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: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Propentofylline (HWA 285, 3-methyl-1-(5-oxo-hexyl)-7-propylxanthine) is an adenosine uptake and phosphodiesterase inhibitor that has been shown to be neuroprotective in both global and permanent focal ischemia animal models. However, to date, the efficacy of propentofylline has never been examined in an animal model of temporary focal ischemia or the 'therapeutic window' systematically examined in a focal ischemia model. The present experiments were designed to investigate these. Temporary (3 h) middle cerebral artery occlusion was accomplished by the monofilament method. Infarct volumes were determined at 24 h from 2,3,5-triphenyltetrazolieum chloride (TTC) stained coronal slices. Animals were dosed with vehicle or propentofylline at 3 mg/kg bolus and/or a 6 mg/kg per h infusion (24 h infusion) at 30 min, 1 h or 3 h post ischemia onset. Physiological monitoring on a subset of animals indicated no changes in mean arterial pressure, blood gases, blood pH, and glucose levels with either ischemia or drug treatment. Propentofylline treatment resulted in a statistically significant decrease in infarct volume when an infusion dose of 6 mg/kg per h was initiated at 30 min or when a bolus of 3 mg/kg plus an infusion dose was initiated at 1 h but not 3 h post ischemia. Therefore, propentofylline is neuroprotective in a model of temporary focal ischemia. This suggests that combination therapy with propentofylline might lead to clinical improvement beyond that which would occur with thrombolytics alone. The apparent short window of opportunity for effective dosing is consistent with the proposed mechanism of action for propentofylline.
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PMID:Temporal dependent neuroprotection with propentofylline (HWA 285) in a temporary focal ischemia model. 965 54

Several signal transduction pathways have been implicated in the mechanism of protection induced by ischemic preconditioning (PC). For example, stimulation of a variety of G-protein coupled receptors results in stimulation of protein kinase C (PKC) which has been suggested to act as common denominator in eliciting protection. PC also significantly attenuated cAMP accumulation during sustained ischemia, suggesting involvement of an anti-adrenergic mechanism. The aim of this study was to evaluate the beta-adrenergic signal transduction pathway (as evidenced by changes in tissue cAMP and cAMP- and cGMP-phosphodiesterase) during the PC protocol as well as during sustained ischemia. Isolated perfused rat hearts were preconditioned by 3 x 5 min global ischemia (PC1,2,3) interspersed by 5 min reperfusion, followed by 25 min global ischemia. Tissue cAMP- and cGMP-PDE activity as well as cAMP and cGMP levels were determined at different time intervals during the PC protocol and sustained ischemia. Tissue cAMP increased with each PC ischemic event and normalized upon reperfusion, while PDE activity showed the opposite, viz a reduction during ischemia and an increase during reperfusion. Except for PC1, tissue cGMP showed similar fluctuations. Throughout 25 min sustained ischemia, cAMP- and cGMP-PDE activities were higher in PC than in nonpreconditioned hearts, associated with a significantly lesser accumulation in cAMP and higher cGMP levels in the former. Fluctuations in cyclic nucleotides during preconditioning were associated with concomitant changes in PDE activity, while the attenuated beta-adrenergic response of preconditioned hearts during sustained ischemia may partially be due to increased PDE activity.
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PMID:Role of cyclic nucleotide phosphodiesterases in ischemic preconditioning. 977 98

Prostaglandin E(1) (PGE(1)) has cardioprotective effects on the ischemic-reperfused heart. To clarify the mechanisms underlying the protective action of PGE(1) on myocardium, we examined the effect of PGE(1) on the L-type Ca(2+) current (I(Ca)) using single atrial cells from rabbits. PGE(1) did not show a significant effect on basal I(Ca) but inhibited the I(Ca) prestimulated by isoproterenol (Iso, 30 nM). This inhibition was concentration dependent (EC(50) = 0.027 microM). Both sulprostone, a specific PGE receptor subtype (EP(1) and EP(3)) agonist, and 11-deoxy-PGE(1), an EP(3) agonist, inhibited the Iso-stimulated I(Ca), similar to PGE(1). Pretreatment with pertussis toxin (PTX) abolished the PGE(1) inhibition of I(Ca). Both the application of forskolin plus IBMX and intracellular dialysis with 8-bromoadenosine 3',5'-cyclic monophosphate eliminated the effect of PGE(1). PGE(1) did not show any further inhibition of I(Ca) when the effect of Iso was almost fully antagonized by acetylcholine. Methylene blue (guanylate cyclase inhibitor), KT-5823 (cGMP-dependent protein kinase inhibitor), and erythro-9-(2-hydroxy-3-nonyl)adenine (type II phosphodiesterase inhibitor) did not significantly change the inhibitory effect of PGE(1). These findings suggest that 1) PGE(1) inhibits Iso-stimulated I(Ca) by binding to the EP(3) receptor and 2) the PTX-sensitive and cAMP-dependent pathway is involved in the PGE(1) inhibition of I(Ca), but the nitric oxide-cGMP-dependent pathway is not. The PGE(1)-induced antiadrenergic effect shown in this study may contribute to the PGE(1) protection of myocardium against ischemia.
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PMID:EP receptor-mediated inhibition by prostaglandin E(1) of cardiac L-type Ca(2+) current of rabbits. 1051 71

Inflammatory mediators are implicated in the pathogenesis of ischemic injury in immature brain. The phosphodiesterase inhibitor pentoxifylline inhibits production of tumor necrosis factor-alpha and platelet-activating factor. We hypothesized that pentoxifylline treatment would attenuate hypoxic-ischemic brain injury in immature rats. Seven-day-old rats (n = 79) underwent right carotid ligation, followed by hypoxia (FiO2 = 0.08). Rats received pentoxifylline immediately before and again after hypoxia (two doses, 25-150 mg/kg/dose, n = 34), or vehicle (n = 27). In separate experiments, rats received pentoxifylline treatment (40 mg/kg/dose, n = 8), or vehicle (n = 10) immediately and again 3 h after hypoxia-ischemia. Severity of injury was assessed 5 d later by visual evaluation of ipsilateral hemisphere infarction and by measurement of bilateral hemispheric cross-sectional areas. Pentoxifylline pretreatment reduced the incidence of liquefactive cerebral infarction, from 75% in controls to 10% with pentoxifylline, 40 mg/kg/dose (p<0.001, chi2 trend test). Quantification of hemispheric areas confirmed these findings. In contrast, posthypoxic-ischemic treatment with pentoxifylline resulted in only a modest reduction in cortical damage, without an overall reduction in incidence of infarction. Phosphodiesterase inhibition may be an effective strategy to use to decrease the severity of neonatal hypoxic-ischemic brain injury. Pretreatment regimens could be clinically relevant in settings in which an increased risk of cerebral ischemia can be anticipated, such as in infants undergoing surgery to correct congenital heart disease.
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PMID:Pentoxifylline attenuates hypoxic-ischemic brain injury in immature rats. 1062 85

A pathological glia activation, stimulated by inflammatory proteins, beta-amyloid, or brain ischemia, is discussed as a common pathogenic factor for progressive nerve cell damage in vascular and Alzheimer dementia. A critical point seems to be reached, if the cytokine-controlled microglial upregulation causes a secondary activation of astrocytes which loose the negative feedback control, are forced to give up their physiological buffering function, and may add to neuronal damage by the release of nitric oxide (NO) and by promoting toxic beta-amyloid formation. A strengthening of the cyclic adenosine-5',3'-monophosphate (cAMP) signaling exerted a differential inhibition of the stimulatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) released from cultured rat microglia, but maintained the negative feedback signal IL-6; cAMP inhibited also the release of free oxygen radicals (OR) but not of NO. Reinforcement of the NO-induced cyclic guanosine monophosphate (cGMP) increase by blockade of the phosphodiesterase (PDE) subtype-5 with propentofylline counterbalanced the toxic NO action that causes with OR neuronal damage by peroxynitrate formation. In rat cultured astrocytes, a prolonged cAMP elevation favored cell differentiation, the expression of a mature ion channel patter, and an improvement of the extracellular glutamate uptake. Cyclic AMP signaling could be strengthened by PDE blockade and by raising extracellular adenosine, which stimulates A2 receptor-mediated cAMP synthesis. Via an A1 receptor-mediated effect, elevated adenosine was found to overcome a deficient intracellular calcium mobilization resulting from an impaired muscarinic signaling at pathologically decreased acetylcholine concentrations. We suggest that pharmaca, which elevate extracellular adenosine and/or block the degradation of cyclic nucleotides, may be used to counteract glia-related neuronal damage in dementing processes.
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PMID:Cascading glia reactions: a common pathomechanism and its differentiated control by cyclic nucleotide signaling. 1081 85

In view of the use of synthetic propentofylline (PPF) as a protective agent in brain ischemia, its possible side effects on vision capacities have been explored by electroretinography in comparative experiments with theophylline. We used eyecup preparations of small-spotted dogfish sharks and of European eels, particularly suitable for long-lasting experiments. The drug exerted profound but reversible modifications of ERG records: (1) a dose-dependent increase of the amplitude and duration of the chemically isolated late receptor potential (LRP), (2) a partial unmasking of LRP, (3) a strong potentiation of the LRP-unmasking effect of low temperature, (4) a potentiation of light adaptation effects, and (5) a strong potentiation of the post-illumination hyperexcitability. The effects were explicable as due to a strong phosphodiesterase (PDE) inhibiting, cyclic guanosine monophosphate (cGMP) promoting, action of the drug. The effects were considerably stronger, or even of opposite sign, in comparison to those of the chemically related theophylline. PPF did not seriously affect the ERG c-wave originating in the pigment epithelium. The results suggested that the effects of PPF on vision may not seriously hamper the therapeutic use of the drug. They indicated, on the other hand, that PPF was a retinoactive drug of potential usefulness in the exploration of the complex biochemical events underlying visual transduction.
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PMID:Effects of xanthine derivatives on electroretinographic responsiveness. 1085 70

Disruption of endothelial barrier properties with development of noncardiogenic pulmonary edema is a major threat in lung ischemia-reperfusion (I/R) injury that occurs under conditions of lung transplantation. Inhaled nitric oxide (NO) reduced vascular leakage in lung I/R models, but the efficacy of this agent may be limited. We coadministered NO and zaprinast, a cGMP-specific phosphodiesterase inhibitor, to further augment the NO-cGMP axis. Isolated, buffer-perfused rabbit lungs were exposed to 4.5 h of warm ischemia. Reperfusion provoked a transient elevation in pulmonary arterial pressure and a negligible rise in microvascular pressure followed by a massive increase in the capillary filtration coefficient and severe lung edema formation. Inhalation of 10 parts/million of NO or intravascular application of 100 microM zaprinast on reperfusion both reduced pressor response and moderately attenuated vascular leakage. Combined administration of both agents induced no additional vasodilation at constant microvascular pressures, but additively protected against capillary leakage paralleled by a severalfold increase in perfusate cGMP levels. In conclusion, combining low-dose NO inhalation and phosphodiesterase inhibition may be suitable for the maintenance of graft function in lung transplantation by amplifying the beneficial effect of the NO-cGMP axis and avoiding toxic effects of high NO doses.
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PMID:The PDE inhibitor zaprinast enhances NO-mediated protection against vascular leakage in reperfused lungs. 1095 24

Raising intracellular cAMP or cGMP concentrations protects lungs from ischemia-reperfusion injury. These nucleotides are catabolized by a number of distinct phosphodiesterase (PDE) isoenzyme subfamilies. We examined the ability of PDE inhibitors of differing selectivities to protect lungs from the effects of prolonged hypothermic storage. Rat lungs were perfused with bicarbonate buffer mixed with rat blood (4:1 vol/vol, 37 degrees C), ventilated, and vascular resistance, airway compliance, and resistance, and gas exchange measured. Lungs were then flushed with, and immersed in, St. Thomas' Hospital Solution (STH) (4 degrees C) or STH containing rolipram, milrinone, zaprinast, or theophylline. After 8 h storage, function was reassessed during 40 min reperfusion. Lungs stored in STH containing rolipram or theophylline had improved function on reperfusion. After 40 min reperfusion, pulmonary compliance (Cstat) was 0.07 +/- 0.01 ml/cm H(2)O in lungs stored in STH alone. Adding rolipram (100 microM) or theophylline (3,000 microM) to the STH used for flushing and storage improved Cstat after reperfusion to 0.17 +/- 0.02 ml/cm H(2)O (p < 0.05) and 0.17 +/- 0.02 ml/cm H(2)O (p < 0. 05), respectively. Theophylline also improved the increase in perfusate PO(2) on transit through the lung after storage to 25.16 +/- 2.33 compared with 4.72 +/- 2.18 mm Hg in lungs stored in STH alone (p < 0.05). Of the selective PDE inhibitors tested, rolipram (type IV inhibitor) was most effective. However, the nonselective agent, theophylline, provided the best protection of function after storage and reperfusion of rat lungs.
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PMID:Comparison of phosphodiesterase inhibitors of differing isoenzyme selectivity added to St. Thomas' hospital cardioplegic solution used for hypothermic preservation of rat lungs. 1098 94

Erectile dysfunction (ED) is common in men with cardiovascular disease. The introduction of sildenafil citrate, the first oral agent for the treatment of this disorder, has increased awareness about the risks of sexual activity in cardiac patients and raised concerns about the safety of sildenafil in patients being treated for coronary disease. Sildenafil is a potent and selective inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP). Sildenafil acts along the same general pathway as nitric oxide donors to increase cGMP levels and enhance erections. Sildenafil is a modest vasodilator that causes small decreases in systemic arterial pressure and mild preload and afterload reductions. It does not cause major decreases in blood pressure when administered with one or more standard antihypertensive agents. Because PDE5 is also present in small amounts in the systemic vasculature, sildenafil can cause a synergistic and major decrease in pressure when combined with organic nitrates. Use of organic nitrates is the only contraindication to sildenafil use. Data on sildenafil in patients with recent (less than 6 months) myocardial infarction (MI), unstable angina, stroke, and recent life-threatening arrhythmias are not available, so the drug should be used with caution in patients with unstable cardiac conditions. Placebo-controlled and open-label phase 2/3 trials including men with ischemic heart disease did not show an increase in MI or serious cardiovascular events in patients treated with sildenafil versus placebo. None of the serious cardiovascular events reported in these trials were considered treatment related by the investigators. There is a small but finite increased risk of developing ischemia or infarction with sexual activity. Therefore, before prescribing sildenafil or any current or future treatment for ED to patients with known cardiac disease or multiple cardiovascular risk factors, physicians should discuss the potential cardiac risk of sexual activity and perform a complete medical assessment, including an exercise stress test if appropriate.
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PMID:Sex and the patient with cardiovascular risk factors: focus on sildenafil. 1113 98

Studies suggest that pulmonary vascular ischemia-reperfusion injury (IRI) can be attenuated by increasing intracellular cAMP concentrations. The purpose of this study was to determine the effect of IRI on capillary permeability, assessed by capillary filtration coeficient (Kfc), in lungs retrieved from non-heart-beating donors (NHBDs) and reperfused with the addition of the beta(2)-adrenergic receptor agonist isoproterenol (iso), and rolipram (roli), a phosphodiesterase (type IV) inhibitor. Using an in situ isolated perfused lung model, lungs were retrieved from NHBD rats at varying intervals after death and either ventilated with O(2) or not ventilated. The lungs were reperfused with Earle's solution with or without a combination of iso (10 microM) and roli (2 microM). Kfc, lung viability, and pulmonary hemodynamics were measured. Lung tissue levels of adenine nucleotides and cAMP were measured by HPLC. Combined iso and roli (iso/roli) reperfusion decreased Kfc significantly (p < 0.05) compared with non-iso/roli-reperfused groups after 2 h of postmortem ischemia. Total adenine nucleotide (TAN) levels correlated with Kfc in non-iso/roli-reperfused (r = 0.89) and iso/roli-reperfused (r = 0.97) lungs. cAMP levels correlated with Kfc (r = 0.93) in iso/roli-reperfused lungs. Pharmacologic augmentation of tissue TAN and cAMP levels might ameliorate the increased capillary permeability observed in lungs retrieved from NHBDs.
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PMID:Maintenance of cAMP in non-heart-beating donor lungs reduces ischemia-reperfusion injury. 1140 88


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