Expression, Purification, and Characterization of Human cAMP-Specific Phosphodiesterase (PDE4) Subtypes A, B, C, and D

Wang, Peng; Myers, Joyce G.; Cheewatrakoolpong, Boonlert; Egan, Robert W.; Billah, M. Motasim

doi:10.1006/bbrc.1997.6636

Cited by 119 publications

(51 citation statements)

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“…A recent report has indicated that PDE4 isozymes exhibit differential sensitivity to classical PDE4 inhibitors, such as rolipram and Ro 20-1724. 51 The rat aortic VSMCs used here predominantly express PDE4D (authors' unpublished data, 1997), a PDE4 isozyme that is inhibited potently by Ro 20-1724 (IC 50 , Ϸ0.7 mol/L), 51 thus validating the selection and dose of our selective PDE4 inhibitor.…”

Section: Discussionmentioning

confidence: 79%

Synergistic Inhibition of Vascular Smooth Muscle Cell Migration by Phosphodiesterase 3 and Phosphodiesterase 4 Inhibitors

Palmer

Tsoi

Maurice

1998

Circulation Research

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Abstract-Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze cAMP or cGMP and terminate their signaling. Two important families of PDEs that regulate cAMP signaling in cardiovascular tissues are the cGMP-inhibited PDEs (PDE3) and the cAMP-specific PDEs (PDE4). In this study, we have used a combination of an in vitro motility assay and a sensitive method for the measurement of cAMP in order to determine the relative roles of PDE3 and of PDE4 in the regulation of cAMP-mediated inhibition of VSMC migration. Our data demonstrate that forskolin, an activator of adenylyl cyclases, causes concentration-dependent inhibition of platelet-derived growth factor-induced VSMC migration. Incubation of cultured VSMCs with a PDE4-selective inhibitor, Ro 20-1724, markedly potentiated both the antimigratory effect and the increase in cAMP caused by forskolin. Cilostamide, a PDE3-selective compound, did not affect either the antimigratory activity of forskolin or its ability to increase cAMP. Cilostamide and Ro 20-1724 interacted synergistically to potentiate the inhibition of VSMC migration by forskolin and caused a supra-additive increase in cAMP. These data are consistent with an important role for both PDE3 and PDE4 in the regulation of cAMP-mediated inhibition of VSMC migration. (Circ Res. 1998;82:852-861.)

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Section: Discussionmentioning

confidence: 79%

Synergistic Inhibition of Vascular Smooth Muscle Cell Migration by Phosphodiesterase 3 and Phosphodiesterase 4 Inhibitors

Palmer

Tsoi

Maurice

1998

Circulation Research

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“…Etazolate inhibits mammalian PDE4s (26) and is reported to inhibit T. brucei PDEs. In earlier studies, etazolate showed antiproliferative effects, causing slender-to-stumpy transformation at concentrations of 1-2 M (12).…”

Section: Hydrolysis-resistant Cell-permeable Camp Analogs Do Not Showmentioning

confidence: 99%

Hydrolysis products of cAMP analogs cause transformation ofTrypanosoma bruceifrom slender to stumpy-like forms

Laxman¹,

Riechers²,

Sadı́lek

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

110

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African sleeping sickness is a disease caused by Trypanosoma brucei. T. brucei proliferate rapidly in the mammalian bloodstream as long, slender forms, but at higher population densities they transform into nondividing, short, stumpy forms. This is thought to be a mechanism adopted by T. brucei to establish a stable hostparasite relationship and to allow a transition into the insect stage of its life cycle. Earlier studies have suggested a role for cAMP in mediating this transformation. In this study, using membranepermeable nucleotide analogs, we show that it is not the cAMP analogs themselves but rather the hydrolyzed products of membrane-permeable cAMP analogs that prevent proliferation of T. brucei. The metabolic products are more potent than the cAMP analogs, and hydrolysis-resistant cAMP analogs are not antiproliferative. We further show that the antiproliferative effect of these membrane-permeable adenosine analogs is caused by transformation into forms resembling short, stumpy bloodstream forms. These data suggest that the slender-to-stumpy transformation of T. brucei may not be mediated directly by cAMP and also raise the possibility of using such adenosine analogs as antitrypanosomal drugs.adenosine ͉ EPACs ͉ phosphodiesterases ͉ trypanosomes

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“…PDE Enzyme Assays. The PDE activity was determined radiometrically as described previously (Wang et al, 1997) by SPA. The assay mixture contained 50 mM Tris, pH 7.5, 8.3 mM MgCl 2 , 1.7 mM EGTA, various concentrations of inhibitor, and an aliquot of the enzyme solution in a final volume of 100 l. After preincubation for 5 min at 30°C, the reaction was started by the addition of substrate (cAMP or cGMP).…”

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confidence: 99%

Pharmacology ofN-(3,5-Dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline Carboxamide (SCH 351591), a Novel, Orally Active Phosphodiesterase 4 Inhibitor

Billah¹,

Cooper²,

Minnicozzi³

et al. 2002

J Pharmacol Exp Ther

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-5-quinoline carboxamide (SCH 351591) has been identified as a potent (IC 50 ϭ 58 nM) and highly selective type 4 phosphodiesterase (PDE4) inhibitor with oral bioactivity in several animal models of lung inflammation. N-(3,5-Dichloro-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline carboxamide (SCH 365351), the only significant in vivo metabolite, is also a potent and highly selective PDE4 inhibitor (IC 50 ϭ 20 nM). Both SCH 351591 and SCH 365351 inhibited cytokine production in human blood mononuclear cell preparations. Oral SCH 351591 significantly attenuated allergen-induced eosinophilia and airway hyperreactivity in allergic guinea pigs at doses as low as 1 mg/kg. In this model, oral SCH 365351 showed similar potency. When SCH 351591 was administered orally to allergic cynomolgus monkeys at 3 mg/kg, Ascaris suuminduced lung eosinophilia was blocked. Hyperventilationinduced bronchospasm in nonallergic guinea pigs, a model for exercise-induced asthma, was also suppressed significantly by oral SCH 351591 at 0.3 mg/kg. Cilomilast (SB 207499; Ariflo), a PDE4 inhibitor currently being developed for asthma and chronic obstructive pulmonary disease (COPD), was 10-to 30-fold less potent than SCH 351591 at inhibiting guinea pig lung eosinophilia and hyperventilation-induced bronchospasm. In a ferret model of emesis, maximum nonemetic oral doses of SCH 351591 and cilomilast were 5 and 1 mg/kg, respectively. Comparison of plasma levels at these nonemetic doses in ferrets to those at doses inhibiting hyperventilation-induced bronchospasm in guinea pigs gave a therapeutic ratio of 16 for SCH 351591 and 4 for cilomilast. Thus, SCH 351591 exhibits a promising preclinical profile as a treatment for asthma and COPD.

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Expression, Purification, and Characterization of Human cAMP-Specific Phosphodiesterase (PDE4) Subtypes A, B, C, and D

Cited by 119 publications

References 1 publication

Synergistic Inhibition of Vascular Smooth Muscle Cell Migration by Phosphodiesterase 3 and Phosphodiesterase 4 Inhibitors

Synergistic Inhibition of Vascular Smooth Muscle Cell Migration by Phosphodiesterase 3 and Phosphodiesterase 4 Inhibitors

Hydrolysis products of cAMP analogs cause transformation ofTrypanosoma bruceifrom slender to stumpy-like forms

Pharmacology ofN-(3,5-Dichloro-1-oxido-4-pyridinyl)-8-methoxy-2-(trifluoromethyl)-5-quinoline Carboxamide (SCH 351591), a Novel, Orally Active Phosphodiesterase 4 Inhibitor

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