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)

Infants of diabetic mothers are at increased risk of a number of problems at birth. Among these problems are increased risks of respiratory distress syndrome and transient tachypnea of the newborn. Because surfactant synthesis, surfactant secretion, and lung fluid resorption are all mediated in part by beta-adrenergic responses, we asked if excess insulin interferes with the beta-adrenergic response cascade in fetal lung. Lungs from fetal rabbits (26 day) were grown in explant culture in hormone-supplemented culture medium. The explants were harvested after 48 h exposure to hormones and processed for determination of beta-adrenergic receptor concentration, guanine nucleotide regulatory proteins (Gs, Gi), beta-agonist stimulated adenosine 3',5'-cyclic monophosphate (cAMP) generation, cAMP-dependent phosphodiesterase activity, and choline incorporation into phosphatidylcholine. Although insulin did not change the concentration of beta-adrenergic receptors, it decreased the ability of isoproterenol to stimulate cAMP generation. Increase in stimulation over basal was similar in explants treated with dexamethasone and dexamethasone plus insulin, but absolute levels of isoproterenol-stimulated cAMP were less in the explants treated with dexamethasone plus insulin. We speculate that insulin inhibition of cAMP generation may be important in the pathogenesis of the respiratory problems of infants of diabetic mothers.
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PMID:Insulin inhibits beta-adrenergic responses in fetal rabbit lung in explant culture. 133 1

Autopsy findings suggest that lung surfactant is damaged in the adult respiratory distress syndrome. In the present study 225 bronchoalveolar lavage specimens (78 from 36 patients, 1-78 yr old with respiratory failure, 135 from another 128 patients with other respiratory disease, and 12 from healthy controls) were assayed for the lung profile [lecithin/sphingomyelin (L/S) ratio, saturated lecithin, phosphatidylinositol, and phosphatidylglycerol]. Bronchoalveolar lavage fluid was further analyzed for phospholipids and for phosphatidic acid phosphohydrolase, phospholipase A2, and phosphatidylinositol phosphodiesterase activities. A lipid-protein complex was isolated and analyzed for surface activity, and plasma was measured for myoinositol. There were only small differences seen in the recovery of total phospholipid between respiratory failure patients and normal controls. However, in respiratory failure, phospholipids in bronchoalveolar lavage were qualitatively different from those recovered either from normal controls or from patients with other lung disease: the LO/S ratio, phosphatidylglycerol, and disaturated lecithin were low, whereas sphingomyelin and phosphatidylserine were prominent. These abnormalities were present early in respiratory failure and tended to normalize during recovery. Low L/S ratio (less than 2), and low phosphatidylglycerol (1% or less of glycerophospholipids) in bronchoalveolar lavage was always associated with respiratory failure. Abnormal lavage phospholipids were not due to plasma contamination. The phospholipase studies revealed little evidence of increased catabolism of phospholipids. In respiratory failure, the lipid-protein complexes from lung lavage were not surface active, whereas that from healthy controls had surface properties similar to lung surfactant. Phospholipids from patients with respiratory failure were similar to those from respiratory distress syndrome in the newborn. However, the latter condition is characterized by fast recovery of surfactant deficiency and by high plasma myoinositol that suppresses the synthesis of surfactant phosphatidylglycerol and increases phosphatidylinositol (Pediatr. Res. 1981. 15: 720). On the other hand, in adult respiratory distress syndrome, the abnormality in surfactant phospholipids may last for weeks and in most cases is associated with low phosphatidylinositol, low phosphatidylglycerol, and low plasma myoinositol.
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PMID:Evidence of lung surfactant abnormality in respiratory failure. Study of bronchoalveolar lavage phospholipids, surface activity, phospholipase activity, and plasma myoinositol. 689 15

A 17 year old male with a history of bronchial asthma was admitted to the intensive care unit in severe respiratory distress. During a two week period of intensive respiratory care he received large doses of aminophylline and corticosteroids. In addition, pancuronium was given to facilitate ventilation and to reduce airway pressure. Large doses of pancuronium, as much as 5 mg/hr, were required to stop spontaneous respiratory efforts and restlessness. The total pancuronium dose given during the two week period was 800 mg. One hour after pancuronium was discontinued the patient could open his eyes and move his lips. Peripheral nerve stimulation indicated partial paralysis which improved promptly following a test dose of edrophonium. The authors speculate the aminophylline, which is a known inhibitor of the enzyme phosphodiesterase, raised the level of c-AMP and, in turn, the level of acetylcholine at the neuromuscular junction and thus antagonized the blocking effect of pancuronium. In addition, the large doses of corticosteroids that the patient had received may have enhanced the release of acetylcholine and further facilitated neuromuscular transmission.
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PMID:Resistance to pancuronium in an asthmatic patient treated with aminophylline and steroids. 707 8

Pulmonary hypertension is a common finding in pulmonary circulatory disorders of different origin. Chronic pulmonary hypertension may develop due to either cardiopulmonary or systemic diseases whereas acute and acute-on-chronic pulmonary hypertension often occur in the course of cardiothoracic surgery. Right heart failure is the major risk particularly in the course of acute pulmonary hypertension. Thus, besides basic treatment of the underlying disease the use of vasodilators is a valuable therapeutic option to decrease right ventricular afterload, but intravenous vasodilators may provoke systemic arterial hypotension and impair gas exchange due to vasodilation of pulmonary shunt areas. Therefore, inhaled vasodilators such as nitric oxide and prostacyclin have been suggested for the treatment of pulmonary hypertension especially when concomitant hypoxemia is present due to a ventilation-perfusion mismatch. However, randomised controlled trials performed to evaluate long-term effects revealed different results: thus, in chronic pulmonary hypertension inhaled vasodilators improved outcome whereas the results for the treatment of the acute respiratory distress syndrome revealed beneficial effects only when used as a rescue and/or bridging therapy in severe hypoxemia. In cardiothoracic surgery, inhaled vasodilators have been shown to improve pulmonary circulation when severe pulmonary hypertension is present. Although effective in experimental studies no clear recommendation can be made in view to the use of other vasodilators such as phosphodiesterase inhibitors or endothelin antagonists. Likewise, the combination of different vasodilators merit further investigations to prove efficacy in randomised controlled trials.
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PMID:Modulating the pulmonary circulation: an update. 1517 3

The pleiotropic cytokine tumor necrosis factor-alpha (TNF-alpha) and thrombin lead to increased endothelial permeability in sepsis. Numerous studies demonstrated the significance of intracellular cyclic nucleotides for the maintenance of endothelial barrier function. Actions of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are terminated by distinct cyclic nucleotide phosphodiesterases (PDEs). We hypothesized that TNF-alpha could regulate PDE activity in endothelial cells, thereby impairing endothelial barrier function. In cultured human umbilical vein endothelial cells (HUVECs), we found a dramatic increase of PDE2 activity following TNF-alpha stimulation, while PDE3 and PDE4 activities remained unchanged. Significant PDE activities other than PDE2, PDE3, and PDE4 were not detected. TNF-alpha increased PDE2 expression in a p38 mitogen-activated protein kinase (MAPK)-dependent manner. Endothelial barrier function was investigated in HUVECs and in isolated mice lungs. Selective PDE2 up-regulation sensitized HUVECs toward the permeability-increasing agent thrombin. In isolated mice lungs, we demonstrated that PDE2 inhibition was effective in preventing thrombin-induced lung edema, as shown with a reduction in both lung wet-to-dry ratio and albumin flux from the vascular to bronchoalveolar compartment. Our findings suggest that TNF-alpha-mediated up-regulation of PDE2 may destabilize endothelial barrier function in sepsis. Inhibition of PDE2 is therefore of potential therapeutic interest in sepsis and acute respiratory distress syndrome (ARDS).
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PMID:Tumor necrosis factor-alpha-dependent expression of phosphodiesterase 2: role in endothelial hyperpermeability. 1565 61

Findings coming from autopsies and serum of SARS patients suggest an important immune-inflammatory implication in the evolution to respiratory distress. Conditions such as HIV infection or treatment with immunosuppressors (in cancer or autoimmune diseases) are not among the bad prognosis factors for development of distress. To date, there have been no reported case fatalities in children, probably due to their more immature immune system. Our conclusions follow: (1) The milder form of SARS in children and the apparent protective factor that immunosupression represent rules out a significant viral cytopathic effect (they would be the most affected). (2) The evidence for immune implication in distress strongly supports immunomodulators for therapy: phosphodiesterase inhibitors (due to their down-modulating activity on proinflammatory cytokines); inhaled corticoids (aimed at producing a local immunomodulation); teophylline or nedocromil sodium (which prevents inflammatory cell recruitment into the airway wall). (3) An early immunomodulatory therapy, based on the levels of proinflammatory cytokines and clinical parameters to evaluate the respiratory function such as arterial oxygen saturation, could prevent the occurrence of distress. (4) Vaccine design should consider the immune origin of distress. (5) Physicians should be aware of mildly symptomatic patients (children, immuno-compromised hosts) to avoid transmission to immunocompetent adults.
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PMID:Severe acute respiratory syndrome, a pathological immune response to the new coronavirus--implications for understanding of pathogenesis, therapy, design of vaccines, and epidemiology. 1567 50

Neutrophils are relatively insensitive to the anti-inflammatory actions of conventional chemotherapeutic agents, including corticosteroids, emphasizing the requirement for novel pharmacological strategies to control the potentially harmful proinflammatory activities of these cells. In the case of commonly-occurring inflammatory diseases of the airways, the neutrophil is the primary mediator of inflammation in conditions such as chronic obstructive pulmonary disease, cystic fibrosis, acute respiratory distress syndrome, bronchiectasis and non-eosinophilic bronchial asthma. Recent insights into the mechanisms utilized by neutrophils to restore Ca(2+) homeostasis following activation with Ca(2+)-mobilizing, proinflammatory stimuli have facilitated the identification of novel targets for anti-inflammatory chemotherapy in these cells. The most amenable of these from a chemotherapeutic perspective, is the cyclic AMP-dependent protein kinase-modulated endomembrane Ca(2+)-ATPase which promotes clearance of the cation from the cytosol of activated neutrophils. Second generation type 4 phosphodiesterase inhibitors and adenosine receptor agonists operative at the level of subtype A2A adenosine receptors, which are currently undergoing clinical and preclinical assessment respectively, hold promise as pharmacologic modulators during the restoration of Ca(2+) homeostasis. If this promise is realized, it may result in novel chemotherapeutic strategies for the control of hyperacute and chronic inflammatory conditions in which neutrophils are primary offenders. Alternative, potential future targets include the Na(+), Ca(2+)-exchanger and store-operated Ca(2+) channels, which cooperate in the refilling of intracellular Ca(2+) stores.
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PMID:Taming the neutrophil: calcium clearance and influx mechanisms as novel targets for pharmacological control. 1599 82

Pulmonary arterial hypertension (PH) is a pathologic condition in dogs characterized by abnormally high pressures in the pulmonary circulation and has been associated with a poor outcome. Sildenafil is a type V phosphodiesterase inhibitor that produces nitric oxide mediated vasodilatation. Sildenafil treatment decreases pulmonary arterial pressure and pulmonary vascular resistance in people with PH. The purpose of this study was to describe the clinical characteristics and outcome of dogs with PH treated with sildenafil. The cardiology database was searched for dogs with PH treated with sildenafil. PH was defined as systolic pulmonary arterial pressure (PAPs) > or = 25 mmHg at rest. Medical records were reviewed for the following information: signalment, duration and type of clinical signs before treatment, underlying disease, estimated or measured PAPs, dosage and dosing interval of sildenafil, and the effect of treatment on clinical signs and pulmonary arterial pressure and survival time. Thirteen affected dogs were identified. Clinical signs included collapse, syncope, respiratory distress, and cough. Duration of clinical signs before presentation ranged from 3 days to 5 months. An underlying cause was identified in 8 dogs. The median sildenafil dosage was 1.9 mg/kg. Ten dogs received concurrent medications. Median PAPs was 90 mmHg; 8 dogs were reevaluated after therapy, and the median decrease in PAPs was 16.5 mmHg. The median survival time of all dogs was 91 days. Sildenafil appeared to be well tolerated in dogs with PH and was associated with decreased PAPs and amelioration of clinical signs in most. Sildenafil represents a reasonable treatment option for dogs with pulmonary hypertension.
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PMID:Retrospective evaluation of sildenafil citrate as a therapy for pulmonary hypertension in dogs. 1819 19

2-Choloroethyl Ethyl Sulfide (CEES) exposure causes inflammatory lung diseases, including acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. This may be associated with oxidative stress, which has been implicated in the desensitization of beta-adrenergic receptors (beta-ARs). The objective of this study was to investigate whether lung injury induced by intratracheal CEES exposure (2 mg/kg body weight) causes desensitization of beta-ARs. The animals were sacrificed after 7 days and lungs were removed. Lung injury was established by measuring the leakage of iodinated-bovine serum albumin ([(125)I]-BSA) into lung tissue. Receptor-binding characteristics were determined by measuring the binding of [(3)H] dihydroalprenolol ([(3)H] DHA) (0.5-24 nM) to membrane fraction in the presence and absence of DLDL-propranolol (10 micro M). Both high- and low-affinity beta-ARs were identified in the lung. Binding capacity was significantly higher in low-affinity site in both control and experimental groups. Although CEES exposure did not change K(D) and B(max) at the high-affinity site, it significantly decreased both K(D) and B(max) at low affinity sites. A 20% decrease in beta(2)-AR mRNA level and a 60% decrease in membrane protein levels were observed in the experimental group. Furthermore, there was significantly less stimulation of adenylate cyclase activity by both cholera toxin and isoproterenol in the experimental group in comparison to the control group. Treatment of lungs with 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of phosphodiesterase (PDE) could not abolish the difference between the control group and the experimental group on the stimulation of the adenylate cyclase activity. Thus, our study indicates that CEES-induced lung injury is associated with desensitization of beta(2)-AR.
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PMID:Desensitization of beta-adrenergic receptors in lung injury induced by 2-chloroethyl ethyl sulfide, a mustard analog. 1920 64

Glucocorticoid resistance or insensitivity is a major barrier to the treatment of several common inflammatory diseases-including chronic obstructive pulmonary disease and acute respiratory distress syndrome; it is also an issue for some patients with asthma, rheumatoid arthritis, and inflammatory bowel disease. Several molecular mechanisms of glucocorticoid resistance have now been identified, including activation of mitogen-activated protein (MAP) kinase pathways by certain cytokines, excessive activation of the transcription factor activator protein 1, reduced histone deacetylase-2 (HDAC2) expression, raised macrophage migration inhibitory factor, and increased P-glycoprotein-mediated drug efflux. Patients with glucocorticoid resistance can be treated with alternative broad-spectrum anti-inflammatory treatments, such as calcineurin inhibitors and other immunomodulators, or novel anti-inflammatory treatments, such as inhibitors of phosphodiesterase 4 or nuclear factor kappaB, although these drugs are all likely to have major side-effects. An alternative treatment strategy is to reverse glucocorticoid resistance by blocking its underlying mechanisms. Some examples of this approach are inhibition of p38 MAP kinase, use of vitamin D to restore interleukin-10 response, activation of HDAC2 expression by use of theophylline, antioxidants, or phosphoinositide-3-kinase-delta inhibitors, and inhibition of macrophage migration inhibitory factor and P-glycoprotein.
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PMID:Glucocorticoid resistance in inflammatory diseases. 1948 16


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