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

---

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

Oxidative stress is believed to affect the development of diabetic-associated vasculopathy, endothelial dysfunction, and neuropathy within erectile tissue. Our hypothesis is that, given adequate concentrations of the oxygen free radical scavenger vitamin E, enhanced levels of circulating nitric oxide (NO) should improve erectile function with the potential for a synergistic effect with a phosphodiesterase type 5 (PDE5) inhibitor. Twenty adult male Sprague-Dawley streptozotocin-induced (60 mg/kg intraperitoneally) diabetic rats were placed in 4 therapeutic groups (n = 5 per group) as follows: 1) peanut oil only (diabetic control), 2) 20 IU of vitamin E per day, 3) 5 mg/kg of sildenafil per day, and 4) vitamin E plus sildenafil using oral gavage for 3 weeks. In addition, 5 age-matched rats served as normal nondiabetic controls (normal). Erectile function was assessed by measuring the rise in intracavernous pressure (ICP) following cavernous nerve electrostimulation. Penile tissue was evaluated for neuronal NO synthase (nNOS), smooth muscle alpha-actin, nitrotyrosine, and endothelial cell integrity. Urine nitrite and nitrate (NOx) concentration was quantified, and electrolytes were tested by a serum biochemistry panel. A significant decrease in ICP was recorded in the diabetic animals, with improvement measured in the animals receiving PDE5 inhibitors either with or without vitamin E; the controls had a pressure of 54.8 +/- 5.3 cm H2O, the vitamin E group had a pressure of 73.5 +/- 6.6 cm H2O, the sildenafil group had a pressure of 78.4 +/- 10.77 cm H2O, and the vitamin E plus sildenafil group had a pressure of 87.9 +/- 5.5 cm H2O (P <.05), compared with the normal cohorts at 103.0 +/- 4.8 cm H2O. Histoexaminations showed improved nNOS, endothelial cell, and smooth muscle cell staining in the vitamin E plus sildenafil group compared to the control animals. Urine NOx increased significantly in all the diabetic groups but was blunted in the vitamin E and vitamin E plus sildenafil groups. A significant increase in positive staining for nitrotyrosine was observed in the vitamin E plus sildenafil group. Vitamin E enhanced the therapeutic effect of the PDE5 inhibitor in this study, supporting the potential use of oxygen free radical scavengers in salvaging erectile function in diabetic patients.
...
PMID:Oxidative stress and antioxidant therapy: their impact in diabetes-associated erectile dysfunction. 1529 17

Statins have cholesterol-independent effects including an increased vascular nitric oxide (NO) activity and are commonly used by patients with cardiovascular disease. Such patients frequently have erectile dysfunction, which may be treated with sildenafil, a selective inhibitor of phosphodiesterase type 5. Since statins and sildenafil can activate the NO-cGMP pathway, we investigated whether pre-treatment with atorvastatin (0, 5 and 30 mg/kg/day) for 2 weeks affects sildenafil (1 pM-100 mM)-induced relaxation of aortic rings isolated from Wistar rats. We also examined the hemodynamic consequences of this interaction in Wistar rats. Plasma nitrite/nitrate (NOx) concentrations were determined using an ozone-based chemiluminescence assay. While pre-treatment with atorvastatin increased the potency of sildenafil-induced vasorelaxation (P<0.01), no differences were observed in the maximum sildenafil-induced relaxation. Pre-incubation of aortic rings with NG-nitro-L-arginine methyl ester (L-NAME) reversed atorvastatin-induced increase in the potency of sildenafil relaxation. In addition, pre-treatment with atorvastatin enhanced plasma NOx concentrations and sildenafil-induced hypotension and tachycardia (all P<0.05). These results suggest that atorvastatin increases the vascular sensitivity to sildenafil through NO-mediated mechanisms.
...
PMID:Atorvastatin enhances sildenafil-induced vasodilation through nitric oxide-mediated mechanisms. 1536 94

Corticosteroids are used to reduce the oedema and prevent scar tissue formation of the upper airways by their ability to inhibit influx of inflammatory cells, limit capillary permeability and block collagen synthesis in the early stages of wound healing. Triazolopyrimidine (Trapidil) is an antiplatelet agent that acts in part as a phosphodiesterase inhibitor and as a competitive inhibitor of the platelet-derived growth factor (PDGF) receptor. Trapidil, with its vasodilator and NO releasing effect may have some potential to diminish the tissue injury. This study was carried out to evaluate the effects of trapidil (triazolopyrimidine) on lipid peroxidation and nitric oxide in the corticosteroid-impaired healing of tracheal anastomoses. Thirty-four adult Wistar rats were divided into five groups. The animals underwent tracheal transection and primary anastomoses. The groups were assigned as follows: group I, control, (GI, n = 6); group II, sham, (GII, n = 6); group III, dexamethasone, 0.1 mg kg(-1) twice daily intramuscularly, (GIII, n = 8); group IV, trapidil, 6 mg kg(-1) twice daily intraperitoneally (GIV, n = 7); group V, dexamethasone, 0.1 mg kg(-1) plus trapidil, 6 mg kg(-1) twice daily (GV, n = 7), for 1 week. After 1 week, anastomotic healing was assessed by measurement of bursting pressure, evaluation of histopathology, measurement of MDA and nitrite/nitrate levels. In GIII, GIV and GV bursting pressures resulted in significantly reduced anastomotic strength compared to the controls (p < 0.001 for all groups). The difference between bursting pressures of GIII and GIV was not found to be statistically significant (p = 0.966). In regard to fibroblast proliferation and collagen content, a significant difference was found between GIII and GI (p < 0.01), A significant difference was also found when GIV and GV were compared to GIII (p < 0.01). MDA and nitrite/nitrate levels were found to be higher in GIII when compared to all other groups. MDA levels of GIV and GV rats were found to be lower than GIII (p < 0.001, for both groups). The nitrite/nitrate levels of GIV and GV rats were found to be lower than GIII (p < 0.05), and higher than GI (p < 0.001). Trapidil may be useful for its preventive effects on lipid peroxidation and possible increases in NO in cases with corticosteroid-impaired healing of trachea anastomoses.
...
PMID:Effects of triazolopyrimidine on lipid peroxidation and nitric oxide levels in the corticosteroid-impaired healing of rat tracheal anastomoses. 1538 39

1. It is well documented that cisplatin (CDDP) treatment increases the expression of adenosine A(1) receptors in both kidney and testes. However, the effect of adenosine at these receptors is controversial. Adenosine A(1) receptors have been documented to be involved in either cytoprotection or aggravation of nephrotoxicity. The aim of the present study was to examine the effect of the non-selective adenosine receptor inhibitor theophylline and the phosphodiesterase inhibitor pentoxifylline on CDDP-induced renal and testicular toxicity. 2. Male Wister rats were divided into six groups. Two control groups received plain drinking water and a third control group received theophylline 0.8 mg/mL in the drinking water for 2 weeks. One group of animals drinking plain water was injected intraperitoneally (i.p.) with pentoxifylline 50 mg/kg per day for 2 weeks. The remaining groups were treated in the same manner and received single dose of CDDP 7 mg/kg, i.p., 1 week after starting theophylline and pentoxifylline treatment and all animals were killed 1 week after CDDP treatment. 3. Rats treated with CDDP developed nephrotoxicity, as demonstrated by increased kidney and testes weight as a percentage of total bodyweight, blood urea nitrogen and serum creatinine levels and decreased serum calcium and albumin levels. In addition, CDDP treatment resulted in an increase in the production of malondialdehyde (MDA) and decreases in total nitrate/nitrite levels, as well as depletion of reduced glutathione (GSH) content and glutathione peroxidase (GPX) activity in both the kidney and testes. Administration of theophylline in the drinking water to CDDP-treated rats resulted in exacerbation of the indices of nephrotoxicity, depletion of GSH content and GPX activity levels, with increased MDA production and platinum accumulation in both the kidney and testes. However, pentoxifylline administration reduced CDDP-induced biochemical changes and reduced platinum accumulation in both organs. Histopathological examination of the kidney revealed that CDDP treatment produced multifocal tubular atrophy, atypical reparative changes of the tubular epithelium and marked tubular necrosis. Animals treated with the theophylline/CDDP combination showed extensive widespread damage with intratubular calcification. However, pentoxifylline treatment ameliorated the overt changes induced by CDDP treatment. 4. Theophylline exacerbates the deleterious effects of CDDP on rat kidney and testes. However, pentoxifylline alleviates CDDP-induced renal and testicular toxicity.
...
PMID:Role of non-selective adenosine receptor blockade and phosphodiesterase inhibition in cisplatin-induced nephrogonadal toxicity in rats. 1565 50

Roflumilast, a potent and selective phosphodiesterase 4 (PDE4) inhibitor, has been demonstrated to be an effective anti-inflammatory agent in airway inflammatory diseases. In the present study, we investigated the mechanism of anti-inflammatory effects of roflumilast in murine macrophage cell line RAW264.7 cells. Roflumilast inhibited NO, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta production via suppression of their gene expressions in lipopolysaccharide (LPS)-stimulated macrophages. To elucidate the mechanism by which roflumilast inhibits the production of inflammatory mediators, we examined the effect of roflumilast on the activation of nuclear factor-kappaB (NF-kappaB) in these cells. Roflumilast inhibited the DNA binding activity of NF-kappaB by preventing inhibitor kappaBalpha phosphorylation and degradation. The phosphorylation of mitogen-activated protein (MAP) kinases, including stress-activated protein kinase/c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase, was also markedly inhibited by roflumilast. Similar to the effects of roflumilast, treatment of either SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)imidazole] or SP600125 [anthra(1,9-cd)pyrazol-6(2H)-one 1,9-pyrazoloanthrone], specific inhibitors of p38 MAP kinase and JNK, respectively, suppressed NO, TNF-alpha, and IL-1beta production. Consistent with in vitro results, administration of roflumilast recovered the survival rate of LPS-treated mice, with concurrent suppression of plasma levels of nitrite/nitrate, TNF-alpha, and IL-1beta. These results suggest that the inhibitory activity of roflumilast on the production of inflammatory mediators seems to be mediated via inhibition of NF-kappaB, p38 MAP kinase, and JNK activation in macrophages.
...
PMID:Roflumilast inhibits lipopolysaccharide-induced inflammatory mediators via suppression of nuclear factor-kappaB, p38 mitogen-activated protein kinase, and c-Jun NH2-terminal kinase activation. 1612 38

TNF-alpha, including other proinflammatory cytokines alone or in combination, induces iNOS expression and upregulates inflammatory responses. We evaluated the relationship between TNF-alpha and iNOS expression in indomethacin-induced jejunoileitis in male Sprague-Dawley rats. Rats were fed a daily dose of a phosphodiesterase inhibitor-either theophylline or pentoxifylline-for 2 days. Jejunoileitis was induced with two subcutaneous injections of indomethacin (7.5 mg/kg) 24 hr apart and theophylline or pentoxifylline continued for 12 hr or 4 days. Other rats received a single intraperitoneal injection of anti-TNF-alpha monoclonal antibody (TNF-Ab) 30-min before indomethacin. At 4 days TNF-Ab, theophylline, or pentoxifylline treatment significantly decreased indomethacin-induced ulceration, myeloperoxidase activity, and disease activity index. Although indomethacin significantly increased serum TNF-alpha and nitrate/nitrite levels over the control value as early as 12 hr, iNOS expression was detected only after 4 days. Serum IL-1beta level did not change at 12 hr but increased fourfold at 4 days. Treatment with TNF-Ab, theophylline, or pentoxifylline significantly reduced serum/tissue TNF-alpha, IL-1beta, nitrate/nitrite, and iNOS expression. The downregulation of nitrate/nitrite by these inhibitors suggests that TNF-alpha modulates iNOS expression.
...
PMID:Inhibition of TNF-alpha improves indomethacin-induced enteropathy in rats by modulating iNOS expression. 1613 68

Currently, 3 phosphodiesterase 5 (PDE5) inhibitor agents are available worldwide for the treatment of erectile dysfunction (ED): sildenafil, vardenafil, and tadalafil. Each of these agents is effective across a broad range of etiologies, including vasculogenic ED in men. Because PDE5 enzyme is found within the vascular smooth muscle cells in the walls of systemic arteries and veins, PDE5 inhibitors are mild vasodilators associated with small (and in general, clinically insignificant) decreases in blood pressure. However, because of the synergistic decrease in blood pressure (both systolic and diastolic) in the presence of organic nitrates, these 3 agents are contraindicated in patients receiving organic nitrates. The duration of interaction between a PDE5 inhibitor and nitrate administration depends on the specific drug being studied. The interaction between sildenafil or vardenafil and nitroglycerin is no longer observed by 24 hours. A preliminary study with sildenafil and sublingual nitroglycerin suggested the interaction is no longer observable by 4 hours. The interaction between tadalafil and nitroglycerin has dissipated by 48 hours after tadalafil administration. This is consistent with the longer elimination half-life of the drug. When PDE5 inhibitors are administered to patients with hypertension who are taking most antihypertensive agents (eg, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium antagonists, diuretics), there are usually small additive decreases in blood pressure without a significant increase of adverse events. Some patients develop orthostatic hypotension when PDE5 inhibitors are used in conjunction with an alpha-blocker (typically for hypertension or for urologic conditions, such as benign prostatic hypertrophy). Precautions are necessary for all 3 of the PDE5 inhibitors regarding this potential interaction. Some studies suggest that the interaction is less relevant clinically if the patient has been undergoing long-term alpha-blocker therapy. Several analyses have suggested that PDE5 inhibitors do not increase myocardial infarction rates or death rates compared with placebo controls or expected rates from age-matched populations. In contrast, recent studies have shown that PDE5 inhibitors may have therapeutic potential for a host of cardiovascular diseases. In general, these agents, when used appropriately, are highly safe and effective.
...
PMID:Pharmacology and drug interaction effects of the phosphodiesterase 5 inhibitors: focus on alpha-blocker interactions. 1638 66

The introduction of oral agents for the treatment of erectile dysfunction (ED) has revolutionized the treatment of men with erection problems of all severities and etiologies. Sildenafil, available on the world market since 1998 was joined in 2003 by tadalafil and vardenafil as effective save and reliable oral agents. While these agents share the method of action in common and are all contraindicated with nitrate medications, these are differences among the three agents. Sildenafil has the longest patient experience and the most robust data confirming its activity, safety and tolerability. It has recently been released for use in pulmonary hypertension as well as ED. Vardenafil, the most biochemically potent of the molecules has also been demonstrated to be effective in men with severe ED and in some patients failing sildenafil. Tadalafil is unique in its longer half life and is also tolerable, safe and effective in all severities and etiologies of ED. Tadalafil is also unique in its inhibition of PDE 11, a characteristic of unknown but probably negligible importance. Newer data have also suggested that these agents may be helpful in the treatment of lower urinary tract symptoms. Since the introduction of sildenafil in 1998, erectile dysfunction has been effectively treated with oral medications. The recent addition of vardenafil and tadalafil to the market has increased the number of phosphodiesterase type 5 inhibitors (PDE5) to three agents used throughout the world. Each of these agents has similar mechanism of action, but has distinct differences. All three drugs in this class have similar pharmacokinetic and pharmacodynamic profiles and each is effective for patients with ED of all ages, severities and etiologies. While there are clear pharmacokinetic and pharmacodynamic differences amongst these agents, clinical differences are somewhat more difficult to identify. Indeed the data of preference trials, head to head clinical trials, and selection trials are few. The differences in pharmacokinetics while having distinct advantages in marketing each drug may be difficult for clinicians and patients to identify. With the lack of data and well done clinical trials, it is difficult for the clinician to differentiate amongst the three agents and to select a PDE5 inhibitor for a specific ED patient or a specific agent to switch to if an initial PDE5 agent is unsuccessful or poorly tolerated. This discussion summarizes some of the current data on PDE5 inhibitors and their efficacy, safety, and use in other conditions.
...
PMID:PDE5 inhibitors: are there differences? 1652 79

Nitrates are very effective antianginal and anti-ischaemic agents. Provision of a long nitrate-free interval or low plasma nitrate levels prior to the morning dose prevents the loss of clinical efficacy by preventing the development of tolerance. However, side effects during nitrate therapy are common. Headache is the most common side effect of nitrates; often dose-related and reported by up to 82% of patients in placebo-controlled trials. Nearly 10% of patients are unable to tolerate nitrates due to disabling headaches or dizziness. In others, headaches are mild-to-moderate in severity and either resolve or diminish in intensity with continued nitrate therapy. Nitrate-induced hypotension is common, but often asymptomatic. In rare instances, nitrate-induced hypotension is severe and accompanied by marked slowing of the heart rate and syncope. Use of nitrates in patients who experience syncope after administration of nitrates is contraindicated. Nitrates rarely cause coronary steal and myocardial ischaemia. Nitrate rebound may occur and patients may experience nocturnal anginal episodes during intermittent therapy with nitroglycerin patches. Administration of nitrates is contraindicated with concomitant use of phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction, as combination therapy may lead to profound hypotension and even death. There are disturbing observational reports in the literature that continuous, prolonged use of nitrates may lead to increased mortality and recurrent myocardial infarctions. Large, randomised, placebo-controlled studies are needed to confirm or refute these reports; until then, the use of nitrates to treat angina is here to stay.
...
PMID:Side effects of using nitrates to treat angina. 1690 56

1. Application of the nitric oxide (NO) donor, sodium nitrite and the NO synthase substrate l-arginine had no effect on nerve-evoked transmitter release in the rat isolated phrenic nerve/hemidiaphragm preparation; however, when adenosine A(1) receptors were blocked with the adenosine A(1) receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) prior to application of sodium nitrate or l-arginine, a significant increase in transmitter release was observed. In addition, the NO donor s-nitroso-N-acetylpenicillamine (SNAP) significantly increased transmitter release in the presence of DPCPX. In the present study, we have made the assumption that these NO donors elevate the level of NO in the tissue. Future studies should test other NO-donating compounds and also monitor the NO concentrations in the tissue to ensure that these effects are, in fact, NO induced. 2. Elevation of cGMP in this preparation with the guanylyl cyclase activator 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) significantly enhanced transmitter release. In the presence of DPCPX and the selective guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), which blocks the production of cGMP, the excitatory effects of sodium nitrite and l-arginine were abolished. 3. These results suggest that NO serves to enhance transmitter release at the rat neuromuscular junction (NMJ) via a cGMP pathway and this facilitation of transmitter release can be blocked with adenosine. Previously, we demonstrated that adenosine inhibits N-type calcium channels. Because NO only affects transmitter release when adenosine A(1) receptors are blocked, we suggest that NO enhances transmitter release by enhancing calcium influx via N-type calcium channels. Further studies are needed to confirm that NO alters transmitter release via cGMP and that this action involves the N-type calcium channel. 4. The results of the present study are consistent with a model of NO neuromodulation that has been proposed for the mammalian vagal-atrial junction. This model suggests that NO acts on NO-sensitive guanylyl cyclase to increase the intracellular levels of cGMP. In turn, cGMP inhibits phosphodiesterase-3, increasing levels of cAMP, which then acts on the N-type calcium channels to enhance calcium influx, leading to an increase in transmitter release. Our only modification to this model for the NMJ is that adenosine serves to block the modulation of transmitter release by NO.
...
PMID:Does nitric oxide modulate transmitter release at the mammalian neuromuscular junction? 1732 44


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---