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)

Ruthenium red inhibited Ca2(+)-dependent phosphodiesterase (Ca2(+)-PDE) selectively with an IC50 value of 15 microM. Increasing calmodulin concentration in the presence of both 100 microM and 4000 microM Ca2+ completely reversed the inhibition of Ca2(+)-PDE activity by ruthenium red. Ruthenium red-induced inhibition of Ca2(+)-PDE activity was also overcome by increasing the concentration of Ca2+ in the presence of both 200 ng and 2000 ng calmodulin, in sharp contrast to fluphenazine-induced inhibition of Ca2(+)-PDE. These results indicate that ruthenium red has distinct inhibitory mechanism which differs from that of calmodulin antagonists previously reported.
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PMID:Effects of ruthenium red on activation of Ca2(+)-dependent cyclic nucleotide phosphodiesterase. 169 2

The involvement of rolipram-sensitive phosphodiesterase (PDE IV) in regulation of cardiac contraction was investigated by studying the effect of selective inhibitors (rolipram, denbufylline, Ro 20-1724) on guinea pig left atria contraction. In contrast to milrinone and SK&F 94120 (inhibitors of the cyclic GMP-inhibited PDE, PDE III), (+/-)-rolipram and denbufylline (0.1-30 microM) did not produce any positive inotropic effect in normal (2.5 mM) or elevated (3-3.2 mM) external CaCl2 concentration. In these conditions, Ro 20-1724 produced only a slight but significant increase of contraction over control levels. In the presence of forskolin (an adenylate cyclase activator) or SK&F 94120 (a PDE III inhibitor), which produced an increase of the response to electrical stimulation of approximately 10%, (+/-)-rolipram, denbufylline, and Ro 20-1724 all exerted concentration-dependent positive inotropic effects (mean EC50 values were 20, 25, and 125 nM, respectively, in the presence of forskolin). Rolipram exhibited stereospecificity: the (-)-enantiomer was 10 times more potent than the (+)-enantiomer. Neither preincubation of the atria with atenolol nor pretreatment of the guinea pigs with reserpine significantly modified the effect of PDE IV inhibitors obtained in the presence of forskolin. These data show that in the presence of cyclic AMP-dependent positive inotropic agents, PDE IV inhibitors exert a positive inotropic effect which probably does not involve enhanced catecholamine release from sympathetic nerve endings. This suggests that PDE IV may play a role in regulation of cardiac contraction in physiologic conditions in which the sympathetic outflow produces a stimulation of adenylate cyclase in cardiac cells.
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PMID:Involvement of rolipram-sensitive cyclic AMP phosphodiesterase in the regulation of cardiac contraction. 170 3

EMD 53 998, a novel thiadiazinone derivative, increases the contractile force of cardiac tissue in vitro through both an inhibition of phosphodiesterase III (PDE III) and a sensitization of cardiac contractile proteins to Ca2+. Guinea pig ventricular PDE III is selectively inhibited by EMD 53 998 (IC50 = 60 nM) without major effects on other PDE isoenzymes. Consonant with this is an increase in cAMP content of rat ventricular cells and a potentiation by EMD 53 998 of the cAMP-elevating action of isoprenaline (increase by 50% at 1.3 microM). Sensitization to Ca2+ by EMD 53 998 (3-30 microM) finds its expression in a leftward shift of the Ca2+ response curve for force generation in skinned fibers from porcine ventricular muscle and failing human heart as well as for activation of bovine cardiac myofibrillar actomyosin ATPase. Interestingly, EMD 53 998 elevates the maximum of the Ca(2+)-response curve for both parameters. Pimobendan studied under identical conditions was 100 times less potent than EMD 53 998. EMD 53 998 increases force development of guinea pig papillary muscle in a concentration-dependent manner with an EC50 of 3.6 microM, thus being 10 times more potent than pimobendan. In contrast to pimobendan, the positive inotropic effect of EMD 53 998 is barely affected by carbachol. Further evidence for a Ca(2+)-sensitizing effect of EMD 53 998 is provided by an additional increase in force generation in the presence of supramaximal isoprenaline concentrations. It is concluded that the positive inotropic action of EMD 53 998 is mediated through both cAMP-independent and cAMP-dependent mechanisms, with the former probably prevailing. We are not aware of other compounds with a similarly high Ca(2+)-sensitizing potency. On these grounds. EMD 53 998 appears to be a promising inotropic agent.
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PMID:The novel cardiotonic agent EMD 53 998 is a potent "calcium sensitizer". 171 87

The purpose of this study was to determine if idazoxan, an alpha 2-adrenergic antagonist, could enhance the antithrombotic activity of pelrinone, a PDE III inhibitor, in a canine model of coronary thrombosis that uses electrical current to injure the coronary endothelium. Thrombus mass in vehicle-treated animals was 37.9 +/- 8 mg. Pelrinone, 0.625 and 2.5 mg/kg decreased thrombus size by 46 and 21%, respectively, while idazoxan, 0.75 mg/kg decreased thrombus mass by 43%. When this dose of idazoxan was combined with pelrinone, 0.625 and 2.5 mg/kg, thrombus mass was decreased by 71 and 91%, respectively. Antithrombotic efficacy correlated with the ability of these treatments to inhibit epinephrine-sensitized, collagen-induced platelet aggregation. Sixty minutes following drug administration, idazoxan, 0.50 mg/kg inhibited aggregation by 50%, while pelrinone, 0.625 and 2.5 mg/kg inhibited aggregation by 55 and 68%, respectively. Combined administration of idazoxan with pelrinone, 0.625 and 2.5 mg/kg resulted in 80 and 95% inhibition of aggregation, respectively. Similar trends in inhibiting platelet aggregation to epinephrine-sensitized ADP and arachidonic acid were also observed. Experimental treatments did not affect hematocrit or circulating platelet count, although pelrinone was observed to prolong prothrombin time slightly. To examine the effect of drug-induced increases in coronary blood flow on thrombus formation, the potassium channel activator drug cromakalim was studied at a dose (0.1 mg/kg) that increased coronary blood flow by 25-35 ml/min above baseline in sham control animals. Animals treated with cromakalim showed a shorter time to coronary occlusion (103 +/- 11 min) vs. vehicle (173 +/- 24 min) and developed larger thrombi (53.7 +/- 19 mg). These results demonstrate that coronary vasodilation does not contribute to antithrombotic activity in this model. Results from the study also show that alpha-adrenergic inhibition of platelet function can potentiate phosphodiesterase inhibitor antiaggregatory and antithrombotic activity.
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PMID:Antithrombotic activity of the phosphodiesterase III inhibitor pelrinone in a canine model of coronary artery thrombosis: enhancement of efficacy with concurrent alpha 2-adrenergic antagonism. 172 88

An adrenal cGMP-stimulated phosphodiesterase (cGS-PDE) has been shown to mediate atrial natriuretic peptide (ANP)-induced reductions in aldosterone secretion and cAMP levels in primary bovine glomerulosa cells. High concentrations of cGS-PDE have been localized to the zona glomerulosa cell layer of the adrenal cortex using biochemical and immunological techniques. Immunoblot analysis using an affinity-purified, isozyme-specific antiserum revealed a single band that comigrated with a purified cGS-PDE (105 kDa) (1) and that was most highly concentrated in the outermost 1-2 mm of the cortex, representing the capsule and zona glomerulosa regions. Greater than 90% of the overall phosphodiesterase activity present in tissue extracts prepared from these regions was immunoprecipitated using a solid-phase monoclonal antibody reagent, indicating the cGS-PDE as the predominant phosphodiesterase isozyme. Immunohistochemical staining experiments of frozen thin sections of intact adrenal tissue revealed that the cGS-PDE present in this region was localized in the glomerulosa cells themselves. The role of this isozyme as a mediator of ANP-induced decreases in intracellular cAMP concentrations and aldosterone production was tested in primary cultures of bovine adrenal glomerulosa cells. In cells stimulated by ACTH, ANP treatment produced dose-dependent reductions in aldosterone secretion and cellular cAMP content over the same concentration range. Increases in aldosterone production elicited by three cell-permeable cAMP derivatives (8-bromo-cAMP, 8-p-chlorophenylthio-cAMP, and N6-2'-O-dibutyryl-cAMP) were antagonized by ANP, indicating a site of action distal to adenylate cyclase for this hormone. Because the relative magnitude of the ANP effect differed depending upon the derivative used, the three derivatives were compared with respect to their relative rates of in vitro hydrolysis by adrenal cGS-PDE. A positive correlation between their rates of hydrolysis and the degree to which the steroidogenic response produced by these derivatives was antagonized by ANP was demonstrated, further suggesting an ANP-induced activation of the cGS-PDE as being responsible for this effect. The possible contribution of an additional pathway mediated by an inhibitory guanine nucleotide binding regulatory protein (Gi) acting on adenylate cyclase was tested by pretreatment of primary glomerulosa cells with pertussis toxin. Levels of pertussis toxin sufficient to inhibit subsequent in vitro ribosylation did not significantly alter the ANP effect on aldosterone production, although a partial reduction in the ANP effect on cAMP levels was observed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:High concentrations of a cGMP-stimulated phosphodiesterase mediate ANP-induced decreases in cAMP and steroidogenesis in adrenal glomerulosa cells. 184 62

An equilibrium kinetics model is proposed to described some of the enzymatic properties of the cyclic GMP-stimulated phosphodiesterase activity associated with brain clathrin coated vesicles. The model assumes the presence of pharmacologically distinct regulatory and catalytic domains in the enzyme. The model contemplates that random fashion occupancy of the regulatory site by the substrate, cyclic GMP, induces a conformational change which leads to the generation of an actived catalytic state. Therefore, cyclic GMP is a positive allosteric modulator of the coated vesicle enzyme. Experimental data revealed that occupancy or activation of the regulatory site was not essential for catalysis to occur since hydrolysis occurred after loss (200%) of the activation by cyclic GMP. This constitutes an example of non-essential substrate activation. Analysis of this PDE following activation by cGMP and after loss of the regulation, activation capacity of the enzyme allows the calculation of the various kinetic parameters inherent in the model.
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PMID:Equilibrium kinetics model for the cGMP-stimulated phosphodiesterase of brain coated vesicles. 196 77

Phosphodiesterase inhibitors that are selective for cAMP-specific cardiac and vascular PDE III comprise a new group of agents for the treatment of heart failure, which at present are limited to clinical shortterm intravenous use and research uses only. Although both intravenous amrinone and milrinone are FDA approved, only amrinone is available for general clinical use. Selective phosphodiesterase inhibition produces beneficial actions of positive inotropy and peripheral vasodilation that result from increased cardiac and vascular muscle concentrations of intracellular cAMP and ionic calcium. In addition, a positive lusitropic action (enhancement of cardiac relaxation) has been observed. Neither beta-adrenergic agonist activity nor inhibition of the sodium-potassium ATPase is produced by these agents. The magnitude of hemodynamic improvement generally exceeds that of the cardiac glycosides and is comparable with that of intravenous catecholamines such as dobutamine. The different pharmacodynamic profile of the PDE inhibitors is additive to the effects of cardiac glycosides, complementary and synergistic to the actions of catecholamines, and has been shown to have favorable effects on coronary hemodynamics. As a result there is continued enthusiasm for the short-term intravenous use of amrinone and potentially milrinone in the setting of acute heart failure resulting from systolic dysfunction (after myocardial infarction, open heart surgery, or infectious or toxic myocarditis), heart failure resulting from right ventricular systolic dysfunction, and when patients with severe heart failure await cardiac transplantation. Initiation of treatment with an intravenous bolus followed by a maintenance infusion provides prompt increases in stroke volume and cardiac output and simultaneous reductions in right and left ventricular filling pressures and systemic vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acute positive inotropic intervention: the phosphodiesterase inhibitors. 203 20

During the course of our screening of bioactive natural products, three new saponins named periandradulcins A (1), B (2) and C (3) were isolated as phosphodiesterase (PDE, EC 3.1.4.17) inhibitors from 80% MeOH extract of the roots of Periandra dulcis Mart. (Leguminosae) by a combination of column chromatography and reversed- and normal-phase high-performance liquid chromatography (HPLC). On the basis of 1H-, 13C- and two-dimensional nuclear magnetic resonance (NMR) spectral data and chemical evidence, their chemical structures were characterized as 3-O-beta-[alpha-L-rhamnopyranosyl(1----2)-beta-D-xylopyranosyl(1----2)-b eta-D- glucuronopyranosyl]-30-hydroxyl-25-formylolean-18-ene-22 beta-O-syringate, 3-O-beta-[alpha-L-rhamnopyranosyl(1----2)-beta-D- xylopyranosyl(1----2)-beta-D-glucuronopyranosyl]-22 beta-hydroxyl-25- formylolean-12-ene and 3-O-beta-[alpha-L-rhamnopyranosyl(1----2)-beta-D- glucopyranosyl(1----2)-beta-D-glucuronopyranosyl]-22 beta-hydroxyl-25-formylolean-18-ene, respectively. The concentrations of periandradulcins A, B and C required to give 50% inhibition (IC50 values) of PDE from bovine heart, were 0.033, 7.6 and 7.7 microM, respectively. Compound 1 was the most potent among the known PDE inhibitors; it inhibited PDE-I (IC50:0.0022 microM) twenty and forty times more effectively than PDE-II and -III, respectively.
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PMID:Periandradulcins A, B and C: phosphodiesterase inhibitors from Periandra dulcis Mart. 207 Apr 39

Enoximone is a selective inhibitor of the phosphodiesterase-III enzyme (PDE-III) and possesses positive inotropic and vasodilatory properties. The PDE-inhibitor amrinone has been associated with adverse effects on coagulation by decreasing platelets. To investigate the influence of enoximone on hemostasis, 18 patients undergoing elective aorto-coronary bypass grafting and receiving enoximone were compared to a control group (n = 18). In addition, the plasma levels of enoximone and its major metabolite (enoximone-sulfoxide) were studied following a single injection (0.5 mg/kg) and during a continuous infusion (5 and 10 micrograms/kg.min) before, during and after extracorporeal circulation (ECC). No difference between study and control groups was found for the parameters of coagulation during the investigation period; in particular there were no differences in platelet count and platelet function (thrombelastography). Following the single bolus, peak plasma levels decreased during ECC to ineffective levels. Continuous infusion, however, maintained effective plasma levels of enoximone; sulfoxide levels were twice as high as enoximone concentrations up until the end of the investigation period. It is concluded that enoximone can be judged to be safe in respect to its effects on coagulation even following ECC and at relatively high doses. The use of continuous infusion results in plasma levels which remain at an effective concentration through to the time that the patient is transferred to the intensive care unit.
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PMID:The new phosphodiesterase inhibitor enoximone in patients following cardiac surgery--pharmacokinetics and influence on parameters of coagulation. 213 82

Experiments were carried out in order to isolate and characterize the cyclic nucleotide phosphodiesterase activities in primary and low passages of cultured bovine aortic endothelial cells. The subcellular characterization of the cyclic nucleotide hydrolytic activity showed that both cAMP and cGMP hydrolytic activities were predominant in the cytosolic rather than the particulate fraction of the endothelial cell homogenate. At a low substrate concentration (0.25 microM), the major hydrolytic activity was for cAMP while at a high concentration (20 microM) it was for both cAMP and cGMP. Both cAMP and cGMP hydrolytic activities were insensitive to calmodulin. Cytosolic cyclic nucleotide phosphodiesterase activity was resolved into two distinct phosphodiesterase forms using HPLC. The first eluted form was designated cGS-PDE: it hydrolysed both cAMP and cGMP and its cAMP hydrolytic activity was markedly enhanced by the presence of cGMP. The second form was designated cAMP-PDE: it selectively hydrolysed cAMP. The cytosolic cAMP-PDE was inhibited by micromolar concentrations of cAMP-PDE inhibitors such as trequinsin, rolipram, dipyridamole or papaverine. The cGS-PDE was inhibited by micromolar concentrations of trequinsin, dipyridamole and papaverine and was insensitive to rolipram, except for the hydrolysis of cAMP which was inhibited in the micromolar range. Both the cAMP-PDE and the cGS-PDE were relatively insensitive to the selective cGMP-PDE inhibitor, zaprinast which was about 750-fold less potent on endothelial PDEs than on smooth muscle cGMP-PDE. The identification of selective and specific PDE inhibitors of the different PDE forms may allow a better understanding of the regulation and the role of cyclic nucleotides in endothelial cells.
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PMID:Characterization of cyclic nucleotide phosphodiesterases from cultured bovine aortic endothelial cells. 215 83


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