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: pde 4
1,625 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1 The aims of the present study were to characterize the cyclic nucleotide phosphodiesterase (PDE) isoenzyme activities present in human bronchi and to examine the ability of selective isoenzyme inhibitors to relax histamine and methacholine precontracted preparations of human bronchi. 2 Three separations of pooled human bronchial tissue samples were performed. Ion-exchange chromatography showed that the soluble fraction of human bronchial preparations contains PDE I, II, III, IV and V isoenzyme activities. Multiple forms of PDE I and PDE IV were observed and PDE IV was the main cyclic AMP hydrolytic activity. 3 3-Isobutyl-l-methylxanthine (IBMX) non-selectively inhibited all separated isoenzyme activities. Zaprinast selectively inhibited PDE V, but also effectively inhibited one of the two PDE I isoforms identified. The PDE IV selective inhibitors rolipram and RO-201724, inhibited the PDE IV activities as did the dual PDE III/IV inhibitor, Org 30029. Org 9935, a PDE III selective inhibitor, potently attenuated part of the PDE IV activity peak in one of three separations performed, indicating that some PDE III activity may co-elute with PDE IV under the experimental conditions employed. 4 PDE IV-selective (rolipram), PDE III-selective (Org 9935) and dual PDE III/IV (Org 30029) inhibitors were effective relaxants of human bronchial smooth muscle. The PDE V/PDE I inhibitor, zaprinast was relatively ineffective. 5 The present study demonstrates in human bronchi, as in animal airways smooth muscle, that inhibitors of PDE III, PDEIV and dual PDE III/IV have potentially useful bronchodilator activity and are worthy of further consideration as anti-asthma drugs.
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PMID:Human bronchial cyclic nucleotide phosphodiesterase isoenzymes: biochemical and pharmacological analysis using selective inhibitors. 139 76

1. SK&F 95654 inhibited the guanosine 3':5'-cyclic monophosphate (cyclic GMP)-inhibited phosphodiesterase (cGI-PDE) with an IC50 value of 0.7 microM. The IC50 values were greater than 100 microM for the other four phosphodiesterase isoenzymes tested. The R-enantiomer of SK&F 95654 (IC50 = 0.35 microM) was a more potent inhibitor of cGI-PDE than was the S-enantiomer (IC50 = 5.3 microM). 2. In the guinea-pig working heart, SK&F 95654 produced a positive inotropic response without altering heart rate. 3. Oral administration of SK&F 95654 to conscious dogs caused dose-dependent increases in left ventricular dp/dtmax in the range 10-50 micrograms kg-1. These positive inotropic responses were maintained for 3 h without simultaneous changes in heart rate or blood pressure. The peak effects on left ventricular dp/dtmax were similar for orally and intravenously administered compound, indicating good oral bioavailability. 4. SK&F 95654 caused a potent inhibition of U46619-induced aggregation in both a human washed platelet suspension (WPS) (IC50 = 70 nM) and in human platelet-rich plasma (PRP) (IC50 = 60 nM), indicating that the compound shows negligible plasma binding. 5. The R-enantiomer of SK&F 95654 was twenty fold more potent as an inhibitor of platelet aggregation than was the S-enantiomer. The similarity of this ratio to that obtained on the cGI-PDE suggests that SK&F 95654 inhibits platelet aggregation via its effects on cGI-PDE. This was also indicated by studies which showed that SK&F 95654 increased adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels and activated cyclic AMP-dependent protein kinase in human platelets. 6. Collagen-induced aggregation of rat PRP was also inhibited by SK&F 95654 (ICso = 65 nM). The effects of SK&F 95654, administered intravenously, on ex vivo platelet aggregation were studied in the conscious rat. At 1 mg kg-', SK&F 95654 inhibited aggregation for at least 4 h post dose and was more potent than the two other cGI-PDE inhibitors studied (siguazodan and SK&F 94120).7. In contrast to its potent effects on heart and platelets, SK&F 95654 caused only a modest relaxation of histamine- or U46619-induced bronchoconstriction in the anaesthetized, ventilated guinea-pig.8. Taken together, these results indicate that SK&F 95654 may be a suitable agent for the treatment of congestive heart failure.
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PMID:The effect of SK&F 95654, a novel phosphodiesterase inhibitor, on cardiovascular, respiratory and platelet function. 142 92

In order to develop new oral bronchodilators, a series of novel imidazol[4,5-c][1,8]naphthyridin-4(5H)-ones 5 were designed and synthesized. Some of these new heterocycles exhibited more potent bronchodilator activity in vitro and in vivo than theophylline. With respect to modification at the 5-position, both phenyl and n-butyl substitution produced potent activity. Though bulk tolerance at N-3 is observed with short and small lipophilic groups, any substitution at the other positions and transformations of the parent skeleton eliminated activity. Thus 5-phenyl-1H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-one (23) (KF17625), which satisfied these conditions, was selected for further studies (antigen inhalation-induced bronchospasm model; minimum effective dose (MED) = 1 mg/kg, po; antigen-induced contraction of trachea (the Schultz-Dale reaction), IC50 = 2.2 microM). Compound 23 inhibited carbachol-, histamine-, or leukotriene D4-induced contraction and relaxed spontaneous tone in guinea pig isolated tracheal preparations with, 4- to 16-fold greater potency than aminophylline. Thus it appeared to relax directly the airway smooth muscle. 23 did not have any influence on adenosine binding at 10 microM, but inhibited canine tracheal phosphodiesterase (PDE) IV (IC50 = 12 microM) and concanavalin-A-induced histamine release from rat mast cells (44% inhibition at 10 microM). Although the detailed mechanisms of these compounds remain to be elucidated, this series of novel tricyclic heterocycles represents a new class of bronchodilator.
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PMID:New bronchodilators. 3. Imidazo[4,5-c][1,8]naphthyridin-4(5H)-ones. 147 86

By the reaction of 2-chloro-5-(4-pyridinyl)pyridines 1-6 with morpholine as well as by derivation of the 2-morpholino-pyridine-3-carboxamide 8 the 3-substituted 2-morpholino-5-(4-pyridinyl)pyridines 7-14 were prepared. The evaluation for positive inotropic properties in spontaneously beating isolated guinea pig atria gave for the 3-cyano derivative 7 (AWD 122-14) the best activity. The potency is comparable to that of milrinone and is due to partial by inhibition of phosphodiesterase III (PDE III).
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PMID:[Potential cardiotonics. 14. Synthesis and in vitro positive inotropic actions of 4-morpholino-5-(4-pyridinyl)pyridine derivatives]. 148 Jun 54

Inotropic support is often required for post-operative management of patients following mitral valve operation. The use of positive inotropes is limited by tolerance development and increase in myocardial oxygen demand. We have compared i.v. enoximone (E) (group E, n = 13), a recently developed phosphodiesterase (PDE) inhibitor, to the conventional i.v. therapeutics dopamine (D) and glyceroltrinitrate (G) in patients following mitral valve operation. The two groups were comparable in terms of physical and pre-operative haemodynamic data. Haemodynamic measurements including cardiac index (CI) determinations were recorded for the first 18 h post surgery in both groups. Group E received a bolus of 1 mg.kg-1 E followed by 4-20 micrograms.kg-1.min-1 (mean = 5 +/- 2 micrograms.kg-1.min-1) for 14 h according to therapeutic requirements, while group D received dopamine (4-10 micrograms.kg-1.min-1, mean = 3.8 +/- 1.9 micrograms.kg-1.min-1) and glyceroltrinitrate (0.5-5 micrograms.kg-1.min-1; mean = 4 +/- 2 micrograms.kg-1.min-1). Adrenaline was added if the MAP was below 60 mmHg or the CI was below 2.5 in both groups (range 50-500 ng.kg-1.min-1; mean E = 0.7 +/- 2 ng.kg-1.min-1; mean D = 2 +/- 2.8 ng.kg-1.min-1). Bolus injection of E resulted in a rise in CI from 2.6 to 3.21.min-1.m-2 (P less than 0.05) within 30 min, followed by a further rise to a maximum of 3.51.min-1.m-2 6 h post bolus. Termination of the E drip resulted in a drop of CI to baseline values (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enoximone, a post-operative inodilator in patients following mitral valve operation: a prospective and controlled study. 153 88

Pterins were extracted with methanol from sporangiophores of the lower fungus Phycomyces blakesleeanus and separated and identified by high performance liquid chromatography (HPLC) with fluorescence detection. The following pterins were found and identified for the wild-type strain NRRL1555: carboxypterin (6.7 x 10(-6) M), neopterin (4.2 x 10(-7) M), xanthopterin (5.3 x 10(-6) M), biopterin (3.9 x 10(-7) M), pterin (9.1 x 10(-7) M), and 6,7-dimethylpterin (1.2 x 10(-6) M). The HPLC elution profiles of the wild type were compared to a set of phototropism mutants (genotype mad) with specific defects in the light-transduction pathway. The mutant profiles were qualitatively similar to those of the wild type. Quantitative differences were, however, discerned for madA, madC, and madH mutants. The madA mutation was associated with increased amounts of biopterin and 6,7-dimethylpterin and a reduction of neopterin, pterin, xanthopterin, and unidentified pterins eluting at 14-18 min. The stimulatory effect of the madA mutation on biopterin and 6,7-dimethylpterin appears to be compensated by a secondary mutation (pde) which is responsible for the loss of 75% of adenosine 3',5'-cyclic monophosphate (cAMP)-phosphodiesterase activity. In a madA pde double mutant the amounts of biopterin and 6,7-dimethylpterin fell below the wild-type level. These results suggest that an increased level of endogenous cAMP represses the biosynthesis of these pterins. The madC mutation increased the amounts of biopterin and xanthopterin and that of the unidentified pterins which could be derivatized to carboxypterin. Single madB mutations had, compared to the wild type, two times higher amounts of biopterin and two times lower amounts of neopterin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Altered pterin patterns in photobehavioral mutants of Phycomyces blakesleeanus. 154 5

Amrinone is the only phosphodiesterase fraction III inhibitor currently available in the USA for the treatment of perioperative biventricular failure. Patients with chronic congestive heart failure (CHF) show down-regulation of the beta 1-adrenergic receptor with a decrease in receptor density and altered responses to catecholamines. Intravenous administration of amrinone can transiently restore beta 1-adrenergic responses in patients who have CHF. Amrinone's mechanism of vasodilatation, independent of the beta 1-adrenergic receptor, nitrates, and calcium entry blockers, proves an important therapeutic option for pulmonary hypertension. The elimination half-life of amrinone in volunteers is 2.6-4.1 h, and 3.5 h when administered into the cardiopulmonary bypass (CPB) circuit. Different loading and infusion doses have been reported for amrinone. Investigators have demonstrated that increases in cardiac output following amrinone administration are directly related to plasma concentration. In cardiac surgical patients, following a dose of 0.75 mg kg-1 administered into the CPB circuit, plasma concentrations are subtherapeutic after 10 min. We believe that, when using amrinone to facilitate separation from CPB, a bolus dose of 1.5 mg kg-1 or more should be administered. If therapeutic levels need to be maintained in patients with biventricular failure, an infusion should also be administered after the bolus dose. Additive effects have been demonstrated when catecholamines are administered concomitantly with amrinone and other PDE III inhibitors to increase cyclic AMP in cardiac muscle and improve contractility. The use of amrinone with catecholamines is also important clinically, because together they attenuate the vasoconstrictive effects of catecholamines alone, while the catecholamines support perfusion pressure. Amrinone represents a novel drug for managing biventricular dysfunction in cardiac surgical patients.
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PMID:Perioperative experience with amrinone. 160 Sep 63

1. For the purpose of clarifying the mechanism of the airways smooth muscle relaxant action of xanthines, cyclic guanosine monophosphate (GMP) phosphodiesterase (PDE) from guinea-pig trachealis muscle was purified with diethylaminoethyl ether (DEAE) cellulose column chromatography. 2. Five 3-alkylxanthines (3-methylxanthine, 3-ethylxanthine, 3-n-propylxanthine (enprofylline), 3-n-butylxanthine, and 3-iso-butylxanthine), and five 1-methyl-3-alkylxanthines (1-methyl-3-methyl-xanthine (theophylline), 1-methyl-3-ethylxanthine, 1-methyl-3-n-propylxanthine, 1-methyl-3-n-butylxanthine, and 1-methyl-3-iso-butylxanthine (IBMX] were compared in terms of purified cyclic GMP PDE inhibition. The relationship between the structure and inhibition of cyclic GMP PDE was studied. 3. The -log EC50 values for relaxation of spontaneous tone of isolated guinea-pig trachealis preparations by the 3-alkylxanthines and 1-methyl-3-alkylxanthines were determined. 4. The five 1-methyl-3-alkylxanthines were each more potent in relaxing isolated trachealis smooth muscle than the corresponding 3-alkylxanthines. The 1-methyl-3-alkylxanthines were also more potent than the corresponding 3-alkylxanthines in their cyclic GMP PDE inhibitory effect. There was a strong positive correlation between the concentration of inhibitor which inhibited hydrolysis by 50% (IC50) values for cyclic GMP PDE inhibition by the xanthine derivatives and their EC50 values for trachealis muscle relaxation. 5. It is suggested that the mechanism by which xanthine derivatives relax trachealis smooth muscle involves inhibition of cyclic GMP PDE in addition to inhibition of cyclic adenosine monophosphate PDE.
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PMID:Inhibition of cyclic GMP phosphodiesterase by xanthine derivatives relaxes guinea-pig trachealis smooth muscle. 164 81

Canine cardiac muscle contains a type IV cyclic AMP (cAMP) phosphodiesterase (PDE) that is composed of two subtypes. One subtype is sensitive to rolipram inhibition (RSPDE), whereas the other is not inhibited significantly by rolipram (RIPDE). The RIPDE is inhibited by several cardiotonic agents operating by a PDE-inhibitory mechanism. Bemoradan [RWJ-22867; 7-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-2H-1,4-benzoxazin -3(4H)-one], a novel, potent positive inotropic agent, demonstrated biphasic inhibition of the fraction III enzyme from canine cardiac muscle. Inhibition by rolipram of the RSPDE converted the IC50 curves of bemoradan, indolidan, pimobendan, and imazodan to sigmoidal, monophasic curves. Lineweaver-Burk analysis yielded competitive inhibition KI values of 0.023, 0.09, 0.065 and 0.60 microM, respectively, for these compounds. The cardiotonic compounds, however, were not potent inhibitors of the Type I and Type II cAMP PDEs found in canine ventricular muscle. The order of potency for inhibiting the RIPDE cAMP PDE subtype was bemoradan greater than pimobendan greater than indolidan greater than imazodan. Bemoradan is, therefore, a potent inhibitor of the cardiac muscle cAMP PDE which could, in part, be responsible for its cardiotonic activity.
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PMID:Bemoradan--a novel inhibitor of the rolipram-insensitive cyclic AMP phosphodiesterase from canine heart tissue. 165 Feb 19

Cyclic nucleotide phosphodiesterases (PDEs) are the only enzymes that inactivate intracellular cyclic AMP (cAMP). Because the functions of T-lymphocytes are modulated by cAMP levels, the isozymes of PDE in these cells are potential targets for new drugs designed to modify the body's immunity through selective alteration of T-lymphocyte PDE activity. Cyclic GMP and 3(2H)-pyridazinone-4,5- dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-5-methyl-monohydrochloride (CI-930) selectively inhibit the catalytic activity of one of the two high affinity cAMP-PDE isozyme families known to occur in mammals, whereas d,l-1,4-[3-butoxy-4-methoxybenzyl]-2-imidazolidinone (Ro 20-1724) selectively inhibits the other. The objectives of this investigation were: (1) to determine whether human T-lymphocytes contain one or both of these pharmacologically distinguishable high-affinity cAMP-PDEs, and (2) to determine the effects of selective inhibitors of these PDEs on lymphocyte blastogenesis. High-affinity cAMP-PDE was found in both the soluble and particulate fractions of T-lymphocyte sonicates. Cyclic GMP and CI-930 inhibited PDE in the particulate fraction better than in the soluble fraction, but the converse was found for Ro 20-1724. CI-930 or Ro 20-1724, used alone, attenuated T-lymphocyte blastogenesis, but neither suppressed it completely. In combination, the same PDE inhibitors caused greater suppression of blastogenesis than either produced alone. The results indicate that human T-lymphocytes contain both CI-930- and Ro 20-1724-inhibitable isozymes. Either of the isozymes can modulate human T-lymphocyte blastogenesis, but inhibition of both isozymes produces synergistic antiblastogenic effects.
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PMID:Multiple high-affinity cAMP-phosphodiesterases in human T-lymphocytes. 165 Oct 80


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