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)

Smooth muscle-mediated expansion and contraction of the vascular sinusoids of the corpora cavernosa may modulate male erectile function. To elucidate the biochemical events that control erection by promoting or inhibiting contraction of cavernosal smooth muscle, tissue from a potent man was grown in cell culture. The cells grew as noncontractile cultures, but had the following smooth muscle cell properties: These cells expressed desmin, the muscle cell-specific intermediate filament protein. They accumulated 45Ca2+ from the medium, which was released by exposure to the ionophore A23187, to cyclic nucleotides (cyclic guanosine 5'-monophosphate [GMP] much greater than cyclic adenosine 3',5'-monophosphate [AMP]), and to the phosphodiesterase inhibitor, papaverine; and; they accumulated Ca2+ in an ATP-dependent manner when the cultured cells were permeabilized by digitonin extraction. ATP-dependent Ca2+ uptake was inhibited approximately 80% by ruthenium red and simulated by cyclic GMP much greater than cyclic AMP. Inositol 1,4,5-trisphosphate (IP3), which is thought to mediate the release of Ca2+ by the smooth muscle cell sarcoplasmic reticulum in vivo, released approximately 0.85 pmol Ca2+/million cells from the digitonin-extracted cells. IP3-dependent release occurred in the presence of ruthenium red and was not affected by cyclic GMP or cyclic AMP. These results indicate that smooth muscle from this human source can be grown successfully in cell culture and that the biochemical pathways that regulate tension in vivo may be perpetuated in vitro. Moreover, some of the clinical responses to drugs administered in situ for erectile dysfunction (e.g. papaverine) may be the result of altered cavernosal smooth muscle cell Ca2+ exchange and may be mediated by cyclic GMP.
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PMID:Characterization of cyclic nucleotide and inositol 1,4,5-trisphosphate-sensitive calcium-exchange activity of smooth muscle cells cultured from the human corpora cavernosa. 246 20

To elucidate the sequence of events between the release of neurotransmitters and cavernous smooth muscle relaxation in erection, we studied the role of the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) systems. In a well-established simian model, the effects of specific agonists and antagonists of the intracellular sequence for smooth muscle relaxation and potassium channel openers on the intracavernous pressure were examined. Sodium nitroprusside (10(-3) M), a nitric oxide releaser and thus a stimulant of the cGMP system, caused an increase in the intracavernous pressure from 82 to 115 cm H2O for 7 to 19 min and penile diameter from 24.8 +/- 2.28 to 43 +/- 4.87 mm. When nitroprusside was injected after methylene blue (10(-3) M), a specific antagonist of the enzyme guanylate cyclase, intracavernous pressure rise decreased significantly, but cromakalin, a potassium channel opener, provoked excellent increases after the block. A smaller dose of sodium nitroprusside (10(-4) M) caused an increase in intracavernous pressure from 35 to 85 cm H2O for 7 to 11.5 min. When nitroprusside was injected after zaprinast, a phosphodiesterase inhibitor, the increase in pressure ranged from 80 to 116 cm H2O for 15 to 30 min. Prostaglandin E1, an activator of the cAMP system, caused an increase in the intracavernous pressure of 20-80 cm H2O for 5 to 10 min, and an increase in penile diameter from 25 +/- 2.22 to 35 +/- 3.48 mm. The erectile response to PGE1, but not to cromakalin, was nearly abolished by ethylmaleimide, an adenylate cyclase blocker. The response to nitroprusside was significantly greater (P < 0.05) than to PGE1. Both systems, cAMP and cGMP, may be involved in cavernous smooth muscle relaxation, and cGMP is probably the predominant intracellular second messenger in penile erection in monkeys. Stimulants of the cGMP system, such as nitric oxide releasers, could represent a more physiological and effective approach in the treatment of erectile dysfunction.
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PMID:Intracellular mechanism of penile erection in monkeys. 815 77

Sildenafil (Viagra, UK-92,480) is a novel oral agent under development for the treatment of penile erectile dysfunction. Erection is dependent on nitric oxide and its second messenger, cyclic guanosine monophosphate (cGMP). However, the relative importance of phosphodiesterase (PDE) isozymes is not clear. We have identified both cGMP- and cyclic adenosine monophosphate-specific phosphodiesterases (PDEs) in human corpora cavernosa in vitro. The main PDE activity in this tissue was due to PDE5, with PDE2 and 3 also identified. Sildenafil is a selective inhibitor of PDE5 with a mean IC50 of 0.0039 microM. In human volunteers, we have shown sildenafil to have suitable pharmacokinetic and pharmacodynamic properties (rapid absorption, relatively short half-life, no significant effect on heart rate and blood pressure) for an oral agent to be taken, as required, prior to sexual activity. Moreover, in a clinical study of 12 patients with erectile dysfunction without an established organic cause, we have shown sildenafil to enhance the erectile response (duration and rigidity of erection) to visual sexual stimulation, thus highlighting the important role of PDE5 in human penile erection. Sildenafil holds promise as a new effective oral treatment for penile erectile dysfunction.
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PMID:Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. 885 89

Previously, men with erectile dysfunction (ED) were frequently treated with penile prosthesis implants or considered to have psychogenic impotence. Since the reports by Virag and Brindley in 1932 and 1983, pharmacotherapy, by self-injection programs has become a new therapeutic concept for impotent men. In clinical practice, this application model has been generally accepted as the "golden standard" in the treatment of ED. Papaverine was first used as monotherapy, but because of side-effects such as prolonged erection, priapism, and fibrosis of the corpus cavernosum, single use of the drug was abandoned. Instead, papaverine was introduced in mixtures, e.g. together with alpha adrenoceptor-blockers as phentolamine, and/or prostaglandin E1 (PGE1) in these "cocktails", the dose of papaverine is reduced to 10-15 mg compared to the high doses (80-120 mg) that were used initially. By having two or more drugs in the mixture, a facilitating cascade effect as probably obtained. PGE1 is the only drug that has been approved by the FDA and is today registered in more than 50 countries. Other combination therapies such as vasoactive intestinal polypeptide+ phentolamine, or calcitonin gene-related peptide+ PGE1, have been suggested as suitable alternatives for intracavernosal injection. Transdermal and intraurethral application models may be considered in selected patients. Recently, oral administration of a phosphodiesterase inhibitor (UK-92.480) was reported to improve penile erection in patients with psychogenic impotence. Further clinical results from controlled trials will probably explain if this new oral drug will compete with PGE1 or other agents in self-injection programs.
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PMID:Pharmacotherapy in erectile dysfunction agents for self-injection programs and alternative application models. 890 79

Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are important second messengers in mediating relaxation of various smooth-muscle cells. This second-messenger pathway also appears to be essential for cavernous smooth-muscle relaxation on the basis of the assumption it would be of theoretical and clinical interest to determine the functional relevance of various phosphodiesterase (PDE) isoenzymes in human cavernous smooth-muscle This study was concentrated on characterizing PDE isoenzymes that exist in cavernous smooth muscle and evaluating the effect of selective PDE inhibitors on relaxation that is needed for the initiation of erection. Separation of PDE isoenzymes was performed using anion-exchange chromatography [diethylaminoethanol (DEAE)-Sepharose column], and a modification of the PDE-assay method proposed by Thompson and Lakey was used. The relaxation effect of PDE inhibitors was evaluated in an organ-bath study. Three different PDE isoenzymes have been shown in human cavernous smooth-muscle homogenate: cGMP-inhibited PDE (PDE III), cAMP-specific PDE (PDE IV), and cGMP-specific PDE (PDE V). All PDE inhibitors tested showed a relaxation effect on isolated human cavernous smooth-muscle, albeit with differing potency. Quazinone (a selective PDE III inhibitor) had potency at least equal to that of papaverine (a non-selective PDE inhibitor) and had a superior effect as compared with Rolipram (a selective PDE IV inhibitor) and zaprinast (a selective PDE V inhibitor). The present study provides the rationale and opens the possibility of using selective PDE inhibitors in the treatment of patients with erectile dysfunction.
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PMID:Cyclic nucleotide phosphodiesterase in human cavernous smooth muscle. 906 92

Intracavernous pharmacotherapy of erectile dysfunction has been established for over 10 years, with prostaglandin E1 (PGE1) being the standard substance with the lowest rate of side effects. Recent investigations deal with the identification of intracellular mechanisms of smooth muscle relaxation in cavernous tissue as the most important aspect of penile erection. Nitric oxide and specific phosphodiesterase-isoenzymes seem to play a central role. This resulted in clinical studies with the intracavernous injected nitric oxide-donor linsidomine (SIN 1) and the orally given phosphodiesterase-inhibitor sildenafil. Furthermore new ways of pharmaco-application are tested, e.g. transdermal treatment with nitroglycerin, minoxidil or papaverine, as well as intraurethral injection of prostaglandin E1.
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PMID:[Pharmacological therapy in erectile dysfunction--current standards and new viewpoint]. 919 Jul 65

Sildenafil citrate has been shown to be effective in a wide range of patients with erectile dysfunction and has been approved in the United States for this indication. The overall clinical safety of oral sildenafil, a potent inhibitor of phosphodiesterase type 5, in the treatment of erectile dysfunction was evaluated in more than 3700 patients (with a total of 1631 years of exposure worldwide). Safety and tolerability data were analysed from a series of double-blind, placebo-controlled studies and from 10 open-label extension studies of sildenafil in the treatment of erectile dysfunction. A total of 4274 patients (2722 sildenafil, 1552 placebo; age range 19-87 y) received double-blind treatment over a period of up to six months' duration, and 2199 received long-term, open-label sildenafil for up to 1 y. The most commonly reported adverse events (all causes) were headache (16% sildenafil, 4% placebo), flushing (10% sildenafil, 1% placebo), and dyspepsia (7% sildenafil, 2% placebo) and they were predominantly transient and mild or moderate in nature. These adverse events reflect the pharmacology of sildenafil as a phosphodiesterase type 5 inhibitor. No cases of priapism were reported. The rate of discontinuation due to adverse events (all causes) was comparable for patients treated with sildenafil (2.5%) and placebo (2.3%). In open-label extension studies, 90% of patients completed long-term sildenafil treatment, with only 2% withdrawing due to adverse events. Sildenafil is a well-tolerated oral treatment for erectile dysfunction.
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PMID:Clinical safety of oral sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction. 964 40

Erectile dysfunction may have psychological as well as a variety of organic causes. This necessitates in each case a careful medical evaluation. Various commonly used drugs, as well as alcohol and narcotics, may interfere with erection and should, whenever possible, be discontinued before starting treatment. Organic diseases should be identified and, if feasible, specially treated. In the remaining majority of afflicted men, psychological treatment and partner counseling may produce an improvement, but ultimately what is necessary remains an effective and safe medication. The drug, Sildenafil, introduces a new therapeutic principle. During sexual nerve stimulation, nitric oxide (NO) is released from nerves into the cells of the penile erectile bodies. NO activates in turn its "second messenger", the substance cyclic GMP, and the latter induces the vasorelaxation and blood filling of the erectile bodies. Orally administered Sildenafil competitively inhibits phosphodiesterase type 5, which physiologically inactivates cyclic GMP in the erectile bodies. Thus, Sildenafil increases in men with erectile dysfunction the NO-stimulated cyclic GMP concentration and, thereby, improves erection. This new therapy is attractive because 1. Sildenafil is the first pill (for oral use) with established efficacy that benefits most men with insufficient erection; 2. compared with previous therapeutic approaches (such as drug injections in the penis, instillations into the urinary duct, vacuum pumps or even prostheses), Sildenafil is at least as effective, is easy to take and appears well tolerated with no risk of a prolonged erection; 3. remarkably, this medication stimulates erection only during sexual arousal and, thus, has a rather "natural" effect, and 4. side effects (including headache, facial flushing and dyspepsia or epigastric discomfort) were mostly of mild degree and transient, so that only 4% of men interrupted treatment for this reason. Sildenafil does not need to be taken daily, but may be taken, when needed, 1 hour before a planned sexual activity. The new pill has the potential to enliven the boys "wunder horn" with fresh sound.
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PMID:[New principle in therapy of erectile dysfunction: sildenafil]. 965 82

Pharmacotherapy of erectile dysfunction comprises oral and local application of drugs. Today, Yohimbin is the only drug listed for this indication. Yohimbin acts via central alpha-receptor blockade and showed a significant effect in a recent double blind study compared to placebo. The centrally acting substances Apomorphin and Trazodone were also tested for their potential use with Apomorphin showing promising results. The orally active phosphodiesterase-V inhibitor Sildenafil acts predominantly on the peripheral side; broad clinical studies demonstrated a significant effect of the drugs compared to placebo. For local use, intraurethral (MUSE) and intracavernous applications are available with PGE1 being the drug the most widely used for the moment. Since many different drugs with various modes of action and different modes of application are being developed at the moment, future pharmacological treatments will allow a more refined approach towards an individually adapted regimen.
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PMID:[Pharmacological therapy of erectile dysfunction]. 979 31

The efficacy and safety of oral sildenafil, a potent inhibitor of phosphodiesterase type 5, were evaluated in men with diabetes mellitus and erectile dysfunction (ED). Twenty-one men (aged 42-65 years) were enrolled in a double-blind, placebo-controlled, three-way crossover study conducted in two parts. In part I, the effect of a single dose (25 mg or 50 mg) of sildenafil or placebo on penile rigidity was assessed by penile plethysmography during visual sexual stimulation. In part II, daily diary records of erectile activity and a global efficacy question were used to evaluate once-daily dosing with 25 mg or 50 mg of sildenafil or placebo for 10 days. After a single 50 mg dose of sildenafil, the adjusted geometric mean duration (min) of penile rigidity >60% at the base of the penis during visual sexual stimulation was significantly increased (10.1 min) compared with placebo (2.8 min; p = 0.0053). In part II, sildenafil significantly increased the number of erections considered sufficiently hard for vaginal penetration compared with placebo (p = 0.0005). Improved erections were reported by 50% and 52% of patients treated with 25 mg and 50 mg of sildenafil, respectively, compared with 10% of those receiving placebo (p values < 0.05). Adverse events were mostly mild or moderate in nature and included muscular pains, headache, and dyspepsia. Sildenafil is a well-tolerated and potentially efficacious oral treatment for ED in men with diabetes mellitus.
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PMID:Sildenafil: study of a novel oral treatment for erectile dysfunction in diabetic men. 979 81


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