Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experimental models to study the effect of agents on penile erection usually include electrical stimulation of peripheral nerves in anesthetized animals combined with systemic or intracavernous injection of drugs. The objective of this study was to demonstrate that conscious rabbits can be used as a simple and quantitative model for the assessment of compounds that show potential for the treatment of erectile dysfunction. Erection was assessed by measuring the length of uncovered penile mucosa before and after the intravenous (i.v.) administration of agents. Animals did not require anesthesia during the course of the study. The phosphodiesterase 5 (PDE5) inhibitors vardenafil x HCl (hereafter called vardenafil) and sildenafil were given intravenously, and measurements were taken for 0-5 h. The effects of phentolamine and milrinone were also evaluated. Vardenafil (0.1-3 mg/kg) induced dose-dependent penile erections in conscious rabbits following i.v. administration. The efficacy of vardenafil was potentiated, and the minimal effective dose was reduced significantly to 0.01 mg/kg by simultaneous administration of the nitric oxide (NO) donor sodium nitroprusside (SNP). Administration of the NO-synthase inhibitor L-NAME abolished the effect. Sildenafil was effective in this model after i.v. administration. The alpha-adrenergic receptor antagonist phentolamine (0.1, 0.3 and 1 mg/kg i.v.) induced erections with a slower t(max) compared with vardenafil and sildenafil. Intravenous administration of the PDE3 inhibitor milrinone (1 mg/kg i.v.) was less effective than the PDE5 inhibitor vardenafil. The conscious rabbit is a suitable and reliable model for the evaluation of compounds with potential for the treatment of erectile dysfunction. This was demonstrated using compounds that target different signaling pathways that induce smooth muscle relaxation in the penis.
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PMID:A conscious-rabbit model to study vardenafil hydrochloride and other agents that influence penile erection. 1149 80

1. Type 4 phosphodiesterase (PDE4) inhibitors mimic the pharmacological actions of alpha(2)-adrenoceptor antagonists. This has been postulated as the mechanism by which PDE4 inhibitors induce emesis and was also demonstrated by their ability to reverse xylazine/ketamine-induced anaesthesia. We further characterized this latter effect since it appears to reflect the emetic potential of PDE4 inhibitors. 2. Selective inhibitors of PDE 1, 2, 3, 4 and 5 were studied in rats, on the duration of anaesthesia induced by the combination of xylazine (10 mg kg(-1), i.m.) and ketamine (10 mg kg(-1), i.m.). PMNPQ (i.e. 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline) - PDE4 inhibitor: 0.01 - 3 mg kg(-1)), like MK-912 (alpha(2)-adrenoceptor antagonist: 0.01 - 3 mg kg(-1)), dose-dependently reduced the duration of anaesthesia. In contrast, vinpocetine (PDE1 inhibitor), EHNA (PDE2 inhibitor), milrinone (PDE3 inhibitor) and zaprinast (PDE5 inhibitor) had no significant effect at the doses tested (1 - 10 mg kg(-1)). Analysis of plasma and cerebrospinal fluid (CSF) of treated animals confirmed the absorption and distribution to the brain of the inactive inhibitors. 3. Neither MK-912 (3 mg kg(-1)) nor PMNPQ (0.1 - 1 mg kg(-1)) altered the duration of anaesthesia induced via a non-alpha(2)-adrenoceptor pathway (sodium pentobarbitone 50 mg kg(-1), i.p.). 4. Central NK(1) receptors are involved in PDE4 inhibitor-induced emesis. Consistently, [sar(9), Met(O(2))(11)]-substance P (NK(1) receptor agonist, 6 microg i.c.v.) reduced the duration of anaesthesia induced by xylazine/ketamine. 5. In summary, this model is functionally coupled to PDE4, specific to alpha(2)-adrenoceptors and relevant to PDE4 inhibitor-induced emesis. It therefore provides a novel way of evaluating the emetic potential of PDE4 inhibitors in rats.
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PMID:Assessing the emetic potential of PDE4 inhibitors in rats. 1178 86

Diadenosine polyphosphates are naturally occurring substances that facilitate tear secretion. The occurrence of these dinucleotides in human tears has been established and quantified by an HPLC technique and phosphodiesterase treatment. The concentration of these compounds found in tears was 2.0+/-2.2 nM for diadenosine triphosphate (Ap3A), 108.0+/-18.3 nM for diadenosine tetraphosphate (Ap4A) and 37.0+/-6.2 nM for diadenosine pentaphosphate (Ap5A). When subjects were treated with topical ocular anaesthesia, the concentrations of Ap3A, Ap4A and Ap5A changed to 1.5+/-1.7 nM, 189.3+/-19.5 nM and 112.6+/-12.3 nM, respectively. Ap4A and Ap5A increased tear secretion in rabbits, the effect presenting an EC50 value of 19.0+/-1.2 ng/microl and 11.4+/-1.3 ng/microl respectively. In conclusion, diadenosine polyphosphates are released from the corneal epithelium, they stimulate tear production and therefore they may be considered as physiological modulators of tear secretion.
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PMID:Presence of diadenosine polyphosphates in human tears. 1181 Feb 14

First reports on the use of inhaled nitric oxide (NO) in patients were published in 1991. These reports confirmed data from animal experiments which suggested a selective vasodilatory effect of inhaled NO in pulmonary vessels. As the main clinical effects, both improved oxygenation and a drop of pulmonary artery pressure despite unchanged arterial pressure were observed. Since then, many studies have evaluated the effects of inhaled NO as well as of other aerosolised vasodilators (e.g. PGI(2), PGE(1), nitrates, phosphodiesterase-inhibitors) in patients with pulmonary hypertension, acute right heart failure and/or life-threatening hypoxemia. However, primary pulmonary hypertension of the newborn (PPHN) is the only indication for which inhaled NO has been clinically approved so far. Although an obvious clinical benefit in outcome from inhaled vasodilators has never been formally documented, good clinical efficacy has resulted in an increasing "off label" use of the concept both in Germany and worldwide, particularly with respect to anaesthesia and intensive care medicine. The present article aims to review both the pathophysiological and pharmacological basis of inhaled vasodilators, to critically reevaluate their potential clinical indications and to give a perspective on future developments in the field.
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PMID:[Inhaled vasodilators]. 1239 20

We examined the effect of milrinone, a phosphodiesterase III inhibitor, on neuromuscular block induced by vecuronium. Thirty adult patients were randomly assigned to one of two equal groups: the milrinone group and the control group. Subjects in the milrinone group received an intravenous loading dose of milrinone 5 microg x kg-1x min-1 for 10 min, followed by an infusion at a rate of 0.5 microg x kg-1x min-1. Subjects in the control group received normal saline at a rate of 0.1 ml x kg-1 x h-1. Thirty minutes after the beginning of the infusion of milrinone, anaesthesia was induced with intravenous thiopental 4 mg x kg-1 and fentanyl 2 microg x kg-1, and was maintained with isoflurane in oxygen and nitrous oxide. Neuromuscular blockade was monitored electromyographically at the adductor pollicis muscle. The times from the administration of vecuronium 0.1 mg.kg-1 to the onset of neuromuscular block and the return of the first, second, third, and fourth response of the train-of-four were compared between the two groups. Times to the recovery of the ratio of the first twitch to the control twitch to 25%, 50% and 75%, and times to the recovery of train-of-four ratio to 25%, 50% and 75% were also compared between the two groups. The onset of neuromuscular block in the milrinone group was significantly slower than in the control group. The times to the returns of the four twitches of the train-of-four, times to recovery of the ratio of the first twitch to the control twitch to 25% and 50%, and the times to the recovery of the train-of-four ratio to 25% and 50% were significantly shorter in the milrinone group than in the control group. We conclude that milrinone delays the onset of neuromuscular blockade but hastens its recovery in anaesthetised patients receiving vecuronium.
Anaesthesia 2003 Jul
PMID:Effect of milrinone on vecuronium-induced neuromuscular block. 1279 Aug 13

New antiplatelet drugs such as glycoprotein IIb/IIIa receptor antagonists, thienopyridines (adenosine diphosphate receptor antagonists), inhibitors of cyclooxygenase and phosphodiesterase, and antiaggregatory prostaglandins have been introduced in vascular medicine. This paper reviews the pharmacokinetics, mechanisms of action, indications, and side effects of platelet-inhibiting agents as well as methods for coagulation monitoring. Updated guidelines for the management of locoregional anesthesia in patients receiving new antiplatelet drugs are discussed. In this clinical situation, the decision for or against locoregional anesthesia must be preceded by a risk-benefit analysis based on history of bleeding, physical examination, and coagulation monitoring. Blockade should be performed as atraumatically as possible and specific time intervals must be maintained between the last administration of antiplatelet agents and the performance of the blockade or withdrawal of a catheter in all elective patients.
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PMID:[Locoregional anesthesia and blood coagulation: impact of new antiplatelet drugs]. 1283 78

Histidine decarboxylase (HDC) represents the sole enzyme that produces histamine in the body. The present work investigated the role of endogenous histamine in carbachol- and gastrin-induced gastric acid secretion with HDC-knockout (HDC-/-) mice. Acid secretion was measured in either mice subjected to acute fistula production under urethane anesthesia or conscious mice that had previously undergone pylorus ligation. In wild-type mice, carbachol and gastrin significantly stimulated acid secretion, increasing gastric mucosal histamine. In contrast, in HDC-/- mice, carbachol and gastrin had little impact when either delivered alone or together. Nonetheless, the two agents achieved a synergistic effect when delivered together with exogenous histamine, stimulating acid secretion in HDC-/- mice. Such synergism was abolished by the histamine H2-receptor antagonist famotidine. cAMP involvement in acid secretion was also examined with theophylline, a phosphodiesterase inhibitor, and forskolin, an adenylate cyclase activator. In wild-type mice, theophylline significantly increased acid secretion, enhancing carbachol- and gastrin-stimulated acid secretion. In contrast, in HDC-/- mice, theophylline failed to exert an effect on basal acid secretion, as well as carbachol- and gastrin-stimulated acid secretion. Although forskolin interacted with carbachol, allowing acid secretion in HDC-/- mice, similar results were not achieved with gastrin. Such results suggest that 1) histamine is essential for carbachol- and gastrin-stimulated gastric acid secretion in mice; and 2) histamine-induced cAMP production contributes to the in vivo response to carbachol or gastrin.
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PMID:Crucial role of histamine for regulation of gastric acid secretion ascertained by histidine decarboxylase-knockout mice. 1289 47

Cardiovascular diseases including heart failure represent a common disease in patients referred for anesthesia. In most cases, heart failure is caused by left ventricular dysfunction due to coronary heart disease. The aims of the treatment of chronic heart failure are the relief of symptoms, the improvement of prognosis and the prevention of the progression of heart failure. The first-line treatment involves the underlying heart disease such as myocardial revascularisation procedures in coronary heart disease or the correction of valve diseases. The pharmacological therapy depends on the stage of heart failure and symptoms of the patient. Heart failure therapy includes ACE-inhibitors, betablockers, diuretics und digitalis. Nitrates can be prescribed in patients with symptomatic heart failure despite adequate therapy but calcium antagonists are not recommended. Repeated or prolonged treatment with positive inotropic agents like phosphodiesterase inhibitors or beta-adrenergic drugs increases mortality but this is commonly used in acute stages of heart failure refractory to treatment. Interactions of ACE-inhibitors or AT1- antagonists with anesthetic agents can lead to severe hypotension especially in hypovolemic patients. Whether those drugs should be continued perioperatively or not has been controversially discussed. The use of betablockers has a positive impact on cardiac morbidity and mortality during and early after surgery. Chronic treatment with diuretics can be associated with hypovolemia and an imbalance of electrolytes leading to hypotension and arrhythmia during anesthesia but careful evaluation prior to anesthesia can avoid such complications. The continuation of digitalis during anesthesia has been controversially discussed due to the various interactions with anesthetics.
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PMID:[Current treatment of chronic heart failure]. 1289 47

In the present study, the effects of cAMP- and cGMP-phosphodiesterase (PDE) inhibitors, theophylline, and sildenafil on secretion of protein, amylase and epidermal growth factor (EGF) and the flow rate from rat submandibular saliva were examined in an acute experiment. Theophylline at doses of 25, 50, 85mgkg(-1) and sildenafil at doses of 1, 2, 5mgkg(-1) were administered intraperitoneally 2h before saliva collection. Pure submandibular saliva was collected intraorally by microployethylene tubes under anesthesia using dissecting microscope. Theophylline at doses of 25, 50, 85mgkg(-1) increased salivary flow rate to 197% (P<0.01), 186% (P<0.01), and 209% of control, respectively. Sildenafil at doses of 1, 2, 5mgkg(-1) also increased flow rate to 232% (P<0.01), 182% (P<0.01), and 197% of control, respectively. Theophylline at doses of 25, 50, 85mgkg(-1) increased total protein concentration to 98% (P<0.01), 84% (P<0.01), and 210% of control, respectively. Sildenafil at doses of 2 and 5mgkg(-1) increased total protein concentration to 75% (P<0.01), and 240% of control, respectively. Theophylline at dose of 85mgkg(-1) increased EGF concentration to 60% (P<0.01) of control. Sildenafil at doses of 2 and 5mgkg(-1) increased EGF concentration to 44% (P<0.05) and 90% (P<0.01) of control, respectively. No statistically significant change was observed in amylase activity by administration of theophylline or sildenafil. The present results indicate that increasing intracellular levels of cAMP and cGMP have stimulatory effects on salivary functions. Regarding beneficiary effects of increased salivary flow rate and secretion of EGF in maintaining oral health, theophylline and sildenafil may find good places in some oral diseases.
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PMID:Stimulation by theophylline and sildenafil of rat submandibular secretion of protein, epidermal growth factor and flow rate. 1296 88

The role of oxidative stress in lead toxicity has been proposed in many organs, however, no study has been performed in the salivary glands, which are important parts of the gastrointestinal tract with a high implication in health of the whole body. Recently, it has been proposed that increasing the levels of cGMP and cAMP in the cells may protect from the neurotoxicity of lead. The objective of this study was to determine the ability of lead acetate to produce oxidative stress in rat submandibular as the main salivary gland of the body and to study the role of pretreatment by specific phosphodiesterase inhibitors in the prevention of oxidative stress. Lead acetate (100 mg/kg), alone or in combination with theophylline (25 mg/kg) and sildenafil (5 mg/kg), was administered intraperitoneally to rats. After 2 hours and under general anaesthesia, the submandibular gland ducts were cannulated intraorally using microcannula, and pure saliva was collected for 30 min using pilocarpine (8 mg/kg) as a secretagogue. The submandibular glands were then isolated free under surgery. Oxidative stress in the gland and pure saliva were evaluated measuring lipid peroxidation (thiobarbituric acid reactive substances assay), total thiol groups content and total antioxidant capacity (the ferric reducing ability assay). Results showed significant oxidative stress in the gland and secretions as indicated by increased lipid peroxidation, decreased total antioxidant capacity and thiol group levels. The use of cAMP and cGMP phosodiesterase inhibitors, theophylline and sildenafil, prevented lead-induced increased lipid peroxidation and also protected from decreased thiol groups content and total antioxidant power of the gland and secretions. The same trend of effects was observed in gland and saliva. It is concluded that lead toxicity is mediated through oxidative stress in salivary glands, while increasing intracellular cAMP and cGMP levels may prevent lead-induced oxidative stress.
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PMID:Protection by sildenafil and theophylline of lead acetate-induced oxidative stress in rat submandibular gland and saliva. 1468 81


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