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Christian Schudt - One of the best experts on this subject based on the ideXlab platform.
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Zardaverine and aerosolised iloprost in a model of acute respiratory failure
European Respiratory Journal, 2003Co-Authors: Ralph T. Schermuly, Christian Schudt, Hanno Leuchte, Hossein Ardeschir Ghofrani, Norbert Weissmann, Frank Rose, Markus G. Kohstall, Horst Olschewski, F. Grimminger, Werner SeegerAbstract:In this study, the impact of aerosolised prostacyclin (PGI2) and iloprost in the absence or presence of subthreshold intravascular doses of the dual-selective phosphodiesterase-3/4 inhibitor Zardaverine was investigated in an experimental model of acute respiratory failure. In perfused rabbit lungs, continuous infusion of the thromboxane‐A2‐mimetic U46619 provoked pulmonary hypertension, accompanied by progressive lung oedema formation and severe ventilation-perfusion mismatch with predominance of shunt flow (increasing from ∼2 to 58%, as assessed by the multiple inert gas elimination technique). Aerosolisation of PGI2 (in total 1.05 µg·kg−1) for 15 min caused a decrease in pulmonary artery pressure ( P pa) and a limitation of maximum shunt flow to ∼37%. When nebulised PGI2 was combined with subthreshold intravascular Zardaverine, which did not affect pulmonary haemodynamics per se , the duration of the PGI2 effect was increased. Aerosolisation of 3 µg·kg−1 PGI2 resulted in a transient decrease in P pa and a reduction in shunt flow. In the presence of subthreshold Zardaverine, the effects of this PGI2 dose were only marginally increased. Aerosolisation of iloprost (in total 0.7 µg·kg−1) for 15 min caused a more sustained decrease in P pa, some enhanced reduction of oedema formation as compared with PGI2 and a decrease in shunt flow to ∼32%. Most impressively, when combined with subthreshold Zardaverine, iloprost suppressed oedema formation to <15% and shunt flow to ∼8%. In conclusion, combined use of aerosolised iloprost and subthreshold systemic phosphodiesterase-3/4 inhibitor may result in selective intrapulmonary vasodilation, a reduction in oedema formation and an improvement in ventilation-perfusion matching in acute respiratory failure.
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Low-dose Systemic Phosphodiesterase Inhibitors Amplify the Pulmonary Vasodilatory Response to Inhaled Prostacyclin in Experimental Pulmonary Hypertension
American Journal of Respiratory and Critical Care Medicine, 1999Co-Authors: Ralph T. Schermuly, Christian Schudt, Hossein Ardeschir Ghofrani, Norbert Weissmann, Werner Seeger, Beate Enke, Friedrich Grimminger, Dieter WalmrathAbstract:Inhalation of aerosolized prostaglandin I2 (PGI2) causes selective pulmonary vasodilation, but the effect rapidly levels off after termination of nebulization. In experimental pulmonary hypertension in intact rabbits, provoked by continuous infusion of the stable thromboxane mimetic U46619, the impact of intravenous phosphodiesterase (PDE) inhibitors on pulmonary and systemic hemodynamics was investigated in the absence and the presence of aerosolized PGI2. We employed the monoselective inhibitors motapizone (PDE 3), rolipram (PDE 4), and zaprinast (PDE 5), as well as the dual-selective blockers Zardaverine and tolafentrine (both PDE 3/4). All PDE inhibitors dose-dependently reduced the pulmonary artery pressure (Ppa), with doses for an ∼ 20% decrease in pulmonary vascular resistance being 5 μ g/kg for motapizone, 25 μ g/kg for rolipram, 500 μ g/kg for Zardaverine, 1 mg/kg for zaprinast, and 1 mg/kg for tolafentrine. Additive efficacy was noted when combining the monoselective 3 plus 4, 3 plus 5, and 4 pl...
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Cyclic nucleotide phosphodiesterase in human bronchial epithelial cells: characterization of isoenzymes and functional effects of PDE inhibitors.
Pulmonary pharmacology & therapeutics, 1998Co-Authors: Gordon Dent, Christian Schudt, H Tenor, H Magnussen, Steven R. White, K Bodtke, Alan R. Leff, K F RabeAbstract:Cyclic AMP (adenosine 3′:5′-cyclic monophosphate, cAMP) is an intracellular second messenger that mediates the actions of endogenous hormones and neurotransmitters and also of drugs such as β-adrenoceptor agonists. The presence of functional β-adrenoceptors on human airway epithelial cells has been demonstrated but the expression of the cAMP-metabolizing enzyme, cyclic nucleotide phosphodiesterase (PDE) in these cells has not been studied. We investigated the profile of activity of the different PDE isoenzymes in lysates of a pulmonary epithelial cell line, A549, and of human bronchial epithelial (HBE) cells grown in primary culture. The effects of non-selective and isoenzyme-selective PDE inhibitors on β-agonist-induced elevations in intracellular cAMP concentrations and the production of interleukin (IL) 8 and prostaglandin (PG) E2was also investigated. A549 cells expressed a high level of PDE4, lower levels of PDE1 and PDE3, and minor PDE5 activity. Primary HBE cultures expressed PDE4 and PDE1 activity at approximately equal levels with small additional PDE3 and PDE5 activities. The total PDE activity of the HBE cells was approximately nine-fold lower than that of A549 cells. The β-adrenoceptor agonist salbutamol, caused a slow, concentration-dependent increase in intracellular cAMP levels in HBE cells which was not affected by a non-selective PDE inhibitor, IBMX (100 μm), or by a selective PDE4 inhibitor, rolipram (100 μm). Zardaverine, a dual-selective PDE3/PDE4 inhibitor, had no effect on cAMP levels at 10 μmbut did cause a significant enhancement of salbutamol-induced elevations at 100 μm(150±36 pmol/105cells at 10 μmsalbutamol vs. 64±25 pmol/105cells in the absence of Zardaverine; n=3,P
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Attenuation by Phosphodiesterase Inhibitors of Lipopolysaccharide-Induced Thromboxane Release and Bronchoconstriction in Rat Lungs1
1997Co-Authors: Stefan Uhlig, Christian Schudt, Roland Lewis Featherstone, Heinz-dieter Held, Albrecht WendelAbstract:Exposure of perfused rat lungs to lipopolysaccharides (LPS) causes induction of cyclooxygenase-2 followed by throm-boxane (TX)-mediated bronchoconstriction (BC). Recently, phosphodiesterase (PDE) inhibitors have received much in-terest because they not only are bronchodilators but also can suppress release of proinflammatory mediators. In the present study, we investigated the effect of three different PDE inhibitors on TX release and BC in LPS-exposed per-fused rat lungs. The PDE inhibitors used were motapizone (PDE III specific), rolipram (PDE IV specific), and Zardaverine (mixed PDE III and IV specific). At 5 mM, a concentration at which all three compounds selectively block their respective PDE isoenzyme, rolipram (IC50 5 0.04 mM) and Zardaverine (IC50 5 1.8 mM) largely attenuated the LPS-induced BC
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Attenuation by Phosphodiesterase Inhibitors of Lipopolysaccharide-Induced Thromboxane Release and Bronchoconstriction in Rat Lungs
The Journal of pharmacology and experimental therapeutics, 1997Co-Authors: Stefan Uhlig, Christian Schudt, Roland Lewis Featherstone, Heinz-dieter Held, Rolf M. Nüsing, Albrecht WendelAbstract:Exposure of perfused rat lungs to lipopolysaccharides (LPS) causes induction of cyclooxygenase-2 followed by thromboxane (TX)-mediated bronchoconstriction (BC). Recently, phosphodiesterase (PDE) inhibitors have received much interest because they not only are bronchodilators but also can suppress release of proinflammatory mediators. In the present study, we investigated the effect of three different PDE inhibitors on TX release and BC in LPS-exposed perfused rat lungs. The PDE inhibitors used were motapizone (PDE III specific), rolipram (PDE IV specific), and Zardaverine (mixed PDE III and IV specific). At 5 μM, a concentration at which all three compounds selectively block their respective PDE isoenzyme, rolipram (IC50 = 0.04 μM) and Zardaverine (IC50 = 1.8 μM) largely attenuated the LPS-induced BC, whereas motapizone was almost ineffective (IC50 = 40 μM). In contrast to LPS, BC induced by the TX-mimetic U46619 was prevented with comparable strength by motapizone and rolipram. In LPS-treated lungs, the TX release was reduced to 50% of controls by rolipram and Zardaverine but was unaltered in the presence of 5 μM motapizone. Increasing intracellular cAMP through perfusion of db-cAMP or forskolin (activates adenylate cyclase) also reduced TX release and BC. We conclude that PDE inhibitors act via elevation of intracellular cAMP. Although both PDE III and PDE IV inhibitors can relax airway smooth muscle, in the model of LPS-induced BC, PDE IV inhibitors are more effective because (in contrast to PDE III inhibitors) they also attenuate TX release.
C Schudt - One of the best experts on this subject based on the ideXlab platform.
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Zardaverine and aerosolised iloprost in a model of acute respiratory failure.
2015Co-Authors: Ralph T. Schermuly, C Schudt, Hanno Leuchte, Hossein Ardeschir Ghofrani, Norbert Weissmann, Frank Rose, Markus G. Kohstall, Horst Olschewski, F. Grimminger, Werner SeegerAbstract:Zardaverine and aerosolised iloprost in a model of acute respiratory failur
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Zardaverine and aerosolised iloprost in a model of acute respiratory failure.
The European respiratory journal, 2003Co-Authors: Ralph T. Schermuly, C Schudt, Hanno Leuchte, Hossein Ardeschir Ghofrani, Norbert Weissmann, Frank Rose, Markus G. Kohstall, Horst Olschewski, F. Grimminger, Werner SeegerAbstract:In this study, the impact of aerosolised prostacyclin (PGI2) and iloprost in the absence or presence of subthreshold intravascular doses of the dual-selective phosphodiesterase-3/4 inhibitor Zardaverine was investigated in an experimental model of acute respiratory failure. In perfused rabbit lungs, continuous infusion of the thromboxane‐A2‐mimetic U46619 provoked pulmonary hypertension, accompanied by progressive lung oedema formation and severe ventilation-perfusion mismatch with predominance of shunt flow (increasing from ∼2 to 58%, as assessed by the multiple inert gas elimination technique). Aerosolisation of PGI2 (in total 1.05 µg·kg−1) for 15 min caused a decrease in pulmonary artery pressure ( P pa) and a limitation of maximum shunt flow to ∼37%. When nebulised PGI2 was combined with subthreshold intravascular Zardaverine, which did not affect pulmonary haemodynamics per se , the duration of the PGI2 effect was increased. Aerosolisation of 3 µg·kg−1 PGI2 resulted in a transient decrease in P pa and a reduction in shunt flow. In the presence of subthreshold Zardaverine, the effects of this PGI2 dose were only marginally increased. Aerosolisation of iloprost (in total 0.7 µg·kg−1) for 15 min caused a more sustained decrease in P pa, some enhanced reduction of oedema formation as compared with PGI2 and a decrease in shunt flow to ∼32%. Most impressively, when combined with subthreshold Zardaverine, iloprost suppressed oedema formation to
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Low-dose systemic phosphodiesterase inhibitors amplify the pulmonary vasodilatory response to inhaled prostacyclin in experimental pulmonary hypertension.
American journal of respiratory and critical care medicine, 1999Co-Authors: R T Schermuly, C Schudt, F. Grimminger, Beate Enke, H A Ghofrani, N Weissmann, W Seeger, Dieter WalmrathAbstract:Inhalation of aerosolized prostaglandin I(2) (PGI(2)) causes selective pulmonary vasodilation, but the effect rapidly levels off after termination of nebulization. In experimental pulmonary hypertension in intact rabbits, provoked by continuous infusion of the stable thromboxane mimetic U46619, the impact of intravenous phosphodiesterase (PDE) inhibitors on pulmonary and systemic hemodynamics was investigated in the absence and the presence of aerosolized PGI(2). We employed the monoselective inhibitors motapizone (PDE 3), rolipram (PDE 4), and zaprinast (PDE 5), as well as the dual-selective blockers Zardaverine and tolafentrine (both PDE 3/4). All PDE inhibitors dose-dependently reduced the pulmonary artery pressure (Ppa), with doses for an approximately 20% decrease in pulmonary vascular resistance being 5 microgram/kg for motapizone, 25 microgram/kg for rolipram, 500 microgram/kg for Zardaverine, 1 mg/kg for zaprinast, and 1 mg/kg for tolafentrine. Additive efficacy was noted when combining the monoselective 3 plus 4, 3 plus 5, and 4 plus 5 inhibitors. In parallel with the pulmonary vasorelaxant effect, all PDE inhibitors caused a decrease in systemic arterial pressure and an increase in cardiac output. Nebulized PGI(2) (56 ng/kg. min) reduced the U46619-evoked increase in Ppa by approximately 30%. This vasorelaxant effect was fully lost within 10 min after termination of PGI(2) nebulization. Coapplication of subthreshold doses of intravenous PDE inhibitors, which per se did not affect pulmonary and systemic hemodynamics, resulted in a marked prolongation of the post-PGI(2) decrease in Ppa for all blockers (motapizone at 2.2 microgram/kg, rolipram at 5.5 microgram/kg, zaprinast at 100 microgram/kg). The most effective agents, Zardaverine (50 microgram/kg) and tolafentrine (100 microgram/kg), augmented the maximum Ppa drop during nebulization by approximately 30-50% and prolonged the post-PGI(2) pulmonary vasodilation to > 30 min, without affecting systemic arterial pressure and arterial oxygenation. We conclude that subthreshold systemic doses of monoselective PDE 3, 4, and 5 inhibitors and in particular dual-selective PDE 3/4 inhibitors cause significant amplification of the pulmonary vasodilatory response to inhaled PGI(2), while limiting the hypotensive effect to the pulmonary circulation. Combining nebulized PGI(2) with low-dose systemic PDE inhibitors may thus offer a therapeutic strategy to achieve selective pulmonary vasodilation in acute and chronic pulmonary hypertension.
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Hyperpermeability of pulmonary endothelial monolayer: Protective role of phosphodiesterase isoenzymes 3 and 4
Lung, 1996Co-Authors: N. Suttorp, H Tenor, P. Ehreiser, S. Hippenstiel, M. Fuhrmann, M. Krüll, C SchudtAbstract:The regulation of endothelial permeability is poorly understood. An increase in endothelial permeability in the pulmonary microvasculature, however, is critical in noncardiogenic pulmonary edema and other diffuse inflammatory reactions. In the present study thrombin and Escherichia coli hemolysin (HlyA), a membrane-perturbing bacterial exotoxin, were used to alter hydraulic permeability of porcine pulmonary artery and human endothelial cell monolayers. We also investigated the pharmacological approach of adenylyl cyclase activation/phosphodiesterase (PDE) inhibition to block endothelial hyperpermeability. Thrombin (1–5 units/ml) and H1yA (0.5–3 hemolytic units/ml) dose and time dependently (>15 min) increased endothelial permeability. Forskolin, cholera toxin, and prostaglandin E_1, which all stimulate adenylyl cyclase activity, abrogated this effect. One MM dibutyryl CAMP, a cell membrane-permeable CAMP analogue, was similarly active. Endothelial hyperpermeability was also reduced dose dependently by inhibitors of different PDE isoenzymes (motapizone, rolipram, and Zardaverine, which block PDE3 and/or PDE4). The effectiveness of PDE inhibitors was increased in the presence of adenylyl cyclase activators. Analysis of cyclic nucleotide hydrolyzing PDE activity in lysates of human umbilical vein endothelial cells showed high activities of PDE isoenzymes 2, 3, and 4. Consistent with the functional data PDE3 and PDE4 were the major cAMP hydrolysis enzymes in intact endothelial cells. We conclude that the hyperpermeability of pulmonary endothelial monolayers, evoked by thrombin or H1yA, can be blocked by the simultaneous activation of adenylyl cyclase and inhibition of PDEs, especially of PDE3 and PDE4. The demonstration of PDE isoenzymes 2–4 in human endothelial cells will help optimize this therapeutic approach.
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PDE isoenzymes as targets for anti-asthma drugs
The European respiratory journal, 1995Co-Authors: C Schudt, Hermann Tenor, A HatzelmannAbstract:Phophodiesterase (PDE) isoenzyme profiles of human cell preparations and tissues have been analysed by a semiquantitative method using selective PDE inhibitors and activators. Neutrophils, eosinophils and monocytes contain PDE IV exclusively. Lymphocytes, alveolar macrophages and endothelial cells contain PDE IV and PDE III, and in addition, PDE I is measured in macrophages and PDE II in endothelial cells. These basal cell-specific PDE isoenzyme profiles appear to be modified by: 1) substrate concentration; 2) kinase-dependent phosphorylation; and 3) regulated rate of synthesis. Therefore, PDE isoenzyme profiles represent dynamic patterns, which apparently adapt to pathological and environmental conditions. In parallel functional studies, the influence of mono-selective (rolipram, PDE IV; motapizone, PDE III), dual-selective (Zardaverine) and non-selective (theophylline) PDE inhibitors were compared. Corresponding to isoenzyme analysis, it was demonstrated that both PDE III and PDE IV have to be inhibited for complete suppression of either tumour necrosis factor-alpha (TNF-alpha) release from macrophages, or lymphocyte proliferation (PDE III/IV cells). In eosinophils (PDE IV cells) platelet-activating factor (PAF)-induced chemotaxis or C5a-stimulated degranulation are only weakly inhibited by rolipram alone. After addition of a beta 2-agonist, however, the efficacy of rolipram is enhanced due to concomitant influence of synthesis and breakdown of cyclic adenosine monophosphate (cAMP). Theophylline inhibits PDE isoenzyme activities and functions of inflammatory cells with similar potency, and exhibits higher functional efficacy as compared to rolipram.
Werner Seeger - One of the best experts on this subject based on the ideXlab platform.
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Zardaverine and aerosolised iloprost in a model of acute respiratory failure.
2015Co-Authors: Ralph T. Schermuly, C Schudt, Hanno Leuchte, Hossein Ardeschir Ghofrani, Norbert Weissmann, Frank Rose, Markus G. Kohstall, Horst Olschewski, F. Grimminger, Werner SeegerAbstract:Zardaverine and aerosolised iloprost in a model of acute respiratory failur
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Zardaverine and aerosolised iloprost in a model of acute respiratory failure.
The European respiratory journal, 2003Co-Authors: Ralph T. Schermuly, C Schudt, Hanno Leuchte, Hossein Ardeschir Ghofrani, Norbert Weissmann, Frank Rose, Markus G. Kohstall, Horst Olschewski, F. Grimminger, Werner SeegerAbstract:In this study, the impact of aerosolised prostacyclin (PGI2) and iloprost in the absence or presence of subthreshold intravascular doses of the dual-selective phosphodiesterase-3/4 inhibitor Zardaverine was investigated in an experimental model of acute respiratory failure. In perfused rabbit lungs, continuous infusion of the thromboxane‐A2‐mimetic U46619 provoked pulmonary hypertension, accompanied by progressive lung oedema formation and severe ventilation-perfusion mismatch with predominance of shunt flow (increasing from ∼2 to 58%, as assessed by the multiple inert gas elimination technique). Aerosolisation of PGI2 (in total 1.05 µg·kg−1) for 15 min caused a decrease in pulmonary artery pressure ( P pa) and a limitation of maximum shunt flow to ∼37%. When nebulised PGI2 was combined with subthreshold intravascular Zardaverine, which did not affect pulmonary haemodynamics per se , the duration of the PGI2 effect was increased. Aerosolisation of 3 µg·kg−1 PGI2 resulted in a transient decrease in P pa and a reduction in shunt flow. In the presence of subthreshold Zardaverine, the effects of this PGI2 dose were only marginally increased. Aerosolisation of iloprost (in total 0.7 µg·kg−1) for 15 min caused a more sustained decrease in P pa, some enhanced reduction of oedema formation as compared with PGI2 and a decrease in shunt flow to ∼32%. Most impressively, when combined with subthreshold Zardaverine, iloprost suppressed oedema formation to
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Zardaverine and aerosolised iloprost in a model of acute respiratory failure
European Respiratory Journal, 2003Co-Authors: Ralph T. Schermuly, Christian Schudt, Hanno Leuchte, Hossein Ardeschir Ghofrani, Norbert Weissmann, Frank Rose, Markus G. Kohstall, Horst Olschewski, F. Grimminger, Werner SeegerAbstract:In this study, the impact of aerosolised prostacyclin (PGI2) and iloprost in the absence or presence of subthreshold intravascular doses of the dual-selective phosphodiesterase-3/4 inhibitor Zardaverine was investigated in an experimental model of acute respiratory failure. In perfused rabbit lungs, continuous infusion of the thromboxane‐A2‐mimetic U46619 provoked pulmonary hypertension, accompanied by progressive lung oedema formation and severe ventilation-perfusion mismatch with predominance of shunt flow (increasing from ∼2 to 58%, as assessed by the multiple inert gas elimination technique). Aerosolisation of PGI2 (in total 1.05 µg·kg−1) for 15 min caused a decrease in pulmonary artery pressure ( P pa) and a limitation of maximum shunt flow to ∼37%. When nebulised PGI2 was combined with subthreshold intravascular Zardaverine, which did not affect pulmonary haemodynamics per se , the duration of the PGI2 effect was increased. Aerosolisation of 3 µg·kg−1 PGI2 resulted in a transient decrease in P pa and a reduction in shunt flow. In the presence of subthreshold Zardaverine, the effects of this PGI2 dose were only marginally increased. Aerosolisation of iloprost (in total 0.7 µg·kg−1) for 15 min caused a more sustained decrease in P pa, some enhanced reduction of oedema formation as compared with PGI2 and a decrease in shunt flow to ∼32%. Most impressively, when combined with subthreshold Zardaverine, iloprost suppressed oedema formation to <15% and shunt flow to ∼8%. In conclusion, combined use of aerosolised iloprost and subthreshold systemic phosphodiesterase-3/4 inhibitor may result in selective intrapulmonary vasodilation, a reduction in oedema formation and an improvement in ventilation-perfusion matching in acute respiratory failure.
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Low-dose Systemic Phosphodiesterase Inhibitors Amplify the Pulmonary Vasodilatory Response to Inhaled Prostacyclin in Experimental Pulmonary Hypertension
American Journal of Respiratory and Critical Care Medicine, 1999Co-Authors: Ralph T. Schermuly, Christian Schudt, Hossein Ardeschir Ghofrani, Norbert Weissmann, Werner Seeger, Beate Enke, Friedrich Grimminger, Dieter WalmrathAbstract:Inhalation of aerosolized prostaglandin I2 (PGI2) causes selective pulmonary vasodilation, but the effect rapidly levels off after termination of nebulization. In experimental pulmonary hypertension in intact rabbits, provoked by continuous infusion of the stable thromboxane mimetic U46619, the impact of intravenous phosphodiesterase (PDE) inhibitors on pulmonary and systemic hemodynamics was investigated in the absence and the presence of aerosolized PGI2. We employed the monoselective inhibitors motapizone (PDE 3), rolipram (PDE 4), and zaprinast (PDE 5), as well as the dual-selective blockers Zardaverine and tolafentrine (both PDE 3/4). All PDE inhibitors dose-dependently reduced the pulmonary artery pressure (Ppa), with doses for an ∼ 20% decrease in pulmonary vascular resistance being 5 μ g/kg for motapizone, 25 μ g/kg for rolipram, 500 μ g/kg for Zardaverine, 1 mg/kg for zaprinast, and 1 mg/kg for tolafentrine. Additive efficacy was noted when combining the monoselective 3 plus 4, 3 plus 5, and 4 pl...
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Hydrogen peroxide-induced increase in lung endothelial and epithelial permeability--effect of adenylate cyclase stimulation and phosphodiesterase inhibition.
Microvascular research, 1995Co-Authors: Werner Seeger, Norbert Weissmann, Friedrich Grimminger, Dieter Walmrath, Tanja Hansen, Renate Rössig, Thomas Schmehl, Hartwig Schütte, Hans-joachim Krämer, Norbert SuttorpAbstract:Abstract Neutrophil-derived hydrogen peroxide (H2O2) is believed to play an important role in inflammatory lung injury. We investigated the influence of pharmacological agents that increase intracellular c-AMP levels on endothelial and epithelial leakage in response to intravascular H2O2 challenge in buffer-perused rabbit lungs. Endothelial permeability was assessed by determination of the capillary filtration coefficient (Kfc) and lung weight gain. Measurement of the clearance rate of inhaled aerosolized technetium-99m-labeled diethylenetriamine pentaacetic acid ([99mTc]DTPA) from the lungs into the perfusion fluid was used as an index of alveolar epithelial permeability. Experiments were performed in the presence of acetylsalicylic acid to suppress H2O2-induced lung prostanoid generation and concomitant vasoconstriction. Under these conditions, H2O2 admixture to the perfusate (250 μM) caused a greater than eight-fold increase in Kfc values, resulting in >30 g lung weight gain within 30 min in the absence of any significant vasopressor response. Pretreatment with the adenylate cyclase activators prostaglandin E1 (0.1 μM) and forskolin (0.1 μM), the dual phosphodiesterase type III/IV inhibitor Zardaverine (10 μM) as well as combinations of these drugs all caused a nearly complete suppression of this early Kfc increase; and severe edema formation (>30 g) was retarded to ∼50-55 min. In addition to the microvascular leakage response, H2O2 caused a four- to five-fold increase in the [99mTc]DTPA clearance rate, starting within 15 min and culminating after ∼35 min. Adenylate cyclase activation reduced this epithelial leakage response by ∼30%, whereas Zardaverine exerted no significant effect. We conclude that both microvascular endothelial and alveolar epithelial barrier function are severely compromised by intravascular H2O2 challenge in intact lungs. Pharmacological approaches to increase c-AMP levels, including both adenylate cyclase activation and phosphodiesterase inhibition, partially block the endothelial response and, to a lesser extent, the epithelial response.
H Magnussen - One of the best experts on this subject based on the ideXlab platform.
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The effect of selective and non-selective phosphodiesterase inhibitors on allergen- and leukotriene C4-induced contractions in passively sensitized human airways
British journal of pharmacology, 2000Co-Authors: Dunja T Schmidt, Gordon Dent, H Magnussen, N. Watson, E. Rühlmann, Detlev Branscheid, Klaus F. RabeAbstract:Non-selective inhibitors of cyclic nucleotide phosphodiesterase (PDE) block allergen-induced contraction of passively sensitized human airways in vitro by a dual mechanism involving a direct relaxant effect on smooth muscle and inhibition of histamine and cysteinyl leukotriene (LT) release from airways. We investigated the effects of non-selective PDE inhibitors and selective inhibitors of PDE3 and PDE4 in order to determine the involvement of PDE isoenzymes in the suppression of allergic bronchoconstriction. Macroscopically normal airways from 76 patients were sensitized with IgE-rich sera (>250 u ml(-1)) containing specific antibodies against allergen (Dermatophagoides farinae). Contractile responses of bronchial rings were assessed using standard organ bath techniques. Passive sensitization caused increased contractile responses to allergen, histamine and LTC(4). Non-selective PDE inhibitors (theophylline, 3-isobutyl-1-methylxanthine [IBMX]), a PDE3-selective inhibitor (motapizone), PDE4-selective inhibitors (RP73401, rolipram, AWD 12-281) and a mixed PDE3/4 inhibitor (Zardaverine) all significantly relaxed inherent bronchial tone at resting tension and to a similar degree. Theophylline, IBMX, Zardaverine and the combination of motapizone and RP73401 inhibited the contractile responses to allergen and LTC(4). Pre-treatment with motapizone, RP73401, rolipram or the methylxanthine adenosine receptor antagonist, 8-phenyltheophylline, did not significantly decrease responses to either allergen or LTC(4). We conclude that combined inhibition of PDE3 and PDE4, but not selective inhibition of either isoenzyme or antagonism of adenosine receptors, is effective in suppressing allergen-induced contractions of passively sensitized human airways. The relationship between allergen- and LTC(4)-induced responses suggests that PDE inhibitors with PDE3 and PDE4 selectivity are likely to act in part through inhibition of mediator release and not simply through direct relaxant actions on airway smooth muscle.
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Cyclic nucleotide phosphodiesterase in human bronchial epithelial cells: characterization of isoenzymes and functional effects of PDE inhibitors.
Pulmonary pharmacology & therapeutics, 1998Co-Authors: Gordon Dent, Christian Schudt, H Tenor, H Magnussen, Steven R. White, K Bodtke, Alan R. Leff, K F RabeAbstract:Cyclic AMP (adenosine 3′:5′-cyclic monophosphate, cAMP) is an intracellular second messenger that mediates the actions of endogenous hormones and neurotransmitters and also of drugs such as β-adrenoceptor agonists. The presence of functional β-adrenoceptors on human airway epithelial cells has been demonstrated but the expression of the cAMP-metabolizing enzyme, cyclic nucleotide phosphodiesterase (PDE) in these cells has not been studied. We investigated the profile of activity of the different PDE isoenzymes in lysates of a pulmonary epithelial cell line, A549, and of human bronchial epithelial (HBE) cells grown in primary culture. The effects of non-selective and isoenzyme-selective PDE inhibitors on β-agonist-induced elevations in intracellular cAMP concentrations and the production of interleukin (IL) 8 and prostaglandin (PG) E2was also investigated. A549 cells expressed a high level of PDE4, lower levels of PDE1 and PDE3, and minor PDE5 activity. Primary HBE cultures expressed PDE4 and PDE1 activity at approximately equal levels with small additional PDE3 and PDE5 activities. The total PDE activity of the HBE cells was approximately nine-fold lower than that of A549 cells. The β-adrenoceptor agonist salbutamol, caused a slow, concentration-dependent increase in intracellular cAMP levels in HBE cells which was not affected by a non-selective PDE inhibitor, IBMX (100 μm), or by a selective PDE4 inhibitor, rolipram (100 μm). Zardaverine, a dual-selective PDE3/PDE4 inhibitor, had no effect on cAMP levels at 10 μmbut did cause a significant enhancement of salbutamol-induced elevations at 100 μm(150±36 pmol/105cells at 10 μmsalbutamol vs. 64±25 pmol/105cells in the absence of Zardaverine; n=3,P
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Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors.
American Journal of Physiology-Lung Cellular and Molecular Physiology, 1994Co-Authors: K F Rabe, C Schudt, H Tenor, G Dent, M. Nakashima, H MagnussenAbstract:The effects of the nonselective phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the selective PDE inhibitors motapizone (type III), rolipram (type IV), Zardaverine (type II...
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Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors.
The American journal of physiology, 1994Co-Authors: K F Rabe, C Schudt, H Tenor, G Dent, M. Nakashima, H MagnussenAbstract:The effects of the nonselective phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the selective PDE inhibitors motapizone (type III), rolipram (type IV), Zardaverine (type III/IV), and zaprinast (type V and I) on prostaglandin F2 alpha (PFG2 alpha)-induced tone in human pulmonary arteries was investigated. Relaxation was achieved by IBMX [concentration eliciting 50% of maximum response (EC50): 11.3 microM, n = 10], motapizone (EC50:3.0 microM, n = 7), Zardaverine (EC50: 3.2 microM, n = 9), and zaprinast (EC50: 31.8 microM, n = 6), whereas rolipram was almost ineffective. The combination of motapizone and zaprinast (10 microM) was the most effective relaxant with supra-additive relaxation and a motapizone EC50 of 575 nM. Biochemical studies revealed the presence of the PDE isozymes I, III, IV and V in the cytosolic and particulate phases of arterial homogenates; PDE II was not detectable. Partial inhibition of adenosine 3',5'-cyclic monophosphate (cAMP)-hydrolyzing PDE activity was achieved with rolipram (26 +/- 2.2%) or motapizone (60 +/- 5.4%), whereas there was almost complete inhibition of total PDE activity with Zardaverine (81 +/- 2.0%) or the combination of motapizone and rolipram (82 +/- 2.3%). Inhibition of guanosine 3',5'-cyclic monophosphate (cGMP)-hydrolyzing PDE activity was achieved with zaprinast (62 +/- 2.6%) and motapizone (13 +/- 2.3%), indicating the cGMP-hydrolyzing activity of PDE III. We conclude that four out of the five recognized PDE isozyme families are present in human pulmonary artery. PGF2 alpha-induced tone in this tissue is effectively relaxed through PDE inhibitors with selectivity for type III, III/IV, and type V PDE.
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Phosphodiesterase isozymes modulating inherent tone in human airways: identification and characterization.
American Journal of Physiology-Lung Cellular and Molecular Physiology, 1993Co-Authors: K F Rabe, C Schudt, H Tenor, G Dent, S Liebig, H MagnussenAbstract:The effects of the nonselective phosphodiesterase (PDE)-inhibitor 3-isobutyl-1-methylxanthine (IBMX) and the selective PDE inhibitors SKF 94120 (type III), rolipram (type IV), Zardaverine (type III...
Clive P. Page - One of the best experts on this subject based on the ideXlab platform.
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Evidence to suggest that the phosphodiesterase 4 isoenzyme is present and involved in the proliferation of umbilical cord blood mononuclear cells.
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 2000Co-Authors: K H Banner, Clive P. Page, Gabriel Dimitriou, Maria Kinali, Anne GreenoughAbstract:Background The type 4 phosphodiesterase (PDE) isoenzyme is the main isoenzyme of PDE involved in the control of adult mononuclear cell proliferation. Objective To establish whether PDE isoenzymes are present in umbilical cord blood mononuclear cells by the use of selective PDE inhibitors, and to identify which PDE isoenzymes are involved in controlling the proliferation of cord blood mononuclear cells. Methods Cord blood was obtained from normal deliveries and mononuclear cells isolated as described previously [ 1] with some modifications. Mononuclear cells were then stimulated to proliferate with phytohaemagglutinin (PHA) (2 μg/mL) in the presence of selective PDE inhibitors. Proliferation was measured by [3H]-thymidine incorporation. Results The type 4 PDE inhibitors (CDP840, rolipram and RO 20-1724), and the mixed PDE3/4 inhibitor, Zardaverine, produced a concentration-related inhibition of PHA-stimulated cord blood mononuclear cell proliferation (P
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Possible contribution of prostaglandin E2 to the antiproliferative effect of phosphodiesterase 4 inhibitors in human mononuclear cells
Biochemical pharmacology, 1999Co-Authors: Kathy H Banner, J.robin S. Hoult, Magali N Taylor, L J Landells, Clive P. PageAbstract: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 μM to >10 μM, 0.81 μM to 2.82 μM, and 1.58 μM to 4.82 μM, 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 μM. 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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Effect of Isoenzyme Selective Phosphodiesterase Inhibitors on the Proliferation of Murine Thymus and Spleen Cells
Pulmonary pharmacology, 1996Co-Authors: K H Banner, B. Bertin, I. Moodley, Clive P. PageAbstract:The effects of isoenzyme selective phosphodiesterase inhibitors on mitogen-stimulated proliferation of murine thymus and spleen cells was determined. The type 4 phosphodiesterase inhibitors, (rolipram, RO 20-1724 and denbufylline) and the mixed type 3/4 inhibitors, (Zardaverine and benzafentrine) produced a concentration-related inhibition of mitogen stimulated thymus and spleen cell proliferation. Combined addition of the type 4 inhibitor, rolipram and the type 3 inhibitor, SK&F 94836 had no antiproliferative effect additional to that of rolipram alone. The thymus cells were more sensitive to the type 4 inhibitors than the spleen cells. The type 3 phosphodiesterase inhibitor, SK&F 94836 significantly inhibited cell proliferation, but only at high concentrations. The type 1 (vinpocetine) and the type 5 (zaprinast) phosphodiesterase inhibitor had no significant effect on proliferation. These results suggest that thymus and to a lesser extent spleen cell proliferation is dependent on the activity of the type 4 phosphodiesterase isoenzyme.
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Differential effect of phosphodiesterase 4 inhibitors on the proliferation of human peripheral blood mononuclear cells from normals and subjects with atopic dermatitis
British journal of pharmacology, 1995Co-Authors: K H Banner, Nerys M. Roberts, Clive P. PageAbstract:1. The aims of this study were to compare the effects of selective inhibitors of the type 3, type 4 and type 5 phosphodiesterase (PDE) isoenzymes on the phytohaemagglutinin (PHA)-stimulated proliferation of human peripheral blood mononuclear cells (HPBM) from normals and subjects with atopic dermatitis (AD). 2. Mononuclear cells were isolated from peripheral venous blood of normals and subjects with AD. A concentration-response curve was carried out with PHA (0.5-5 micrograms ml-1) and a concentration which produced a submaximal stimulation of proliferation (2 micrograms ml-1) was selected for further experiments. HPBM (10(5) cells per well) were stimulated with PHA (2 micrograms ml-1) in the absence or presence of PDE inhibitor (0.01 microM-10 microM) and 24 h later [3H]-thymidine (0.1 microCi per well) was added. Cells were incubated for an additional 24 h period and [3H]-thymidine incorporation measured. 3. The type 4 PDE inhibitors (rolipram, RO 20-1724 and denbufylline) produced a concentration-related inhibition of proliferation of HPBM from normal and AD subjects. The IC50 for rolipram was significantly (P < 0.05) lower in HPBM from AD patients 0.28 microM (95% confidence limits (CL): 0.158-0.499, n = 5) vs normal subjects 2.6 microM (95% CL: 0.867-7.05, n = 5, P < 0.05) as were the IC50 values for denbufylline: 0.26 microM (95% CL: 0.152-0.440, n = 5) vs 1.84 microM (95% CL: 0.467-7.23, n = 5, P < 0.05) respectively and RO 20-1724: 1.49 microM (95% CL: 0.61 microM-3.64 microM) vs 6.46 microM (95% CL: 2.03 microM-20.46 microM), respectively. 4. The mixed type 3/4 inhibitors (Zardaverine and benzafentrine) produced a concentration-related inhibition of proliferation of HPBM from normal and AD subjects. The IC50 value for Zardaverine in HPBM from normal subjects: 1.8 microM (95% CL: 0.43 microM-7.85 microM, n = 4) was similar to that in AD subjects: 1.03 microM (95% CL: 0.48 microM-2.28 microM) as was the IC50 value for benzafentrine in normal 3.8 microM (95% CL: 2.45 microM-5.9 microM) and atopic 5.5 microM (95% CL: 3.84 microM-7.78 microM) HPBM. The type 5 PDE inhibitor, zaprinast was ineffective at inhibiting the proliferation of normal HPBM. The type 3 PDE inhibitor, siguazodan only inhibited [3H]-thymidine incorporation at a concentration of 10 microM. 5. These results show that combined inhibition of the type 3 and 4 PDE isoenzymes in HPBM from normal subjects has a greater antiproliferative effect than inhibition of the type 4 isoenzyme alone. In addition these data indicate that the proliferative response of HPBM from AD subjects is more sensitive to PDE 4 inhibition than the proliferation of HPBM from normals.
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Acute versus chronic administration of phosphodiesterase inhibitors on allergen‐induced pulmonary cell influx in sensitized guinea‐pigs
British journal of pharmacology, 1995Co-Authors: K H Banner, Clive P. PageAbstract:1. The aims of this study were to determine which phosphodiesterase (PDE) isoenzymes are involved in the control of eosinophil accumulation in the airways of ovalbumin (OVA)-immunized guinea-pigs by the use of isoenzyme selective inhibitors and to compare the effects of acute versus chronic administration of PDE isozyme inhibitors on pulmonary cell influx in ovalbumin-immunized guinea-pigs. 2. Guinea-pigs were sensitized and subsequently challenged with aerosolized OVA. Twenty four hours later bronchoalveolar lavage (BAL) was performed to permit assessment of inflammatory cell accumulation. A significant increase in the number of eosinophils was observed in the lavage fluid from OVA-immunized (13.6 +/- 1.4 x 10(4) ml-1 in acute experiments and 10.1 +/- 1.4 x 10(4) ml-1 in chronic experiments) animals compared with sham-treated controls (5.6 +/- 0.6 x 10(4) ml-1 in acute experiments and 5.1 +/- 0.6 x 10(4) ml-1 in chronic experiments). There was no difference in neutrophil, mononuclear cell or total cell numbers between the two groups. 3. Acute administration of a high dose of selective and non-selective PDE inhibitors by the i.p. route had no significant effect on eosinophil accumulation in the airways. 4. Chronic administration of a low dose (3 mg kg-1, i.p., twice daily for 7 days) of the type IV PDE inhibitor, RO 20-1724, and the PDE III/IV inhibitor, Zardaverine, produced a significant inhibition of eosinophil accumulation (46% and 59% respectively). 5. These results suggest that the type IV PDE isoenzyme plays a role in the control of allergen-induced eosinophil infiltration into the airways, but indicate that a period of low dose chronic treatment with a type IV or mixed type III/IV PDE inhibitor is necessary for eosinophil accumulation in the airways to be reduced.
