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)

Sildenafil (Viagra) is a selective inhibitor of the cyclic guanosine monophosphate (cGMP) specific phosphodiesterase 5 (PDE5) used for the oral treatment of male erectile dysfunction due to vasodilation. However, assessment of direct effects of sildenafil on cerebral arteries is unknown. The aim of this present experiment is to measure the possible changes in blood flow velocity of the middle cerebral artery after the administration of sildenafil and a placebo. Blood-flow velocity changes of the middle cerebral artery were measured before and 1 to 2 h after the administration of the drug. Neither the intake of sildenafil nor the application of placebo resulted in any significant changes in blood flow velocity of the right middle cerebral artery. The next step for future experiments will be in vitro measurement of the diameters of the cerebral arteries under the influence of sildenafil and in vivo measurement of carbon dioxide and cerebral blood flow velocity during sexual stimulation after sildenafil intake instead of under resting conditions.
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PMID:Effect of sildenafil (Viagra) on cerebral blood flow velocity: a pilot study. 1269 95

We investigated cystic fibrosis transmembrane conductance regulator (CFTR) activation by clinically used phosphodiesterase inhibitors (PDEis) in Calu-3 cell monolayers alone and in combination with A2B adenosine receptor stimulation. This receptor pathway has previously been shown to activate wild-type and mutant CFTR molecules. Several PDEis, including milrinone, cilostazol (Pletal), papaverine, rolipram, and sildenafil (Viagra), produced a short circuit current (Isc) that was glibenclamide-sensitive, achieving 20-85% of forskolin-stimulated Isc. Papaverine, cilostazol, and rolipram also augmented both the magnitude and the duration of Isc following low dose stimulation of adenosine receptors with Ado (0.1-1.0 microM, P < 0.01). Subsequent studies demonstrated that very low concentrations of cilostazol or papaverine (approximately 1/2 peak serum concentrations) were sufficient to activate Isc, and both agents markedly augmented Ado-stimulated Isc (1 microM, P < 0.01). Our results provide evidence that select PDEis, at concentrations achieved as part of systemic therapies, can activate CFTR-dependent Isc in Calu-3 cell monolayers. These studies also indicate that PDEis have the capacity to augment an endogenous CFTR-activating pathway in an "in vivo"-like model system, and supports future investigations of these agents relevant to cystic fibrosis.
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PMID:Adenosine receptors and phosphodiesterase inhibitors stimulate Cl- secretion in Calu-3 cells. 1271 75

Sildenafil (Viagra) potentiates penile erection by acting as a nonhydrolyzable analog of cGMP and competing with this nucleotide for catalysis by phosphodiesterase-5 (PDE5), but the characteristics of direct binding of radiolabeled sildenafil to PDE5 have not been determined. [3H]Sildenafil binding to PDE5 was retained when filtered through nitrocellulose or glass-fiber membranes. Binding was inhibited by excess sildenafil, 2-(2-methylpyridin-4-yl)methyl-4-(3,4,5-trimethoxyphenyl)-8-(pyrimidin-2-yl)methoxy-1,2-dihydro-1-oxo-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride (T-0156), 3-isobutyl-1-methylxanthine, EDTA, or cGMP, but not by cAMP or 5'-GMP. PDE5 was the only [3H]sildenafil binding protein detected in human lung extract. Using purified recombinant PDE5, [3H]sildenafil exchange dissociation yielded two components with t1/2 values of 1 and 14 min and corresponding calculated KD values of 12 and 0.83 nM, respectively. This implied the existence of two conformers of the PDE5 catalytic site. [3H]Sildenafil binding isotherm of PDE5 indicated KD was 8.3 to 13.3 nM, and low cGMP decreased the KD to 4.8 nM but only slightly increased Bmax to a maximum of 0.61 mol/mol-subunit. Results suggest that these effects occur via cGMP binding to the allosteric cGMP binding sites of PDE5. Results imply that by inhibiting PDE5 and thereby increasing cGMP, sildenafil accentuates its own binding affinity for PDE5, which further elevates cGMP. The data also indicate that after physiological elevation, cGMP may directly stimulate the catalytic site by binding to the allosteric cGMP-binding sites of PDE5, thus causing negative feedback on this pathway.
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PMID:[3H]sildenafil binding to phosphodiesterase-5 is specific, kinetically heterogeneous, and stimulated by cGMP. 1276 47

The effects of sildenafil (Viagra), a specific inhibitor of phosphodiesterase 5, on ischemic myocardium was examined using an isolated rat heart model. Rats were pretreated with sildenafil at doses ranging from 0.001 mg to 0.5 mg/kg body weight. After 60 min, isolated hearts were subjected to ischemia for 30 min followed by 2 h of reperfusion. The results demonstrated that at 0.05 mg/kg (and to some extent at 0.01 mg/kg), sildenafil provided significant cardioprotection as evidenced by improved ventricular recovery, a reduced incidence of ventricular fibrillation and decreased myocardial infarction. At higher doses, it caused a significant increase in the incidence of ventricular fibrillation while at very low doses it had no effect on cardiac function. As expected, sildenafil increased cyclic 3',5'-monophosphate (cGMP) content in the heart. The results demonstrate for the first time that within a narrow dose range, sildenafil can protect the heart from ischemia/reperfusion injury, probably through a cGMP-signaling pathway.
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PMID:Cardioprotection with sildenafil, a selective inhibitor of cyclic 3',5'-monophosphate-specific phosphodiesterase 5. 1277 74

Here we report that the active component of Viagra, Sildenafil and the first metabolite, N-desmethyl-sildenafil (UK-103, 320) increased the amplitude of flash-evoked electroretinogram (ERG) of dark-adapted albino rat retina. Effects of Sildenafil and N-desmethyl-sildenafil were comparable to those of the known phosphodiesterase inhibitor, Zaprinast. The photoreceptor cell response was isolated by blocking the glial K(+) ion-buffering and the on-bipolar components of the ERG with the use of BaCl(2) (500 microM) and the specific type VI metabotropic glutamate receptor agonist, DL-2-amino-4-phosphonobutyric acid (25 microM), respectively. Zaprinast, Sildenafil and N-desmethyl-sildenafil (1 microM each) increased the amplitude of photoreceptor cell response either. Besides, Sildenafil was significantly more effective than N-desmethyl-sildenafil. These findings suggest an increased sensitivity of photoreceptor cells in the presence of Sildenafil and it is metabolite.
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PMID:Sildenafil, N-desmethyl-sildenafil and Zaprinast enhance photoreceptor response in the isolated rat retina. 1282 Sep 88

Sildenafil citrate, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type V (PDE V), initially designated as compound 92-480-10 by Pfizer, was studied in the late 1980s as an antianginal. An unexpected side effect of the early clinical investigations was improved erectile function among the men studied. This serendipitous finding has transformed the field of erectile dysfunction therapy (1-3). The novelty of this compound is its oral route of delivery and efficacy across a broad range of etiologies.
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PMID:Sildenafil citrate (Viagra). 1287 10

The promising clinical data on the use of the first orally active phosphodiesterase inhibitor sildenafil citrate (Viagra) for treatment of male erectile dysfunction have been accompanied by an increase in research activities on the physiology of the male erectile mechanism. This included both peripheral intracellular signal transduction in the corpus cavernosum as well as central brain and spinal cord pathways that control penile erection. This work provided the basis for the development and introduction of several new therapeutic modalities into the management of erectile dysfunction that is now offered to the patients. Since the concept of 'taking a pill' as a cure for an illness or the relief of symptoms of a disease has become widely accepted by consumers, the pharmacological treatment of erectile dysfunction has primarily focused on selective, orally available drugs that act via influencing intracellular or central regulatory mechanisms, combining a high response rate and the advantage of an 'on-demand' intake. These agents are regarded as more efficacious, have a faster onset of drug action in the target tissue and an improved effect-to-side effect ratio than sildenafil. The purpose of this review is to describe the major novel and evolving pharmacological advances in the field of oral pharmacotherapy for the treatment of male erectile dysfunction.
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PMID:Current and future trends in the oral pharmacotherapy of male erectile dysfunction. 1294 96

Sexual side effects of serotonin reuptake inhibitors, such as antidepressant-associated erectile dysfunction, are common and negatively impact treatment compliance. Current management approaches have important limitations, and most lack clear and meaningful efficacy in double-blind, placebo-controlled trials. A MEDLINE search (English language, 1966-2003) was performed using the terms antidepressive agents, erectile dysfunction, and sildenafil. Emphasis was placed on studies that used specific sexual function measurements and were placebo controlled. Sildenafil citrate, a selective and competitive inhibitor of phosphodiesterase type 5, enhances the cyclic guanosine monophosphate-mediated relaxation of cavernosal smooth muscles in response to sexual stimulation, permitting vascular engorgement and penile erection. The efficacy and tolerability of sildenafil in the treatment of antidepressant-associated erectile dysfunction have been confirmed in double-blind, placebo-controlled trials.
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PMID:Sildenafil citrate for the management of antidepressant-associated erectile dysfunction. 1297 12

Sildenafil citrate (Viagra) is a relatively selective 5-phosphodiesterase (PDE) inhibitor. It is the first oral medication approved for the treatment of erectile dysfunction (ED). The neuronal release of NO which binds to the heme-containing region of guanylate cyclase increases levels of cGMP. This leads to a cascade of reaction which results in corporal smooth muscle relaxation and penile erection. Sildenafil causes an erection by inhibiting PDE5, which in turn causes an increase in the intracellular levels of cGMP. Sildenafil is well absorbed after a single oral administration with a t(1/2) of approximately 4 h. The mode of onset varies from 0.5-4 h. The drug has been used in millions of men since first approved by the U.S. FDA 1 year ago and has revolutionized the approach to, and therapy of, erectile dysfunction.
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PMID:Sildenafil: a new oral therapy for erectile dysfunction. 1297 86

Diabetes affects an increasingly large number of young men of reproductive age. Erectile and ejaculatory difficulties arise due to vascular and neuropathic problems. The treatment of these may have effects on fertility potential. Erectile dysfunction can be treated with mechanical devices and intracavernosal injections. Although these have not been shown to affect fertility directly, they may result in poor compliance and hence reduced frequency of ejaculation with subsequent deterioration in sperm quality. Other medical treatments may have a more direct effect. The phosphodiesterase (PDE) inhibitor pentoxifylline has been shown to affect sperm quality and early embryo development. Therefore, Viagra, also a PDE inhibitor, may affect sperm quality. There is conflicting evidence about this in the literature. Ejaculatory difficulties are also more common in diabetics although treatments such as Trucut testicular biopsy and intracytoplasmic sperm injection have improved the outlook for these patients. There is also some evidence that spermatogenesis is affected by diabetes and that patients have a reduced sperm motility and semen volume. Therefore, diabetes has a significant impact on the fertility of men with this disease both directly and indirectly. The extent of iatrogenic influence on the reduced fertility potential of these patients needs to be researched as a matter of urgency.
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PMID:The hidden impact of diabetes on male sexual dysfunction and fertility. 1461 96


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