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 mechanism of the antiaggregating activity of flavonoids was studied in vitro. The activity of fifteen different compounds was tested on platelet aggregation and arachidonic acid metabolism. The effect of flavonoids on platelet adenosine 3',5'-cyclic monophosphate (cyclic AMP) levels under basal conditions, as well as after stimulation by prostacyclin (PGI2), was also measured. The glycons of flavonoids in general and the flavanone derivatives that we tested did not affect platelet function. On the other hand, flavone, chrysin , apigenin and phloretin inhibited platelet aggregation by depressing the cyclooxygenase pathway. In addition, flavone, chrysin and apigenin reduced the platelet cyclic AMP response to PGI2. This effect was probably mediated by an inhibition of adenylate cyclase. Myricetin and quercetin, however, increased the PGI2-stimulated rise of platelet cyclic AMP. Both of these flavonoids inhibited primarily lipoxygenase activity. Modification of platelet cyclic AMP metabolism through inhibition of phosphodiesterase activity was found to be the probable mechanism of their antiaggregating effect.
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PMID:Modification of platelet function and arachidonic acid metabolism by bioflavonoids. Structure-activity relations. 632 30

According to a pathogenetic concept originally presented by Moncada in 1977 a therapeutic combination of a low-dose cyclooxygenase inhibitor with a phosphodiesterase inhibitor might help in restoring a disturbed hemostatic balance, as thromboxane synthesis in the platelets should be inhibited to a greater extent than the prostacyclin synthesis of the endothelium. Therefore, we evaluated the influence of a therapeutic combination of cyclooxygenase inhibitors in different dosages (sulfinpyrazone, acetylsalicylic acid) with a phosphodiesterase inhibitor (dipyridamole) on platelet sensitivity and plasma factor in comparison to placebo treatment. We examined 76 males with peripheral vascular disease (PVD) stage IIa according to Fontaine in a double-blind randomized study over a 3 months period. Patients were divided into 4 groups and the different drugs were randomized as follows: I. 75 mg sulfinpyrazone and 75 mg dipyridamole, II. 150 mg ASA and 75 mg dipyridamole, III. 330 mg ASA and 75 mg dipyridamole, IV. placebo. Clinical symptoms as well as the plasma factor and the diminished platelet sensitivity to prostacyclin in patients with PVD remained unchanged throughout the whole observation period. Our findings suggest that no improvement in hemostatic dysregulation can be obtained by this combined treatment.
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PMID:Plasma factor and platelet sensitivity to prostacyclin in patients with peripheral vascular disease before and after treatment with a combination of a cyclooxygenase and a phosphodiesterase inhibitor. 643 32

Metabolism of arachidonic acid (AA) in blood platelets and in vascular endothelium does not lead to prostaglandins, but thromboxane A2 and prostacyclin are generated. These labile metabolites of AA antagonize each other: thromboxane A2 is a vasoconstrictor and proaggregatory agent, whereas prostacyclin dilates arteries, prevents platelets from aggregation, and dissipates the preformed platelet clumps. Prostacyclin is a powerful stimulator of adenylate cyclase in platelets and therefore its antiplatelet action is potentiated by phosphodiesterase inhibitors such as theophylline or dipyridamole. Cyclo-oxygenase of AA is inhibited by aspirin, thromboxane synthetase by analogues of prostaglandin endoperoxides, and prostacyclin synthetase by linear lipid peroxides. A hypothesis is put forward that atherosclerosis develops because of pathological, nonenzymic lipid peroxides. A hypothesis is put forward that atherosclerosis develops because of pathological, nonenzymic lipid peroxydation in the body and the subsequent molecular damage to prostacyclin synthetase in the rheologically determined areas of arterial walls. Endothelium deprived of prostacyclin is the basis for microthrombi formation, and follows a sequence of events described by Rokitansky and later by Ross. Prostacyclin is also a circulating hormone which is generated by the lungs. Thereby a damage of this "endocrine gland" by respiratory disorders, air pollution, or tobacco smoking are likely to contribute to pathogenesis of atherosclerosis, myocardial infarction, and arterial thromboembolism. Pharmacological treatment and prevention of these diseases should logically include antioxydants, prostacyclin and its analogues, thromboxane synthetase inhibitors and perhaps cyclooxygenase inhibitors (aspirin ?). Prostacyclin was already infused intravenously to men and its powerful antiaggregatory and deaggregatory actions were demonstrated. These properties of prostacyclin along with its vasodilator and positive inotropic actions destine this hormone to be a new type of antithrombotic drug in acute myocardial infarction.
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PMID:Prostaglandins, platelets, and atherosclerosis. 677 Nov 2

Twenty dogs with naturally occurring metastatic tumors were treated with anticoagulants (Warfarin) or platelet enzyme inhibitor drugs (dipyridamole, dipyridamole plus aspirin, RA233, sulfinpyrazone, or a combination of RA233 and sulfinpyrazone) to determine if tumor-related reductions in platelet survival and concentration could be reversed. Anticoagulation was ineffective, while platelet enzyme inhibitors were able to produce improvements in platelet survival. Of the 18 dogs with metastatic tumor treated with platelet enzyme inhibitors, only 5 (28%) showed a reduction in platelet survival during the first week of observation on therapy compared to their baseline survivals. This is significantly different than the decreases in platelet survivals observed in 8 of 10 untreated dogs (80%) with metastatic tumor observed for the same interval. Furthermore, 8 of the 18 treated dogs (44%) had platelet survivals within 2 standard deviations of normal, compared to only 1 of 10 untreated dogs. Of the 8 dogs with normal platelet survivals, 6 were treated with a combination of a phosphodiesterase inhibitor (RA233 or dipyridamole) and a cyclooxygenase inhibitor (sulfinpyrazone or aspirin). The combination of RA233 and sulfinpyrazone was the best drug program tested and resulted in normal platelet survivals in 63% and improved platelet counts in 75% of the animals treated. Thus, platelet enzyme inhibitors with different mechanisms of action may have a synergistic effect in reversing the abnormal platelet hemostasis found in a variety of spontaneously occurring canine neoplasms.
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PMID:Interruption of tumor-associated platelet consumption with platelet enzyme inhibitors. 680 31

Effects of endothelin-1 (ET-1) and endothelin-3 (ET-3) on cyclic AMP (cAMP) levels were studied in the isolated rat anterior and intermediate-posterior pituitary slices. In the anterior pituitary, ET-1 increased cAMP levels in a concentration-dependent manner (10(-7)-10(-5) M). ET-3 also increased the levels at the same concentration range, but ET-1 was more potent than ET-3 at an approximate ED50, 10(-6) M. The stimulatory effects of ET-1 and ET-3 (10(-6) M) on cAMP levels were antagonized by the ETA receptor antagonist BQ 123, 2 x 10(-6) M, and the ETB receptor agonist IRL 1620 evoked only a weak increase in cAMP levels. Moreover, the effects of ET-1 and ET-3 were completely abolished by the cyclooxygenase inhibitor indomethacin, 2 x 10(-5) M. On the other hand, among prostaglandins, prostaglandin E2 (PGE2) increased cAMP levels in a concentration-dependent manner (10(-7)-10(-5) M), whereas prostaglandin D2 and prostaglandin I2 did not exhibit such effects. PGE2 levels were increased by application of ET-1 (10(-8)-10(-5) M). The ET-1-induced PGE2 accumulation was strongly inhibited by indomethacin and BQ 123, but not by treatment with pertussis toxin (100 ng/ml, 6 hr). Treatment with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also elevated the cAMP level by approximately 9-fold above the basal cAMP level. After 3-isobutyl-1-methylxanthine, ET-1 failed to increase PGE2 and cAMP levels. In the intermediate-posterior pituitary, ET-1 and ET-3 did not affect cAMP levels. The results suggest that endothelins increase cAMP levels via ETA receptor activation interacting with the pertussis toxin-insensitive G-protein, in which PGE2 production is involved in the rat anterior pituitary, whereas endothelins lack these effects in the intermediate-posterior pituitary.
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PMID:Endothelins stimulate cyclic AMP accumulation in the isolated rat anterior pituitary gland: possible involvement of ETA receptor activation and prostaglandin E2 production. 751 15

The pharmacological effects of N-[2-(4-(benzhydryloxy)piperidino)ethyl]-3-hydroxy-5-(3-pyridyl methoxy)-2- naphthamide (F-1322), a novel anti-asthmatic agent, was investigated in vitro. The results obtained were as follows: 1) In the isolated trachea of guinea pigs, F-1322 showed a markedly potent antagonistic action against the contraction induced by histamine, while it had little or no effect on 5-hydroxytryptamine-, acetylcholine-, leukotriene D4- or U-46619-induced contractions. 2) In rabbit platelets, F-1322 did not affect the platelet aggregation induced by platelet activating factor. 3) F-1322 significantly inhibited the thromboxane (TX) A2 synthetase (IC50 value: 1.7 x 10(-8) M) and 5-lipoxygenase (IC50 value: 9 x 10(-7) M) activities. 4) F-1322 had no effect on phospholipase A2, cyclooxygenase, Ca2+/calmodulin-dependent phosphodiesterase and phosphodiesterase activities. These in vitro studies suggest that the anti-asthmatic action of F-1322 is associated with histamine antagonism and an inhibitory action on TXA2 synthetase and 5-lipoxygenase activities.
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PMID:[Pharmacological profiles of F-1322, a novel anti-asthmatic agent. (1). Mechanisms of action]. 759 May 21

The purpose of this study was to examine whether angiotensin II (Ang II) stimulates the release of endothelium-derived nitric oxide, which then impairs the contractions of vascular smooth muscle caused by the peptide, and to determine the receptor subtypes mediating these responses. Experiments were performed on isolated rings of rat carotid artery either incubated in the presence of phosphodiesterase inhibitor for the measurement of intracellular levels of cGMP or suspended in organ chambers for recording of changes in isometric force. Ang II (10(-7) mol/L) caused a twofold increase in intracellular cGMP level in preparations with but not in those without endothelium. The presence of endothelium impaired the contractions evoked by the peptide and caused approximately 50% inhibition of the maximal response to Ang II (3 x 10(-8) mol/L); pD2 values for Ang II were 8.9 +/- 0.1 and 9.6 +/- 0.2 in rings with and without endothelium, respectively. In rings with endothelium the contractions to Ang II were augmented by nitro-L-arginine (an inhibitor to nitric oxide synthase) but not indomethacin (an inhibitor of cyclooxygenase), to reach a response comparable to that of preparations without endothelium. In rings without endothelium losartan (a preferential angiotensin type 1 receptor antagonist) displayed competitive antagonism toward Ang II (pA2 = 9.5); PD 123319 (a preferential angiotensin type 2 receptor antagonist; up to 10(-7) mol/L) did not affect the response to the peptide. Losartan (3 x 10(-9) mol/L) but not PD 123319 (10(-7) mol/L) impaired the endothelium-dependent component of the response to the peptide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endothelial AT1-mediated release of nitric oxide decreases angiotensin II contractions in rat carotid artery. 759 Oct 14

Interferon-gamma (IFN-gamma) production by peripheral blood mononuclear leucocytes (MNL) is reduced in atopic dermatitis (AD) patients. This may be related to abnormalities in second messenger systems, and increased prostaglandin E2 (PGE2) release from monocytes. We compared the effects of manipulating the second messenger activity using the phosphodiesterase (PDE) inhibitor Ro 20-1724, dibutyryl cyclic adenosine monophosphate (cAMP), and cyclooxygenase inhibition of PGE2, on IFN-gamma production by cultured MNL from AD patients (n = 9) and normal controls (n = 10). Ficoll-Hypaque-separated MNL were cultured for 48 h with OKT3 stimulation, and cAMP, Ro 20-1724, or indomethacin. Supernatants were analysed for IFN-gamma by ELISA. Basal IFN-gamma was lower in AD patients, and the increase in IFN-gamma production with OKT3 was 6.5-fold greater in control subjects than patients with AD. Culture with indomethacin significantly enhanced OKT3-stimulated IFN-gamma production in both groups, whereas OKT3-stimulated IFN-gamma production was abolished with dibutyryl cAMP. IFN-gamma production was significantly lower with Ro 20-1742 in AD than in normal controls. We have shown reduced IFN-gamma release from unstimulated and stimulated MNL in AD patients compared with normal controls. The addition of indomethacin increased IFN-gamma production in both groups, although the increase was less in AD patients, suggesting an intrinsic cellular defect. IFN-gamma release from AD MNL was more sensitive to the inhibitory effects of PDE, and this may be due to increased PDE activity, or the hyperdynamic cAMP system present in atopics.
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PMID:gamma-interferon production in atopic dermatitis shows differential modification by phosphodiesterase and prostaglandin inhibition. 766 18

We have investigated the role of cAMP as a signal transducer for TNF-induction of leukocyte adhesion molecule expression in cultured human umbilical vein endothelial cells (EC). Forskolin, a stimulator of adenylate cyclase, either alone or in combination with isobutyl methylxanthine (IBMX), an inhibitor of phosphodiesterase, fails to induce expression of endothelial leukocyte adhesion molecule 1 (ELAM-1 or E-selectin), of vascular cell adhesion molecule 1 (VCAM-1) or of intercellular adhesion molecule 1 (ICAM-1 or CD54). Unexpectedly, this combination of cAMP-elevating drugs inhibits TNF induction of ELAM-1 and VCAM-1 but not ICAM-1 expression. Similar results were observed with the membrane-permeant cAMP mimetics 8 bromoadenosine 3':5' cyclic monophosphate (8Br-cAMP) and N(6)2'-O-dibutyryladenosine 3':5'-cyclic monophosphate. Inhibition was greater at lower TNF concentrations (< 10 U/ml), at higher 8 Br-cAMP concentrations (> 100 microM), and at early times (2 h). Forskolin plus IBMX selectively inhibits TNF-induced increases in ELAM-1 and VCAM-1 mRNA, indicating that the action of cAMP is to block synthesis of these molecules. TNF, through stimulation of prostaglandin synthesis, produces slight elevations in the levels of endothelial cAMP. However, these increases in cAMP appear too small compared to those induced by forskolin plus IBMX to inhibit adhesion molecule expression. Indeed, complete inhibition of the TNF-mediated rise in cAMP, achieved by blocking cyclooxygenase with indomethacin, does not alter ELAM-1 expression. We conclude that cAMP is neither an intracellular mediator nor a physiological regulator of TNF-induced adhesion molecule expression in EC. However, our findings suggest that pharmacological elevations of cAMP in EC, by inhibiting TNF-induced synthesis of ELAM-1 and VCAM-1, could serve to limit inflammation.
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PMID:Elevated cyclic AMP inhibits endothelial cell synthesis and expression of TNF-induced endothelial leukocyte adhesion molecule-1, and vascular cell adhesion molecule-1, but not intercellular adhesion molecule-1. 768 20

Murine peritoneal macrophages primed in vivo by trehalose dimycolate (TDM) express cytostatic activity against tumor cells after treatment in vitro with 10 ng/ml lipopolysaccharide (LPS) during a 4-hr period (activation step). There is a strict correlation (P < 0.0001) between acquisition of antitumoral activity and induction of NO synthase quantified by its end products citrulline and NO2-. LPS also stimulates the release of cyclooxygenase products which exert a retroinhibitory action on NO synthase and cytostatic activities, as judged by an increase of both parameters by indomethacin (1 microM) and a decrease by externally added PGE2 (1 microM). LPS increases cellular and extracellular cAMP levels through an indomethacin-sensitive pathway, pointing to cAMP as a second messenger in the retroinhibitory action of LPS-induced prostaglandins. In fact, the addition of 8-bromo-cAMP or of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine during the activation step decreases NO synthase activity; however, at the same time these drugs increase the apparent efficiency of NO as an antitumor agent.
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PMID:LPS-induced activation of primed murine peritoneal macrophages is modulated by prostaglandins and cyclic nucleotides. 768 61


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