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Phosphodiesterase Inhibitor

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6621. Inhibition of cyclic 3'-5'-guanosine monophosphate-specific phosphodiesterase selectively vasodilates the pulmonary circulation in chronically hypoxic rats. Full Text available with Trip Pro

Inhibition of cyclic 3'-5'-guanosine monophosphate-specific phosphodiesterase selectively vasodilates the pulmonary circulation in chronically hypoxic rats. While it is known that nitric oxide (NO) is an important modulator of tone in the hypertensive pulmonary circulation, the roles of cyclic 3'-5'-guanosine monophosphate (cGMP) and cGMP-phosphodiesterase (PDE) are uncertain. We found that isolated lung perfusate levels of cGMP were over ninefold elevated in hypertensive vs. normotensive (...) control rats. 98-100% of lung cGMP hydrolytic activity was cGMP-specific PDE5, with no significant decrease in PDE activity in hypertensive lungs, suggesting that the elevation in cGMP was due to accelerated production rather than reduced degradation. In pulmonary hypertensive rat lungs, in vitro, cGMP-PDE inhibition by E4021[1-(6-chloro-4-(3,4-methylbenzyl) amino-quinazolin-2-yl)piperdine-4-carboxylate], increased perfusate cGMP threefold, reduced hypoxic vasoconstriction by 58 +/- 2%, and reduced

1996 Journal of Clinical Investigation

6622. Distinctive anatomical patterns of gene expression for cGMP-inhibited cyclic nucleotide phosphodiesterases. Full Text available with Trip Pro

Distinctive anatomical patterns of gene expression for cGMP-inhibited cyclic nucleotide phosphodiesterases. Type III cGMP-inhibited phosphodiesterases (PDE3s) play important roles in hormonal regulation of lipolysis, platelet aggregation, myocardial contractility, and smooth muscle relaxation. We have recently characterized two PDE3 subtypes (PDE3A and PDE3B) as products of distinct but related genes. To elucidate their biological roles, in this study we compare cellular patterns of gene

1995 Journal of Clinical Investigation

6623. Phosphodiesterase 3 inhibitors suppress oocyte maturation and consequent pregnancy without affecting ovulation and cyclicity in rodents. Full Text available with Trip Pro

Phosphodiesterase 3 inhibitors suppress oocyte maturation and consequent pregnancy without affecting ovulation and cyclicity in rodents. During each reproductive cycle, a preovulatory surge of gonadotropins induces meiotic maturation of the oocyte in the preovulatory follicle followed by ovulation. Although gonadotropins stimulate cAMP production in somatic cells of the follicle, a decrease in intra-oocyte cAMP levels is required for resumption of meiosis in oocytes. Based on the observed (...) compartmentalization of the cAMP-degrading enzyme, phosphodiesterase, in follicular somatic and germ cells, inhibitors of phosphodiesterase 3 were used to block meiosis in ovulating oocytes in rodents. By this strategy, we demonstrated that fertilization and pregnancy could be prevented without disturbing follicle rupture and normal estrous cyclicity. In contrast to conventional contraceptive pills that disrupt ovarian steroidogenesis and reproductive cycles, the present strategy achieves effective contraception

1998 Journal of Clinical Investigation

6624. Phosphorylation and activation of phosphodiesterase type 3B (PDE3B) in adipocytes in response to serine/threonine phosphatase inhibitors: deactivation of PDE3B in vitro by protein phosphatase type 2A. Full Text available with Trip Pro

Phosphorylation and activation of phosphodiesterase type 3B (PDE3B) in adipocytes in response to serine/threonine phosphatase inhibitors: deactivation of PDE3B in vitro by protein phosphatase type 2A. Phosphodiesterase type 3B (PDE3B) has been shown to be activated and phosphorylated in response to insulin and hormones that increase cAMP. In order to study serine/threonine protein phosphatases involved in the regulation of rat adipocyte PDE3B, we investigated the phosphorylation and activation (...) of PDE3B in vivo in response to phosphatase inhibitors and the dephosphorylation and deactivation of PDE3B in vitro by phosphatases purified from rat adipocyte homogenates. Okadaic acid and calyculin A induced dose- and time-dependent activation of PDE3B. Maximal effects were obtained after 30 min using 1 microM okadaic acid (1.8-fold activation) and 300 nM calyculin A (4-fold activation), respectively. Tautomycin and cyclosporin A did not induce activation of PDE3B. Incubation of adipocytes with 300

1999 Biochemical Journal

6625. Severe digital ischaemia treated with phosphodiesterase inhibitors Full Text available with Trip Pro

Severe digital ischaemia treated with phosphodiesterase inhibitors 15479910 2004 12 14 2015 11 19 0003-4967 63 11 2004 Nov Annals of the rheumatic diseases Ann. Rheum. Dis. Severe digital ischaemia treated with phosphodiesterase inhibitors. 1522-4 Kumana C R CR Cheung G T Y GT Lau C S CS eng Case Reports Letter England Ann Rheum Dis 0372355 0003-4967 0 Phosphodiesterase Inhibitors 0 Piperazines 0 Purines 0 Sulfones BW9B0ZE037 Sildenafil Citrate IM Adult Aged Female Fingers blood supply Humans (...) Hypertension, Pulmonary complications Ischemia drug therapy etiology Phosphodiesterase Inhibitors therapeutic use Piperazines therapeutic use Purines Raynaud Disease complications Sildenafil Citrate Sulfones Toes blood supply 2004 10 14 9 0 2004 12 16 9 0 2004 10 14 9 0 ppublish 15479910 63/11/1522 10.1136/ard.2003.015677 PMC1754817

2004 Annals of the Rheumatic Diseases

6626. Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. Full Text available with Trip Pro

Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. The molecular signaling events by which leptin exerts its functions in vivo are not well delineated. Here, we show a novel leptin signaling mechanism that requires phosphoinositide 3-kinase (PI 3-kinase)-dependent activation of cyclic nucleotide phosphodiesterase 3B (PDE3B) and subsequent suppression of cAMP levels. In pancreatic beta cells, leptin causes the activation of PDE3B, which leads to marked inhibition (...) of glucagon-like peptide-1-stimulated insulin secretion. The effect of leptin is abolished when insulin secretion is induced with cAMP analogues that cannot be hydrolyzed by PDE3B. Selective inhibitors of PDE3B and PI 3-kinase completely prevent the leptin effect on insulin secretion and cAMP accumulation. The results demonstrate that one of the physiological effects of leptin, suppression of insulin secretion, is mediated through activation of PDE3B and suggest PDE3B as a mediator of leptin action

1998 Journal of Clinical Investigation

6627. cAMP-specific phosphodiesterase HSPDE4D3 mutants which mimic activation and changes in rolipram inhibition triggered by protein kinase A phosphorylation of Ser-54: generation of a molecular model. Full Text available with Trip Pro

cAMP-specific phosphodiesterase HSPDE4D3 mutants which mimic activation and changes in rolipram inhibition triggered by protein kinase A phosphorylation of Ser-54: generation of a molecular model. Ser-13 and Ser-54 were shown to provide the sole sites for the protein kinase A (PKA)-mediated phosphorylation of the human cAMP-specific phosphodiesterase isoform HSPDE4D3. The ability of PKA to phosphorylate and activate HSPDE4D3 was mimicked by replacing Ser-54 with either of the negatively charged (...) amino acids, aspartate or glutamate, within the consensus motif of RRES54. The PDE4 selective inhibitor rolipram ¿4-[3-(cyclopentoxy)-4-methoxyphenyl]-2-pyrrolidone¿ inhibited both PKA-phosphorylated HSPDE4D3 and the Ser-54-->Asp mutant, with an IC50 value that was approximately 8-fold lower than that seen for the non-PKA-phosphorylated enzyme. Lower IC50 values for inhibition by rolipram were seen for a wide range of non-activated residue 54 mutants, except for those which had side-chains able

1998 Biochemical Journal

6628. Theophylline accelerates human granulocyte apoptosis not via phosphodiesterase inhibition. Full Text available with Trip Pro

Theophylline accelerates human granulocyte apoptosis not via phosphodiesterase inhibition. Theophylline, in addition to its bronchodilator effect, is reported to have an antiinflammatory action that may account for its clinical effectiveness in the reduction of inflammatory cells in the airway. In bronchial asthma, such inflammatory cytokines as GM-CSF and IL-5 are upregulated and have been proposed to cause granulocyte infiltration (neutrophils and eosinophils) in the airway by inhibition (...) . The percentage of IL-5 (5 ng/ml)-induced delayed eosinophil apoptosis also increased from 22+/-4% to 33+/-2% (P < 0. 05). In contrast, cyclic AMP (cAMP)-increasing agents (3-isobutylmethylxanthine, dibutyryl cAMP, and rolipram) inhibited granulocyte apoptosis in the control and anti-Fas antibody-treated cells. In eosinophils, the expression of bcl-2 protein decreased after incubation with theophylline. These findings suggest that theophylline accelerates granulocyte apoptosis, which may play an essential

1997 Journal of Clinical Investigation

6629. Phosphodiesterase inhibitors: new opportunities for the treatment of asthma. Full Text available with Trip Pro

Phosphodiesterase inhibitors: new opportunities for the treatment of asthma. 1877039 1991 09 26 2018 11 13 0040-6376 46 7 1991 Jul Thorax Thorax Phosphodiesterase inhibitors: new opportunities for the treatment of asthma. 512-23 Torphy T J TJ Department of Pharmacology, Smith Kline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406. Undem B J BJ eng Journal Article Review England Thorax 0417353 0040-6376 0 Phosphodiesterase Inhibitors IM Asthma drug therapy immunology Humans (...) Leukocytes immunology Muscle Relaxation drug effects Phosphodiesterase Inhibitors adverse effects therapeutic use Respiratory Muscles drug effects 120 1991 7 1 1991 7 1 0 1 1991 7 1 0 0 ppublish 1877039 PMC463251 Thorax. 1981 Oct;36(10):741-4 7330791 J Physiol. 1977 Sep;271(1):193-214 72146 Physiol Rev. 1977 Jul;57(3):421-509 196302 Clin Exp Pharmacol Physiol. 1978 Sep-Oct;5(5):535-9 215363 Mol Cell Biochem. 1978 Oct 13;21(1):9-15 215899 Adv Cyclic Nucleotide Res. 1977;8:119-43 200125 J Exp Med. 1972 Sep

1991 Thorax

6630. Activation of phosphodiesterase 5 and inhibition of guanylate cyclase by cGMP-dependent protein kinase in smooth muscle. Full Text available with Trip Pro

Activation of phosphodiesterase 5 and inhibition of guanylate cyclase by cGMP-dependent protein kinase in smooth muscle. The regulation of cGMP-specific phosphodiesterase (PDE) 5 and soluble guanylate cyclase (GC) by cGMP- and cAMP-dependent protein kinases (PKG and PKA respectively) was examined in gastric smooth muscle. The NO donor, sodium nitroprusside (SNP), stimulated PDE5 phosphorylation and activity, which was blocked by the selective PKG inhibitor, KT5823, resulting in an elevation (...) of cGMP levels. Activation of PKA either directly by Sp-5,6-dichloro-1-beta-d-ribofuranosyl benzimidazole 3',5'-cyclic monophosphothioate, or via isoproterenol- and forskolin-dependent increase in cAMP, also caused an increase in PDE5 phosphorylation and activity, but only in the presence of cGMP; consistent with the dependence of PDE5 phosphorylation and activity on cGMP binding to allosteric sites in the regulatory domain of PDE5. The selective PKA inhibitors, myristoylated protein kinase inhibitor

2001 Biochemical Journal

6631. Pharmacology of a new cyclic nucleotide phosphodiesterase type 4 inhibitor, V11294. (Abstract)

Pharmacology of a new cyclic nucleotide phosphodiesterase type 4 inhibitor, V11294. V11294 is a new cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitor of the rolipram class. In this report we present the pharmacological profile of V11294. V11294 inhibited PDE4 isolated from human lung with IC(50) 405 nM, compared to 3700 nM for rolipram. In contrast, V11294 inhibition of human PDE3 and PDE5 occurred only at concentrations greater than 100,000 nM. Like rolipram, V11294 inhibited PDE4D (...) more potently than other PDE4 subtypes. V11294, when incubated with human anticoagulated whole blood in vitro, or administered to mice, caused increased cAMP concentration, consistent with inhibition of PDE4. V11294 inhibited lectin-induced proliferation and lipopolysaccharide-induced TNFalpha synthesis by human adherent monocytes in vitro and inhibited lipopolysaccharide-induced TNFalpha synthesis in mice. V11294 caused relaxation of guinea pig isolated trachea and inhibited allergen-induced

2003 Pulmonary Pharmacology & Therapeutics

6632. Beneficial effects of phosphodiesterase 5 inhibition in pulmonary hypertension are influenced by natriuretic Peptide activity. (Abstract)

Beneficial effects of phosphodiesterase 5 inhibition in pulmonary hypertension are influenced by natriuretic Peptide activity. Phosphodiesterase type 5 (PDE5) inhibitors (eg, sildenafil) are a novel, orally active approach to the treatment of pulmonary arterial hypertension. The role of natriuretic peptides in the response to sildenafil was examined in mice lacking NPR-A, a guanylyl cyclase-linked natriuretic peptide receptor, in which pulmonary hypertension was induced by hypoxia.Mice (...) homozygous for NPR-A (NPR-A+/+) and null mutants (NPR-A-/-) were studied. Sildenafil inhibited the pressor response to acute hypoxia in the isolated perfused lungs of both genotypes. This effect was greater in the presence of atrial natriuretic peptide in the perfusate in NPR-A+/+ mice but not NPR-A-/- animals. In vivo, NPR-A mutants had higher basal right ventricular (RV) systolic pressures (RVSPs) than did NPR-A+/+ mice, and this was not affected by 3 weeks of treatment with sildenafil (25 mg x kg(-1

2003 Circulation

6633. Prostaglandin E2-mediated anabolic effect of a novel inhibitor of phosphodiesterase 4, XT-611, in the in vitro bone marrow culture. Full Text available with Trip Pro

Prostaglandin E2-mediated anabolic effect of a novel inhibitor of phosphodiesterase 4, XT-611, in the in vitro bone marrow culture. The mechanism of osteoblast formation by a novel PDE4 inhibitor, XT-611, was studied in the in vitro bone marrow culture system. The compound potentiated the osteoblast differentiation through accumulation of cyclic AMP after autocrine stimulation of EP4 receptor by PGE2 in pro-osteoblastic cells.We previously reported that inhibitors of phosphodiesterase (PDE)4 (...) isoenzyme increase osteoblast formation in an in vitro bone marrow culture system and inhibit bone loss in animal osteoporosis models. Here we investigated the mechanism of the effect of a novel PDE4 inhibitor, 3,4-dipropyl-4,5,7,8-tetrahydro-3H-imidazo[1,2-i]-purin-5-one (XT-611), on osteoblast formation in the in vitro bone marrow culture system.Rodent bone marrow cells were cultured in the presence of 0.2 mM ascorbic acid phosphate ester, 1 mM beta-glycerophosphate, and 10 nM dexamethasone for 10

2003 Journal of Bone and Mineral Research

6634. Phosphodiesterase type 4 inhibition of activated polymorphonuclear leukocytes in a simulated extracorporeal circulation model. Full Text available with Trip Pro

Phosphodiesterase type 4 inhibition of activated polymorphonuclear leukocytes in a simulated extracorporeal circulation model. Cardiopulmonary bypass is associated with a systemic inflammatory response syndrome and the risk of multiorgan injuries mediated by activated polymorphonuclear leukocytes. Phosphodiesterase type 4 is the predominant phosphodiesterase isozyme in polymorphonuclear leukocytes and plays a key role in the regulation of polymorphonuclear leukocyte activation. The aim (...) of this study was to examine the effect of rolipram, a selective phosphodiesterase type 4 inhibitor, on the functional changes of polymorphonuclear leukocytes by using simulated extracorporeal circulation.Simulated extracorporeal circulation was established by recirculating heparinized human blood for 120 minutes on a membrane oxygenator with and without 10 micro mol/L rolipram. F-actin content and L-selectin and CD11b expression of polymorphonuclear leukocytes were measured by means of flow cytometry

2003 Journal of Thoracic and Cardiovascular Surgery

6635. Effects of epinephrine and phosphodiesterase III inhibitors on bupivacaine-induced myocardial depression in guinea-pig papillary muscle. (Abstract)

Effects of epinephrine and phosphodiesterase III inhibitors on bupivacaine-induced myocardial depression in guinea-pig papillary muscle. This study was designed to investigate the effects of epinephrine and the phosphodiesterase III inhibitors amrinone and milrinone on bupivacaine-induced myocardial depression in guinea-pig papillary muscles using an electrophysiological method.Electrophysiological studies of the effects of bupivacaine, epinephrine, amrinone and milrinone in normal and high K

2003 British Journal of Anaesthesia

6636. Olprinone, a phosphodiesterase III inhibitor, reduces gut mucosal injury and portal endotoxin level during acute hypoxia in rabbits. (Abstract)

Olprinone, a phosphodiesterase III inhibitor, reduces gut mucosal injury and portal endotoxin level during acute hypoxia in rabbits. Preservation of gut integrity has become a therapeutic goal to obviate bacterial translocation in the critically ill. The authors examined whether olprinone, a phosphodiesterase III inhibitor, protected functional and structural integrity of gut mucosa against acute progressive hypoxia.Thirty-two animals were randomly allocated to a control group (n = 12), a low

2003 Anesthesiology

6637. In vitro and in vivo effects of the phosphodiesterase-III inhibitor enoximone on malignant hyperthermia-susceptible swine. (Abstract)

In vitro and in vivo effects of the phosphodiesterase-III inhibitor enoximone on malignant hyperthermia-susceptible swine. In human skeletal muscles, the phosphodiesterase-III inhibitor enoximone induces in vitro contracture development, and it has been suggested that enoximone could trigger malignant hyperthermia (MH). In this study, the in vitro and in vivo effects of enoximone in MH-normal (MHN) and MH-susceptible (MHS) swine were investigated.Malignant hyperthermia trigger-free general

2003 Anesthesiology

6638. The phosphodiesterase type 4 inhibitor, rolipram, enhances glucocorticoid receptor function. Full Text available with Trip Pro

The phosphodiesterase type 4 inhibitor, rolipram, enhances glucocorticoid receptor function. Previous studies have demonstrated that antidepressants can enhance glucocorticoid receptor (GR) translocation and function, possibly through activation of cAMP and downstream cAMP dependent protein kinases. Accordingly, we examined GR function in cells treated with rolipram, a phosphodiesterase (PDE) type 4 inhibitor that antagonizes cAMP breakdown. Compared with vehicle-treated cells, rolipram alone (...) . These findings broaden the potential pathways by which PDE type 4 inhibitors can influence cellular function and indicate that these agents may have special utility in disorders associated with impaired GR-mediated feedback inhibition.

2002 Neuropsychopharmacology

6639. Overview of phosphodiesterase 5 inhibition in erectile dysfunction. (Abstract)

Overview of phosphodiesterase 5 inhibition in erectile dysfunction. Since the early 1980s, research on the mechanisms of penile erection has done much to clarify erectile physiology and pathophysiology. More recent studies have identified the importance of neurochemical mediators in erection. These include the nitric oxide-cyclic guanosine monophosphate (cGMP) cell-signaling system-a complex molecular pathway that mediates smooth muscle relaxation in the corpus cavernosum. Phosphodiesterase 5 (...) (PDE5) inactivates cGMP, which terminates nitric oxide-cGMP-mediated smooth muscle relaxation. Inhibition of PDE5 is expected to enhance penile erection by preventing cGMP degradation. Development of pharmacologic agents with this effect has closely paralleled the emerging science. The prototype of this new therapeutic class of PDE5 inhibitors is sildenafil, which was approved for treatment of erectile dysfunction in 1998. Tadalafil and vardenafil are new agents in this class. These agents have

2003 American Journal of Cardiology

6640. Efficacy and tolerability of tadalafil, a novel phosphodiesterase 5 inhibitor, in treatment of erectile dysfunction. (Abstract)

Efficacy and tolerability of tadalafil, a novel phosphodiesterase 5 inhibitor, in treatment of erectile dysfunction. Advances in molecular biology and protein chemistry, along with increasing understanding of the mechanisms of penile erection, have spurred development of pharmacologic approaches to the treatment of erectile dysfunction (ED). The next generation of oral agents includes tadalafil, a potent, highly selective phosphodiesterase 5 inhibitor. In vitro studies have shown that tadalafil

2003 American Journal of Cardiology

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