total proteins. These results suggest that PGE2 and PGF2 alpha stimulate the activity of ODC. The action of prostaglandins may be independent of the action of gonadotropic hormones. cAMP appears to mediate the action of prostaglandins in the testis of rat.
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PMID:Effect of prostaglandins on ornithine decarboxylase activity in the testis of immature rat. 625 76

To study the acute and direct effects of GnRH agonists preovulatory follicles were isolated from PMSG-treated immature rats and incubated for 15-360 min in modified Kreb's bicarbonate buffer. The levels of cAMP, prostaglandin E, and progesterone were analysed in the tissue and/or incubation media. GnRH and two GnRH agonists produced a dose-dependent stimulation of progesterone production with maximal levels 5-6-fold higher than the control group. As compared to LH the magnitude of this effect was small and was detected only after 240-360 min of incubation. GnRH also stimulated prostaglandin E accumulation and this effect was as pronounced as for LH. There were no detectable changes in cAMP levels for any concentration of GnRH when the incubation time varied between 15 and 120 min whether or not a phosphodiesterase inhibitor was present, but after 240 min of incubation a 2-fold increase in cAMP was found. Consistent with previous results, LH caused a pronounced (40-50-fold) increase in follicular cAMP which was already detectable after 15 min of incubation. Indomethacin abolished the rise in prostaglandin E induced either by GnRH or LH but did not affect the response in terms of cAMP or progesterone, and did not affect the stimulation of meiotic maturation of the follicle-enclosed oocytes caused by the hormones. It is concluded that GnRH can exert acute and LH-like stimulatory effects on the preovulatory rat follicle but that the mechanism of GnRH action is different from that of LH.
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PMID:Effect of gonadotrophin-releasing hormone (GnRH) and GnRH agonists upon accumulation of progesterone, cAMP and prostaglandin in isolated preovulatory rat follicles. 629 4

The calcium ionophore A23187 (IP) inhibited the antidiuretic hormone (ADH)-stimulated hydro-osmotic response in toad urinary bladder but had no effect on the osmotic transfer of water in the absence of hormone. Extracellular calcium was necessary for this effect at lower but not at higher IP concentrations. The hydro-osmotic response to exogenous cyclic AMP was unaltered by IP, but the same response produced by inhibition of phosphodiesterase was reduced significantly. Cyclic AMP concentrations in isolated toad bladder epithelial cells were reduced by 50% with IP or exogenous prostaglandin E2 (PGE2). Indomethacin, a prostaglandin synthesis inhibitor, prevented the inhibitory actions of the IP on the ADH-mediated response. Collectively, these observations suggest a key role for cellular calcium in modulating the actions of antidiuretic hormone and are consistent with the hypothesis that the ionophore, through increasing intracellular calcium, stimulates the synthesis of prostaglandins which have a negative feedback on adenylcyclase. This effect would terminate the action of the hormone.
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PMID:Role of calcium and prostaglandins in the antidiuretic hormone response. Effect of ionophore A23187. 630 7

The effects of ethanol on parathyroid hormone (PTH)-induced increases in adenosine 3':5'-phosphate (cAMP) concentrations were studied in renal cortical tubules of hamsters in vitro. Ethanol concentrations between 0.1 and 3% were found to augment the PTH response in a dose-related way while, concentrations greater than 3% produced a dose-related inhibition of the PTH response. In the absence of PTH, ethanol did not significantly elevate cAMP accumulations at any concentrations tested. In contrast to its effect on intact tubule cells, ethanol did not alter either adenylate cyclase or phosphodiesterase in renal cortical homogenates. Indomethacin, however, produced a concentration-related inhibition of the ethanol-potentiated response without altering the effects of PTH alone. The results suggest a possible involvement of prostaglandins in the potentiating effect of ethanol on the PTH-dependent accumulation of cAMP in renal tubules.
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PMID:Enhancement by ethanol of parathyroid-hormone-stimulated cyclic AMP accumulation in isolated renal tubules. 630 64

The output of immunoreactive (i) 6 keto prostaglandin F1 alpha (i6ketoPGF1 alpha), iPGE2 and ithromboxane B2 (iTXB2) from isolated colonic epithelium of the rat into the apical and basolateral bathing solution has been measured. In some instances tissues were also voltage clamped at 0 mV to measure short circuit current (SCC). Kallidin (lysylbradykinin) stimulated the output of all three eicosanoids, specifically from the basolateral face of the tissue. The output was similar whether or not the tissues were short circuited. Both the SCC response and eicosanoid output were dependent upon the concentration of kallidin, but not in a strictly proportional manner, there being relatively more eicosanoid output at submaximal kinin concentrations. Indomethacin, 5 microM, abolished the eicosanoid output, in response to kinin, while some part of the SCC response remained. Calcium removal from the basolateral bathing fluid severely attenuated the SCC response, reduced the output of i6ketoPGF1 alpha to half, but left the output of iPGE2 unchanged. In the presence or absence of calcium it is probable that sufficient PGE material is released to cause part of the SCC changes seen with kinin. Kinin and PGE1 increased the cyclic AMP content of intact epithelia, provided a phosphodiesterase inhibitor was added at the same time. It is proposed that kinin causes an increase in calcium influx at the basolateral pole of the tissue. This calcium is necessary for the production of some eicosanoids and the subsequent generation of cyclic AMP, which then increases apical chloride permeability. In addition, calcium may facilitate entry of chloride through the basolateral face of the cells by activating a cotransport mechanism.
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PMID:Mediators of the secretory response to kinins. 633 59


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