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)

1 The effect of 5-hydroxytryptamine (5-HT) on acid secretion by a rat isolated stomach preparation has been studied. 2 5-HT at 10(-5)M in the serosal bathing fluid produced significant inhibition of the acid secretory responses to histamine, pentagastrin and isoprenaline but was without effect on basal secretion or that due to bethanechol, dibutryl cyclic adenosine 3',5'-monophosphate (db cyclic AMP) or phosphodiesterase inhibition with ICI63197. Increasing the concentration of 5-HT to 5 x 10(-5) M did not change this pattern of response whilst 5-HT at 10(-6) M did not cause consistent inhibition. 3 The inhibitory action of 5-HT could be prevented by the antagonist methysergide (2.5 x 10(-5) M). This concentration of methysergide alone did not affect responses to secretagogues or basal acid output. 4 Neither propranolol (2.5 x 10(-5) M) nor tetrodotoxin (10(-6) M) antagonized the inhibitory action of 5-HT. 5 Both indomethacin (2.8 x 10(-5) M) and ibuprofen (2.4 x 10(-4) M) antagonized the action of 5-HT. Indomethacin alone had no effect upon secretagogue responses. 6 5-HT at 10(-5) M had no inhibitory action when applied to the mucosal side of the preparation. 7 The results indicate that 5-HT can act directly on the stomach of the rat to produce inhibition of acid output. This inhibition is selective and may involve the products of cyclo-oxygenase activity.
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PMID:The inhibitory effects of 5-hydroxytryptamine on gastric acid secretion by the rat isolated stomach. 682 10

The effect of several anti-inflammatory drugs (NSAIDs), the calmodulin inhibitor W-7 and cortisol on vanadate-induced tonic contraction and on calmodulin dependent cAMP-phosphodiesterase activity have been assayed. Indomethacin, diclofenac, phenylbutazone, mefenamic acid, naproxen, tolmetin, piroxicam, aspirin and W-7, but not metimazol, produce dose-dependent relaxation of vanadate-induced tonic contraction on isolated rat uterus. Cortisol relaxes the vanadate contraction up to 45%. None of the drugs assayed inhibit the basal activity of phosphodiesterase with concentrations lower than 1 mM. However, indomethacin, diclofenac, phenylbutazone, mefenamic acid, naproxen, piroxicam, aspirin and W-7 inhibit, in a concentration-dependent way, the calmodulin-stimulated activity of phosphodiesterase. The maximum inhibition achieved with tolmetin (1 mM) and cortisol (1 mM) was 38% and 24%, respectively. Metamizol has no effect on basal or/and stimulated phosphodiesterase. This, as far as we know, is the first description of relationship between NSAIDs and calmodulin-dependent processes and our results suggest that the inhibition of calmodulin with NSAIDs may be directly related to their pKa and liposolubility.
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PMID:Spasmolytic and calmodulin inhibitory effect of non-steroidal anti-inflammatory drugs in vitro. 756 80

The marine natural products manoalide and scalaradial are potent anti-inflammatory agents that inactivate the enzyme phospholipase A2 (PLA2) in vitro. To study the mechanism of inhibition of prostaglandin E2 (PGE2) production in human monocytes by manoalide and scalaradial, lipopolysaccharide (LPS)-induced prostaglandin biosynthesis and induction of prostaglandin H synthase (PGHS) were evaluated. LPS (10 ng/mL) and interleukin-1 beta (IL-1 beta, 50-1000 ng/mL) but not tumor necrosis factor alpha (TNF alpha, 300 ng/mL) induced the expression of the PGHS-2 isoform as determined by immunoblot analysis with a specific polyclonal antibody for PGHS-2. Manoalide and scalaradial (1-10 microM) inhibited LPS-induced endogeneous PGE2 production, reduced the LPS-induced PGHS activity, and reduced the expression of PGHS-2. Indomethacin [a PGHS inhibitor (0.01 to 0.1 microM)], zileuton [a 5-lipoxygenase inhibitor (3-10 microM)], and WEB-2806 [a platelet-activating factor (PAF) antagonist (30 microM)] did not affect the LPS-induced expression of PGHS-2 in human monocytes. These results suggest that modulation of lipid mediator production by manoalide or scalaradial may not be involved in the observed effects on the expression of PGHS-2. Manoalide and scalaradial also inhibited the release of IL-1 beta and TNF alpha from LPS-stimulated monocytes. Expression of PGHS-2 induced by either LPS or IL-1 beta was blocked by the IL-1 receptor antagonist (IL-1ra, 2 micrograms/mL) but not by rolipram, a phosphodiesterase IV inhibitor that inhibits TNF alpha but not IL-1 beta release. Similar to LPS, IL-1 beta-induced PGHS-2 expression was apparently not regulated by lipid mediators such as prostaglandins, leukotrienes or PAF as determined with specific inhibitors and antagonists. Scalaradial and to some extent manoalide were capable of blocking the IL-1 beta-induced expression of PHGS-2. These results indicate that IL-1 beta is the predominant cytokine responsible for the induction of PGHS-2 in the human monocyte. Furthermore, marine natural products such as scalaradial have novel effects on the IL-1 beta-mediated induction of PGHS-2 in human monocytes, which appears to be independent of effects on lipid mediator production.
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PMID:Regulation of prostaglandin H synthase 2 expression in human monocytes by the marine natural products manoalide and scalaradial. Novel effects independent of inhibition of lipid mediator production. 757 73

Prostaglandins prevent gastrointestinal mucosal injury and promote healing following mucosal injury by various noxious agents. Preservation or repair of microvascular function appears to be crucial in these processes. The processes involved in prostaglandin-mediated repair and preservation of endothelial function are unclear. In the present study, we investigated the role of prostaglandins on endothelial paracellular barrier function using the filter-grown bovine aortic endothelial cell monolayers. Endothelial paracellular barrier function as assessed using a paracellular marker, mannitol. Prostaglandin analogs 16,16-dimethyl prostaglandin E2 (DMPGE2) and prostaglandin I2 (PGI2) caused an enhancement of endothelial monolayer paracellular barrier function as evidenced by a dose-dependent decrease in endothelial paracellular permeability. DMPGE2 induced enhancement of endothelial paracellular barrier function correlated directly with increasing intracellular cAMP levels. Agents which increase intracellular cAMP levels at different stages of cAMP amplification cascade including phosphodiesterase inhibitor (3-isobutyl-1 methylxanthine [IBMX]), membrane permeable cAMP (8-bromo cAMP), and adenylate cyclase activators (isoproterenol and forskolin) also produced enhancement in endothelial paracellular barrier function. DMPGE2 enhancement of paracellular barrier function correlated with dense accumulation of actin microfilaments near the intercellular junctions. IBMX, isoproterenol, forskolin, and 8-bromo cAMP also produced similar changes in endothelial actin microfilaments. Cytochalasin B prevented the DMPGE2 enhancement of paracellular barrier function. Indomethacin (INDO), a cyclooxygenase inhibitor, caused a dose-dependent increase in endothelial paracellular permeability. Pharmacologic doses of INDO resulted in condensation and disruption of actin microfilaments with formation of large paracellular openings or gaps between the adjacent cells. Pretreatment of endothelial monolayers with DMPGE2 prevented INDO-induced disturbance of actin microfilaments and paracellular barrier function. IBMX, isoproterenol, forskolin, and 8-bromo cAMP also prevented INDO-induced changes in actin microfilaments and paracellular barrier function. These findings indicate that DMPGE2 has a paracellular barrier enhancing effect on filter-grown endothelial monolayers. This effect appears to be mediated through intracellular cAMP and actin microfilaments.
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PMID:16,16-Dimethyl Prostaglandin E2 modulation of endothelial monolayer paracellular barrier function. 861 60

Satigrel (E5510, 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid) is a potent inhibitor of platelet aggregation. Like cyclooxygenase/prostaglandin H synthase (PGHS) inhibitors such as aspirin, which suppress platelet aggregation by inhibiting thromboxane A2 production, satigrel inhibits collagen- and arachidonic acid-induced aggregation of human platelets. In contrast to other PGHS inhibitors, satigrel, like cyclic nucleotide phosphodiesterase (PDE) inhibitors such as cilostazol, shows inhibitory activity against thrombin-induced platelet aggregation. To investigate the mechanism of the anti-platelet activity of satigrel, we examined the selectivity and potency of satigrel against PGHS isozyme activities and PDE isoform activities. Two isozymes of PGHS are known; constitutive enzyme (PGHS1) and inducible enzyme (PGHS2). Satigrel showed inhibitory activity against PGHS1 (IC50: 0.081 microM) and PGHS2 (IC50: 5.9 microM), suggesting the selective inhibition of PGHS1. Indomethacin, which is a selective inhibitor of PGHS1, showed similar selectivity against PGHS isozymes (IC50: 0.12 microM and 1.4 microM, respectively). These results support that satigrel suppresses thromboxane A2 production by inhibiting PGHS1. It is known that three isozymes of PDE exist in human platelets: Type V, which specifically hydrolyzes guanosine 3',5'-cyclic monophosphate (cGMP), Type III, which mainly hydrolyzes cAMP, and Type II, which hydrolyzes both cGMP and cAMP. We separated these three isozymes from human platelets and examined the inhibitory activity of satigrel against each enzyme. Of the three isozymes, the inhibitory activity of satigrel was the most potent against Type III PDE (IC50: 15.7 microM). The IC50 value for Type III corresponded with that for thrombin-induced platelet aggregation. Type V and Type II were also inhibited by satigrel (IC50: 39.8 and 62.4 microM, respectively). In human platelets, satigrel increased both cAMP and cGMP levels in a dose-dependent manner (100, 300 microM). In conclusion, satigrel inhibits collagen- and arachidonic acid-induced platelet aggregation through preventing thromboxane A2 synthesis by selective inhibition of the target enzyme, PGHS1, which exists in platelets. The anti-aggregating activity of satigrel against thrombin-induced aggregation may be due to elevation of the cyclic nucleotide levels through the inhibition of PDE isozymes.
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PMID:Mechanisms of satigrel (E5510), a new anti-platelet drug, in inhibiting human platelet aggregation. Selectivity and potency against prostaglandin H synthases isozyme activities and phosphodiesterase isoform activities. 879 81

The influence of the arachidonic acid metabolism inhibitors, indomethacin and voltaren; an inhibitor of phosphodiesterase activity, theophylline and the protease inhibitor epsilonaminocaproic acid (EACA) on N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was studied in rats. ENU was given to pregnant rats as a single i.v. exposure at a dose of 75 mg/kg body weight on the 21st day after conception. Indomethacin and voltaren (20 p.p.m. in drinking water), theophylline (0.01% in diet) and EACA (1000 p.p.m. in drinking water) were given to the offspring throughout their post-natal life until all survivors were killed at 12 months. In the ENU-only control groups, 100% of the offspring developed tumors of brain, spinal cord, peripheral nervous system or kidneys, with a total average number of 3.1 tumors per rat. The most marked inhibitory effect was exerted by theophylline, which significantly decreased the incidence and multiplicity of total tumors, and at all main sites selectively (brain, spinal cord, peripheral nerves and kidneys). It also prolonged average survival time of the offspring. Indomethacin and voltaren significantly decreased total tumor incidence and multiplicity and brain tumor incidence and multiplicity. Indomethacin also decreased kidney tumor multiplicity and voltaren diminished spinal cord tumor multiplicity. EACA decreased multiplicities of total, brain, peripheral nerve and kidney tumors, and diminished the incidence of brain tumors. These chemopreventive agents decreased tumor incidences 20-33% and tumor multiplicities 1.4-2.7 times, compared with the ENU-only controls.
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PMID:Study of post-natal effect of chemopreventive agents on ethylnitrosourea-induced transplacental carcinogenesis in rats. III. Inhibitory action of indomethacin, voltaren, theophylline and epsilon-aminocaproic acid. 882 17

1. The effect of systemic administration of the nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) on the antihypertensive effects of the angiotensin AT1 receptor antagonist, GR138950, the angiotensin-converting enzyme (ACE) inhibitor, enalapril, or hydralazine has been evaluated in unrestrained, conscious renal artery ligated hypertensive (RALH) rats. The effect of the phosphodiesterase type V inhibitor, zaprinast on the antihypertensive effect of GR138950 in RALH rats was also examined. The effect of GR138950 on blood pressure, and plasma and urine cyclic GMP levels was compared to that of zaprinast in conscious RALH rats. 2. GR138950, enalapril or hydralazine caused marked reductions in blood pressure associated with immediate tachycardia in conscious RALH rats. L-NAME pretreatment attenuated the antihypertensive effects of GR138950 or enalapril but not that of hydralazine in conscious RALH rats. The initial tachycardia caused by GR138950 or enalapril but not hydralazine was attenuated by L-NAME pretreatment. L-NAME alone caused a transient (20 min) pressor response and a prolonged (6 h) bradycardia in conscious RALH rats. 3. Pretreatment with indomethacin did not affect the cardiovascular effect of GR138950 in conscious RALH rats. Indomethacin alone did not significantly change basal blood pressure or heart rate in RALH rats. 4. Zaprinast pretreatment did not affect the antihypertensive effect of GR138950 in conscious RALH rats but potentiated the depressor response to sodium nitroprusside. Zaprinast alone caused a small reduction in basal blood pressure but did not change basal heart rate in RALH rats. 5. The antihypertensive effect of GR138950 was not associated with an increase in plasma or urine cyclic GMP levels in conscious RALH rats, whereas zaprinast caused a small fall in blood pressure associated with increases in plasma and urine cyclic GMP. 6. The ability of L-NAME to inhibit the antihypertensive action of GR138950 or enalapril suggests that these agents release nitric oxide (NO) and/or enhance the cardiovascular effects of NO as part of their mechanism of action. However, the inability of zaprinast to potentiate the antihypertensive effects of GR138950 and the finding that GR138950 did not increase urine and plasma cyclic GMP levels are not consistent with this view. Attenuation of the response to GR138950 or enalapril, but not hydralazine, suggests a selective interaction between L-NAME and inhibitors of the renin-angiotensin system, although the nature of this interaction is unknown.
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PMID:Investigation of the inhibitory effect of N(G)-nitro-L-arginine methyl ester on the antihypertensive effect of the angiotensin AT1 receptor antagonist, GR138950. 942 Dec 86

The present study investigated the effect of prostaglandin (PG) E2 and PGI2 on intercellular adhesion molecule-1 (ICAM-1) expression in interleukin-1 beta (IL-1 beta)-stimulated human gingival fibroblasts (HGF). IL-1 beta potently induced ICAM-1 expression in HGF and indomethacin, a cyclooxygenase inhibitor, enhanced ICAM-1 expression in the cells. These data showed that endogenous PGs generated by HGF stimulated with IL-1 beta downregulated ICAM-1 expression. IL-1 beta significantly increased the levels of PGE2 and, to a lesser extent, those of 6-keto-PGF1 alpha (a stable metabolite of PGI2) in the culture media of HGF. Indomethacin completely inhibited the production of PGE2 and 6-keto-PGF1 alpha in IL-1 beta-stimulated HGF. Exogenous PGE2 and carbacyclin (a stable derivative of PGI2) in the presence of indomethacin dose-dependently suppressed ICAM-1 expression in IL-1 beta-challenged HGF. Since PGE2 and PGI2 are known to elevate intracellular cyclic AMP (cAMP) levels, we examined the effect of dibutyryl cAMP, a cAMP analogue, and isobutylmethylxanthine, a phosphodiesterase inhibitor, on ICAM-1 expression. Both agents downregulated ICAM-1 expression in IL-1 beta-stimulated HGF. These results suggest that PGE2 and PGI2 downregulate ICAM-1 expression in IL-1 beta-stimulated HGF through a cAMP-dependent mechanism and that intracellular cAMP elevation in HGF may control inflammatory and immune responses in periodontal disease.
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PMID:Prostaglandin E2 and I2 regulate intercellular adhesion molecule-1 expression in interleukin-1 beta-stimulated human gingival fibroblasts. 1020 38

The present study was undertaken to examine whether phosphodiesterases III and IV regulate renal cAMP level and whether inhibition of these enzymes influences renal functions in anesthetized dogs. The intrarenal arterial infusion of rolipram (0.1, 0.3, and 1 microgram/kg/min), a selective phosphodiesterase IV inhibitor, increased renal blood flow, glomerular filtration rate, urine flow rate, and urinary Na+ excretion with elevating arterial and renal venous plasma cAMP concentrations and urinary cAMP excretion. However, cilostamide (0.1, 0.3, and 1 microgram/kg/min), a selective phosphodiesterase III inhibitor, did not affect the values of these parameters. Indomethacin (3 mg/kg i.v. bolus and 1 mg/kg/min i.v. infusion), a cyclooxygenase inhibitor, reduced the basal arterial and renal venous plasma cAMP concentrations and blunted the rolipram-induced elevation of cAMP concentrations and urinary cAMP excretion. The effects of rolipram on renal hemodynamics and urine formation were attenuated in the presence of indomethacin. These results suggest that in the dog kidney in vivo, 1) phosphodiesterase IV, but not phosphodiesterase III, participates in degradation of cAMP and 2) the inhibition of phosphodiesterase IV enhances glomerular filtration and urinary Na+ excretion, the responses of which depend in part on indomethacin-susceptible (prostaglandin-mediated, probably) control of basal cAMP level.
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PMID:Effects of rolipram and cilostamide on renal functions and cyclic AMP release in anesthetized dogs. 1033 49

Phosphodiesterase (PDE) 4, mixed PDE3/4, and non-selective PDE inhibitors have been shown to inhibit the proliferation of human peripheral blood mononuclear cells (HPBM). The aim of the present study was to examine whether endogenous prostaglandins, in particular prostaglandin E2 (PGE2), are involved in mediating the antiproliferative actions of PDE inhibitors, by comparing their effects with drugs which elevate or mimic adenosine 3',5'-cyclic monophosphate (cAMP) through mechanisms other than PDE inhibition. Indomethacin significantly reduced the antiproliferative effects of the PDE4 inhibitors rolipram and CDP840 and the mixed PDE3/4 inhibitor zardaverine, increasing the IC50 values from 2.51 microM to >10 microM, 0.81 microM to 2.82 microM, and 1.58 microM to 4.82 microM, respectively (P < 0.05), but did not alter the effects of theophylline. Forskolin, PGE2, and dibutyryl cAMP also inhibited HPBM proliferation, and in the presence of indomethacin the effects of forskolin and dibutyryl cAMP were reduced (although this was not significant), whereas PGE2 was not affected. Rolipram, CDP840, zardaverine, and dibutyryl cAMP all produced a concentration-related increase in PGE2 production (P < 0.05, ANOVA), but theophylline significantly increased PGE2 production only at the highest concentration examined, 1000 microM. The ability of indomethacin to reduce the antiproliferative effects of rolipram, CDP840, and zardaverine, together with the fact that these drugs can stimulate PGE2 production, suggests that their antiproliferative actions may be mediated in part by stimulation of endogenous PGE2 production. In contrast, it appears that endogenous PGE2 is not critical for the antiproliferative actions of theophylline, forskolin, and dibutyryl cAMP in HPBM. These results establish the importance of co-ordinated regulation of the cAMP phosphodiesterase and cyclooxygenase-PGE2 systems for the regulation of lymphocyte function in man, and have clinical implications for therapeutic approaches to diseases associated with lymphocyte dysregulation.
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PMID:Possible Contribution of Prostaglandin E2 to the antiproliferative effect of phosphodiesterase 4 inhibitors in human mononuclear cells. 1051 92


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