Competitive Inhibitor Of Phosphodiesterase Research Articles

The effect of theophylline on acetic acid induced ulcerative colitis in rats

BackgroundUlcerative colitis is a relapsing inflammatory disorder of the colon. There is a need to explore the new treatments for this disorder. Theophylline, a competitive inhibitor of phosphodiesterase, is shown to have anti-inflammatory properties. However, the effect of theophylline on ulcerative colitis has not yet been investigated. The present study evaluated the effect of theophylline on acetic acid induced ulcerative colitis in rats. Materials and methodsColitis was induced by instillation of 2ml of acetic acid solution (3%). Colon samples were evaluated grossly and microscopically and assayed for myeloperoxidase (MPO) activity and proinflammatory cytokine concentrations. ResultsTreatment with theophylline at the doses of 20 and 50mg/kg attenuated acetic acid induced ulcerative colitis as shown by improvement in body weight loss, macroscopic score, ulcer area, hematocrit and histopathological score. Theophylline treatment also reduced MPO activity and tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1 β) and interleukin 6 (IL-6) concentrations in inflamed colon. ConclusionTheophylline has a protective effect in acetic acid-induced ulcerative colitis which might be due to its anti-inflammatory activities. Therefore, theophylline has the potential to be used for successful treatment of ulcerative colitis.

148 EFFECTS OF CAFFEINE SUPPLEMENTATION ON BOVINE OOCYTE DEVELOPMENTAL CAPACITY

Oocyte culture in the presence of the nonspecific competitive phosphodiesterase inhibitor caffeine has been reported to increase developmental capacity of oocytes in different mammalian species. Here, we evaluated the effects of caffeine supplementation during the final phase of in vitro maturation (IVM) on developmental rates and blastocyst cell numbers. Bovine ovaries were collected from a local abattoir. A total of 1142 cumulus-oocyte-complexes were obtained by slicing. Cumulus-oocyte complexes were either in vitro matured for 24 h (Standard) or matured for 20 h followed by additional culture for 6 h in fresh IVM medium supplemented with 10 mM caffeine (Caffeine 6 h). In vitro fertilization was performed for 19 h using frozen-thawed sperm from 2 different bulls. After IVF, presumptive zygotes were cultured in vitro for 8 days until the blastocyst stage. Cleavage and blastocyst rates were evaluated 3 and 8 days after IVF, respectively. Expanded blastocysts from the different treatments were submitted to differential staining. SAS/STAT software (SAS Institute Inc., Cary, NC, USA) was used to evaluate cleavage and blastocyst rates using the Glimmix procedure and blastocyst cell numbers were compared using the linear model procedure. Cleavage rates were lower using caffeine for bull B and blastocyst production decreased for bull A. Caffeine treatment increased inner cell mass (ICM) number for bull B and decreased trophectoderm (TE) and total cell numbers for bull A. However, similar TE and total cells were obtained for bull B (Table 1; P < 0.05). Results show that developmental competence can be affected by caffeine supplementation at the final phase of IVM probably due to oocyte-sperm interaction changes. Table 1. In vitro developmental competence of oocytes cultured with caffeine at the end of IVM

Starting a Beneficial Path

Resveratrol acts as a competitive phosphodiesterase inhibitor to initiate pathways that mediate its beneficial effects on metabolic disorders.

TADALAFIL IN PATIENTS WITH COLLAGEN VASCULAR DISEASE-ASSOCIATED PULMONARY ARTERIAL HYPERTENSION

PURPOSE: Patients with collagen vascular disease (CVD)-associated pulmonary arterial hypertension (PAH) have a poorer prognosis than other PAH patients. Tadalafil, a competitive inhibitor of phosphodiesterase 5 (PDE5), appeared safe and efficacious for PAH in a 16-week, double-blind, placebo controlled trial. We describe results in patients with CVD during the 16-week trial and a blinded extension trial.

LONG-TERM IMPROVEMENTS IN CLINICAL WORSENING WITH TADALAFIL IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION

PURPOSE: Tadalafil, a competitive inhibitor of phosphodiesterase 5, improved exercise capacity and had an acceptable safety profile in patients with pulmonary arterial hypertension (PAH) in a 16-week, phase 3 double-blind, placebo-controlled trial (PHIRST-1 study). In the long-term extension study (PHIRST-2), the six-minute walk distance (6MWD) was maintained over the 52-week period. We report clinical worsening for subjects remaining on tadalafil 20-mg or tadalafil 40-mg for entire 68-week treatment period across the 2 studies.

Atrazine is a competitive inhibitor of phosphodiesterase but does not affect the estrogen receptor

Atrazine (ATR), 2-chloro-4-ethylamino-6-isopropylamino- s-triazine, has been implicated in numerous studies to act as an endocrine disruptor, specifically by altering estradiol signaling via increased aromatase activity. Fluorescence polarization (FP) was used to show that the binding equilibria between estrogen receptor-α or estrogen receptor-β, and estradiol were not affected by ATR and its metabolites: ATR-desethyl (ADE), ATR-desisopropyl (ADI), ATR-desethyldesisopropyl (ADD) and terbuthylazine (TBZ). Therefore, ATR and its degradation products were studied to determine their ability to inhibit phosphodiesterase (PDE), the enzyme responsible for hydrolyzing the second messenger cAMP to 5′-AMP. Using FP, it was found that ATR inhibited PDE with an IC 50 value of 1.8 μM. This was lower than the known PDE inhibitor isobutyl methylxanthine (IBMX), which had an IC 50 value of 4.6 μM. The ATR degradation products ADE, ADI, ADD and TBZ were less effective than ATR at inhibiting PDE when assayed using FP. Classical competitive binding assays, using radiolabeled 14C-cAMP in conjunction with thin layer chromatography (TLC), were used to determine that ATR was a competitive inhibitor of PDE with an association constant of 85 μM.

Cardiovascular activity of WIN 65579, a novel inhibitor of cyclic GMP phosphodiesterase 5

This study describes the phosphodiesterase inhibitory potency and cardiovascular actions of WIN 65579 (1-cyclopentyl-3-ethyl-6-(3-ethoxy-4-pyrridyl)-1H-pyrazolo[3,4- d]pyrimidin-4-one), a potent, new cGMP phosphodiesterase 5 inhibitor. WIN 65579 is a competitive inhibitor of phosphodiesterase 5, with IC 50 values of 2–3 nM for phosphodiesterase 5 from human or canine vascular sources. WIN 65579 has low affinity for phosphodiesterases 1, 2 and 3 (IC 50>3–10 μM), and is somewhat selective for phosphodiesterase 4 (IC 50∼100 nM). WIN 65579 is an endothelial-dependent relaxant of rat aortic smooth muscle (EC 50=60 nM) and lowers mean arterial blood pressure in conscious spontaneous hypertensive rats following intravenous or oral dosing. WIN 65579 also increases plasma cGMP levels, and reinstates vascular responsiveness to nitroglycerin in conscious rats that are nitroglycerin-tolerant. These data show that WIN 65579 is one of the more potent phosphodiesterase 5 inhibitors, and that WIN 65579 possesses cardiovascular activities consistent with vascular phosphodiesterase 5 inhibition in vivo.

The specific interaction of Cibacron and related dyes with cyclic nucleotide phosphodiesterase and lactate dehydrogenase

1. Reactive Blue 2 (Cibacron Blue 3G-A) is a competitive inhibitor of bovine heart cyclic nucleotide phosphodiesterase (K(i) 0.3mum). The K(i) increases with increasing temperature, suggesting that hydrophobic interactions are not largely responsible for the binding of the dye. Another 25 sulphonated aromatic dyes are also competitive inhibitors of the cyclic nucleotide phosphodiesterase (K(i) values in the range of 0.06-13.6mum). 2. These dyes (covalently linked to Dextran 40) inhibit bovine heart cyclic nucleotide phosphodiesterase. Reactive Blue 2 (covalently linked to Dextran 40) is a competitive inhibitor of the phosphodiesterase (K(i) 0.4mum). 3. Bovine heart cyclic nucleotide phosphodiesterase is retained on a column of Reactive Blue 2-Sephacryl S-200 and can be eluted from the column by 3':5'-cyclic AMP. 4. A variety of the dyes (either free or covalently linked to Dextran 40) are competitive inhibitors of rabbit muscle lactate dehydrogenase. 5. The effectiveness of a wide range of structurally dissimilar dyes as competitive inhibitors of lactate dehydrogenase and cyclic nucleotide phosphodiesterase compromises proposals for the use of Reactive Blue 2 as a specific probe for the dinucleotide-binding structural domain present in many dehydrogenases and kinases. Detailed information of the various dyes used has been deposited as Supplementary Publication SUP 50089 (7 pages) at the British Library Lending Division, Boston Spa, Wetherby, West Yorkshire LS23 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1978) 169, 5.