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)

The psychoactive properties of Cannabis sativa and its major biologically active constituent, delta 9-tetrahydrocannabinol, have been known for years. The recent identification and cloning of a specific cannabinoid receptor suggest that cannabinoids mimic endogenous compounds affecting neural signals for mood, memory, movement, and pain. Using whole-cell voltage clamp and the cannabinomimetic aminoalkylindole WIN 55,212-2, we have found that cannabinoid receptor activation reduces the amplitude of voltage-gated calcium currents in the neuroblastoma-glioma cell line NG108-15. The inhibition is potent, being half-maximal at less than 10 nM, and reversible. The inactive enantiomer, WIN 55,212-3, does not reduce calcium currents even at 1 microM. Of the several types of calcium currents in NG108-15 cells, cannabinoids predominantly inhibit an omega-conotoxin-sensitive, high-voltage-activated calcium current. Inhibition was blocked by incubation with pertussis toxin but was not altered by prior treatment with hydrolysis-resistant cAMP analogues together with a phosphodiesterase inhibitor, suggesting that the transduction pathway between the cannabinoid receptor and calcium channel involves a pertussis toxin-sensitive GTP-binding protein and is independent of cAMP metabolism. However, the development of inhibition is considerably slower than a pharmacologically similar pathway used by an alpha 2-adrenergic receptor in these cells. Our results suggest that inhibition of N-type calcium channels, which could decrease excitability and neurotransmitter release, may underlie some of the psychoactive effects of cannabinoids.
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PMID:Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. 131 42

Venoms from 20 species of stinging Hymenoptera, including nine species of ants and nine species of social wasps, were quantitatively analyzed for the following enzymic activities: phospholipase A, hyaluronidase, lipase, esterase, protease, acid phosphatase, alkaline phosphatase and phosphodiesterase. Phospholipase and hyaluronidase were present in all the venoms, with activity levels generally higher among the wasps than the ants (P less than 0.05). Lipase was present in high activity in several social wasp venoms and one ant venom, in low levels in two other ant venoms and absent from four tested snake venoms. Two-carbon esterase activity was present in the venoms of five social wasps and one ant. Non-specific protease was present at very high activity levels in the venoms of an army ant species and was also present in the venoms of a social wasp and another ant. Acid phosphatase activity was present in eight of the nine ant venoms, but was essentially absent from all the social wasp venoms. Alkaline phosphatase activity was clearly detectable in the venoms of only two species of ants. Phosphodiesterase, an enzyme not previously detected in insect venoms, was present in the venoms of three closely related ant species. Venoms with generally high enzymic activities included those of Polistes infuscatus, Vespula (V.) squamosa and Pogonomyrmex badius; those with low activities included Dolichovespula maculata, Apoica pallens and Dasymutilla lepeletierii. The 20 venoms were ranked according to overall activity levels using the eight enzyme activities plus lethal, hemolytic and pain-inducing activities. They were also compared phylogenetically using these 11 activities.
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PMID:Comparative enzymology of venoms from stinging Hymenoptera. 354 39

Extracellular recordings were made of spontaneous neuronal firing and of nociceptive stimulus-evoked neuronal firing in the mesencephalic reticular formation of the rat. Microiontophoretically administered morphine and met-enkephalin blocked the nociceptive stimulus-evoked neuronal firing of some neurons in the mesencephalic reticular formation; naloxone antagonized the effects of morphine and met-enkephalin. In neurons in which morphine and met-enkephalin blocked the nociceptive stimulus-evoked firing, the microiontophoretic administration of dibutyryl cyclic AMP (cAMP), 8-bromo cAMP and Ro 20,1724 (a phosphodiesterase inhibitor) consistently (96%) reversed this blockade of evoked firing. The effects of dibutyryl cAMP were specific, because butyrate and 5'-AMP, possible metabolites of the cAMP analog, reversed the blockade by morphine and met-enkephalin of the nociceptive stimulus-evoked neuronal firing much less frequently (29%). These result support the hypothesis that the occupation of opiate receptors triggers an inhibition of the enzyme, adenylate cyclase, as a mechanism of action. The cAMP analogs excited the spontaneous firing in only 60% of the neurons in which they reversed the opioid blockade of pain-evoked firing. This suggests that the mechanism of action of the cAMP analogs on spontaneous firing may differ from that on pain-evoked firing.
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PMID:Cyclic AMP, morphine, met-enkephalin and neuronal firing. 627 Mar 11

Fibromyalgia, a chronic condition of widespread pain, stiffness, and fatigue, has proven unresponsive to drugs, the use of which is based on the 'serotonin-deficiency hypothesis'. An alternative hypothesis-failed transcription regulation by thyroid hormone-can explain the serotonin deficiency and other objective findings and symptoms of euthyroid fibromyalgia. Virtually every feature of fibromyalgia corresponds to signs or symptoms associated with failed transcription regulation by thyroid hormone. In hypothyroid fibromyalgia, failed transcription regulation would result from thyroid-hormone deficiency. In euthyroid fibromyalgia, failed transcription regulation may result from low-affinity thyroid hormone receptors coded by a mutated c-erbA beta 1 gene, yielding partial peripheral resistance to thyroid hormone. The hypothesis of this paper is that, in euthyroid fibromyalgia, a mutant c-erbA beta 1 gene (or alternately, the c-erbA alpha 1 gene) results in low-affinity thyroid-hormone receptors that prevent normal thyroid hormone regulation of transcription. As in hypothyroidism, this would cause a shift toward alpha-adrenergic dominance and increases in both cyclic adenosine 3'-5'-phosphate phosphodiesterase and inhibitory Gi proteins. The result would be tissue-specific hypothyroid-like symptoms despite normal circulating thyroid-hormone levels.
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PMID:Mutations in the c-erbA beta 1 gene: do they underlie euthyroid fibromyalgia? 907 94

Morphine is the most potent opioid analgesic currently available and its use is increasing for treatment of severe pain, however, long-term morphine exposure induces physical dependence/tolerance. Although the mechanisms underlying this phenomenon have not been established, several biochemical changes including intracellular cAMP systems and Ca2+ mobilization have been suggested. To evaluate the contribution of cAMP, we investigated the effects of nefiracetam [N-(2,6-dimethyl-phenyl)-2(2-oxo-1-pyrrolidinyl)acetamide] and phosphodiesterase inhibitors (theophylline, enprofylline and rolipram) on the development of morphine dependence/tolerance. Mice administered morphine (6 or 10 mg/kg, s.c.) twice daily for 5 days, showed withdrawal signs (jumping, diarrhea and body weight loss) after naloxone challenge (5 mg/kg, i.p.), indicating the physical dependence to morphine. Further, the tolerance to antinociceptive effect of morphine was observed in these mice on the tail-flick test. However, coadministration of nefiracetam (5 or 10 mg/kg, p.o.), enprofylline (30 mg/kg, p.o.) and rolipram (0.3 or 1 mg/kg, i.p.) with morphine during the pretreatment period, significantly reduced the withdrawal signs, moreover, the tolerance was significantly attenuated. Acute administration of nefiracetam failed to reduce the withdrawal signs and did not affect the antinociceptive effect of morphine in morphine-naive mice. Theophylline (3 or 10 mg/kg, p.o.) tended to attenuate the development of morphine dependence/tolerance. The present findings suggest that coadministration of compounds which increase cAMP level with morphine may be a useful strategy to attenuate the development of morphine dependence/tolerance in the clinic.
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PMID:A therapeutic strategy to prevent morphine dependence and tolerance by coadministration of cAMP-related reagents with morphine. 981 8

We designed and evaluated a new class of molecules, nitrosylated alpha-adrenergic receptor antagonists, as potential agents for the treatment of impotence. In in vitro studies with human and rabbit corpus cavernosum strips in organ chambers, the alpha-adrenergic receptor antagonists (alpha-ARAs) moxisylyte and yohimbine and their corresponding nitrosylated compounds, SNO-moxisylyte (NMI-221) and SNO-yohimbine (NMI-187), concentration-dependently relaxed endothelin-induced contraction. The nitrosylated compounds were significantly more potent than the parent alpha-ARA. In human tissues, the specific phosphodiesterase type 5 inhibitor zaprinast potentiated the relaxing effects of the nitrosylated compounds. Only nitrosylated compounds induced accumulation of cyclic GMP in rabbit corpus cavernosum strips. Yohimbine and NMI-187 demonstrated a potent alpha2-blocking activity, with no significant differences in pA2 values (8.9 versus 8.2, respectively). Moxisylyte and NMI-221 showed moderate potency in antagonizing phenylephrine contraction, with comparable pA2 values for both molecules (6.5 versus 6.6, respectively). alpha-Adrenergic receptor-binding studies showed similar binding affinities for the alpha-ARA and their corresponding nitrosylated compounds. In vivo, intracavernosal injection of nitrosylated molecules caused greater increases in intracavernosal pressure (NMI-221 versus moxisylyte) that were more long lasting than those of moxisylyte or yohimbine. There were no significant differences between nitrosylated and non-nitrosylated compounds in the magnitude of systemic mean arterial pressure decrease after intracavernosal injection. alpha-ARA and the nitrosylated compounds showed no pain-inducing activity as evaluated with the paw-lick model in mice. In summary, nitrosylated alpha-ARA have the dual functionalities of nitric oxide donors and alpha-ARA. These drugs induced penile erection in animals, suggesting their possible therapeutic value as agents for the local pharmacological treatment of impotence.
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PMID:Design and evaluation of nitrosylated alpha-adrenergic receptor antagonists as potential agents for the treatment of impotence. 1038 67

The aim of the present study was to investigate the role of phosphodiesterase (PDE) enzyme inhibitors namely rolipram and theophylline in pain and inflammation in experimental animals. Rolipram, a selective PDE IV inhibitor and theophylline a nonspecific PDE inhibitor exerted dose dependent analgesic and anti-inflammatory effect against acetic acid-induced writhing in mice and carrageenan-induced paw edema in rats, respectively. Nimesulide (1, 2 mg/kg) produced significant anti-inflammatory effect. Further, nimesulide (0.5 mg/kg) potentiated analgesic effect of rolipram but it failed to modulate the anti-inflammatory effect of PDE inhibitors. Present study suggests that PDE enzymes might be playing a role in nociceptive and inflammatory responses in animals.
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PMID:Analgesic and anti-inflammatory effects of phosphodiesterase inhibitors. 1123 80

Cilostazol is a phosphodiesterase III inhibitor with antiplatelet, antithrombotic and vasodilatory effects. It raises plasma high-density lipoprotein cholesterol levels by approximately 10% and lowers plasma triglycerides by approximately 15%. Eight US/UK randomized, multicentre, double-blind, placebo-controlled trials lasting 12-24 weeks have been conducted with cilostazol 50, 100 or 150 mg twice daily in more than 2,000 patients with moderate to severe intermittent claudication. In constant- or variable-load treadmill tests, cilostazol increased maximal walking distance by 28-100%, and pain-free walking distance by 45-96%. Comparable changes for patients on placebo were -10 to 30% for maximal walking distance and 9 to 50% for pain-free walking distance. Responses were observed as early as the first observation point of 2 or 4 weeks and increased with time. The response was greater for 100 mg twice daily than for 50 mg twice daily. For the 100 mg twice daily dose, there was no evidence of a plateau in effect. In both the US and the UK, cilostazol is indicated to increase walking distance in patients with intermittent claudication. Cilostazol is generally well tolerated. In clinical trials, the most common adverse effects were headache, palpitation, tachycardia, abnormal stools and diarrhoea. Adverse events were generally mild to moderate in intensity.
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PMID:Cilostazol: a novel treatment option in intermittent claudication. 1135 74

Peripheral arterial disease affects approximately 8-10 million people in the United States. Approximately one-third to one-half of these individuals are symptomatic. The risk factors that contribute to peripheral arterial disease are similar to those associated with other forms of atherosclerosis, including diabetes mellitus, cigarette smoking, hypercholesterolemia, high blood pressure, and hyperhomocysteinemia. Of these, diabetes and cigarette smoking pose the greatest risk for developing peripheral arterial disease. The prognosis of patients with these risk factors is limited because of their greater risks for myocardial infarction, stroke, and cardiovascular death. Cardiovascular mortality correlates inversely with the ankle/brachial index, and the risk of death is greatest in those with the most severe peripheral arterial disease. Treatment regimens to reduce cardiovascular morbidity and mortality in patients with peripheral arterial disease should include risk factor modification and antiplatelet therapy. The cardinal symptoms of peripheral arterial disease include intermittent claudication and rest pain, with the latter being indicative of critical limb ischemia. Therapeutic strategies that focus on improving the patient's quality of life, reducing the severity of claudication, and improving limb viability include supervised exercise training, pharmacotherapy, and revascularization. Two drugs-pentoxifylline and cilostazol-currently are approved by the Food and Drug Administration for the treatment of patients with claudication. Meta-analyses have suggested that, compared with placebo, pentoxifylline improves maximal walking distance by approximately 20-25%. Cilostazol is a phosphodiesterase type 3 inhibitor. In clinical trials, cilostazol has consistently improved maximal walking distance as compared with placebo, with the range of improvement being approximately 40-60%. Drugs that are currently under investigation include propionyl-L-carnitine, vasodilator prostaglandins, L-arginine, and the angiogenic factors, vascular endothelial growth factor and basic fibroblast growth factors.
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PMID:Medical management of peripheral arterial disease. 1140 4

Although several lines of evidence have shown a role of the nitric oxide/cyclic guanosine monophosphate signaling pathway in the nociceptive mechanism, the exact role of the phosphodiesterase (PDE) 5 enzyme via the NO-cGMP pathway is not fully understood in pain response. The present study was aimed at exploring the role of the NO-cGMP pathway in nociceptive conditions in experimental animals. Peripheral nociception was assessed by acetic acid-induced chemonociception or carrageenan-induced hyperalgesia and central nociception was assessed by tail-flick and hot-plate methods. Sildenafil exhibited dose-dependent (1, 2, 5 and 10 mg/kg, i.p.) antinociception in both male and female mice against acetic acid-induced writhing. However, it did not alter the pain threshold in central nociception (5 and 10 mg/kg, i.p.). Local administration of sildenafil (50-200 microg/paw, i.pl) also attenuated carrageenan-induced hyperalgesia. In the peripheral nociceptive reaction (acetic acid-induced chemonociception), the antinociceptive effect of sildenafil (2 mg/kg, i.p.) was enhanced by co-administration of sodium nitroprusside (0.25 mg/kg), and L-arginine (50 mg/kg). Sildenafil-induced analgesia was significantly blocked by methylene blue (1 mg/kg), a guanylate cyclase inhibitor, but was not reversed by L-NAME (10 mg/kg), a nitric oxide synthase inhibitor. But a higher dose of L-NAME (20 mg/kg) significantly reversed sildenafil analgesia. Both of these agents also reversed the facilitatory effect of L-arginine (50 mg/kg) and sodium nitroprusside (0.25 mg/kg) on sildenafil analgesia. These results suggest that sildenafil-induced analgesia is mediated via the inhibition of PDE5. The results also indicate that the guanylate cyclase system is stimulated in the peripheral nociceptive reaction. In conclusion, sildenafil produces antinociception and its effect can be potentiated by sodium nitroprusside and L-arginine, probably through the activation of the NO-cyclic GMP pathway.
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PMID:Sildenafil-induced peripheral analgesia and activation of the nitric oxide-cyclic GMP pathway. 1147 33


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