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)

We examined the contribution of K+ channels to the relaxation responses induced by different redox forms of nitric oxide (NO., NO- and NO+) in comparison with those evoked by electrical field stimulation (EFS) of nitrergic nerves in the sheep urethra. K+ channel blockers with different selectivity profile were used. Sodium nitroprusside (SNP) and different S-nitrosothiols were used as NO+ donors, Angeli's salt as an NO- donor and nitroglycerin (GTN) was chosen as a representative compound known to require metabolic activation in the target tissue. Pure NO gas was used to prepare NO. solutions. Relaxation evoked by EFS of nitrergic nerves or by exogenous NO was not inhibited by any of the K+ channel blockers, but was enhanced by 4-aminopyridine [inhibitor of voltage-dependent K+ (KV) channels]. This suggests that, whereas K+ channel activation and hyperpolarization of the postsynaptic membrane do not contribute to relaxation, prejunctional modulation of the nitrergic neurotransmission by Kv channels may be relevant. Relaxation induced by NO+ or NO- donors was not affected by K+ channel blockade with the following exceptions: glybenclamide, a blocker of ATP-sensitive K+ channels (KATP), enhanced responses to SNP and Angeli's salt, 4-aminopyridine inhibited relaxation evoked by Angeli's salt and GTN, and charybdotoxin, a blocker of large-conductance, Ca2+-activated K+ channels (BKCa) inhibited those induced by the S-nitrosothiol S-nitrosoglutathione. These results do not suggest the existence of a general mechanism of action on K+ channels for compounds releasing either NO+ or NO- in the sheep urethra. None of the K+ channel blockers affected relaxation induced by the membrane-permeable analogue of cGMP, 8-bromo-cGMP. However, the fact that the addition of the phosphodiesterase inhibitor zaprinast (0.1 mM) enhanced the relaxation to Angeli's salt, while preventing the inhibition induced by 4-aminopyridine, suggests that involvement of guanylate cyclase activation in the action of NO donors on K+ channels can not be excluded. Accordingly, the guanylate cyclase inhibitors 1H-[1,2,4]-oxadiazole-[4,3-a]-quinoxalin-1-one (ODQ, 10 microM) and 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one (NS 2028, 10 microM) almost abolished relaxations to EFS and Angeli's salt. In contrast, ODQ only moderately inhibited relaxations to NO.. In addition, the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl imidazoline-1-oxyl 3-oxide (carboxy-PTIO) effectively inhibited responses to NO. whilst not affecting those to EFS or NO-, suggesting a close similarity between the nitrergic transmitter and nitroxyl ion. We conclude that nitrergic relaxation induced either by the endogenous transmitter or by exogenous NO donors in the ovine urethra is not mediated by postsynaptic alterations in the K+ conductance; only a prejunctional modulation through Kv channels seems to be significant. In addition, the production and/or release of alternative redox forms of NO, such as NO-, may be involved in neurotransmission processes in the urethra.
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PMID:Nitrergic relaxation in urethral smooth muscle: involvement of potassium channels and alternative redox forms of NO. 1177 6

For at least a decade, no new drug principles have been added to the therapeutic armamentarium for the treatment of lower urinary tract symptoms (LUTS) associated with or suggestive of benign prostatic hyperplasia (BPH). Theoretically, there seem to be several possibilities to improve the current treatment, which is based mainly on alpha1-adrenoceptor (AR) antagonists, 5alpha-reductase inhibitors and phytotherapy. It cannot be dismissed that subtype selective alpha1-AR antagonists can further improve treatment, but convincing evidence is still lacking. Muscarinic receptor antagonists are currently evaluated in BPH patients, but their eventual place in therapy, as a single treatment or in combination with alpha1-AR antagonists, has to be established. Endothelin receptor antagonists, alone or together with alpha1-AR antagonists, seem to offer a new attractive approach; however, proof of concept studies are lacking. The L-arginine/NO/cGMP pathway awaits further exploration; nitric oxide (NO) donors or phosphodiesterase (PDE) inhibitors may be clinically useful. Purinoceptors are currently the focus of interest as treatment targets in the lower urinary tract and inhibitors of P2X3 (and P2X1) subtypes may offer new opportunities. If a treatment based on desensitising C-fibres in the bladder and urethra is effective, not only in neurogenic bladders, but also for treating LUTS, it would be a viable option. For new treatments of LUTS, targets within the central nervous system (CNS) may offer exciting opportunities.
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PMID:Future drugs for the treatment of benign prostatic hyperplasia. 1202 12

Drugs for the treatment of premature ejaculation (PE) are divided to two categories: oral drugs and local drugs. Oral drugs include antidepressive drugs, alpha-adrenoceptor blocking drugs, phosphodiesterase type V blocking drugs and Chinese herbal medicine. Local drugs include local surface drugs, intracavernosal injective drugs and local urethra drugs. Antidepressive drugs are extensively used, which have moderate efficacy, relatively more side effects and high recurrence rate; alpha-adrenoceptor blocking drugs are seldom used and are less effective than antidepressive drugs; phosphodiesterase type V blocking drugs like sildenafil have good efficacy and few side-effects and are worthy to be studied further. Local surface drugs like SS-Cream have good efficacy and few side-effects and are worthy to be applied and promoted; local urethral drugs like MUSE and Befar may become a new method to treat PE after being further studied. Medication for premature ejaculation shall be made specific and suitable as much as for each individual patient.
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PMID:[Medication for premature ejaculation]. 1286 42

Rapid (premature) ejaculation (RE) is a very common sexual disorder. This condition may be primary or secondary to underlying disease. Control of RE has been primarily focused on behavioural therapy, topical anaesthetics, tricyclic antidepressants and selective serotonin reuptake inhibitors; however, an approved treatment does not exist. Recently, a number of clinical trials have studied the potential effectiveness of the phosphodiesterase (PDE)-5 inhibitor sildenafil in the treatment of RE. Results of most of these studies have been encouraging. Available data indicate that there is clinical, anatomical, physiological, pharmacological and genetic evidence to explain the efficacy of PDE5 inhibitors in RE. The rationale for the use of PDE5 inhibitors in the treatment of RE could be due to possible peripheral and central mechanisms. Possible peripheral ejaculation retarding capabilities may include modulation of the contractile response of the vas deferens (VD), seminal vesicles (SV), prostate and urethra, induction of a state of peripheral analgesia, and prolongation of the total duration of erection. Possible central mechanisms may involve lessening of the central sympathetic output. Furthermore, there is evidence from knockout mice to explain the efficacy of PDE5 inhibitors in RE. Mice lacking the gene for endothelial nitric oxide synthase develop a condition similar to RE. On the other hand, mice lacking the gene for heme oxygenase-2 develop a condition similar to delayed ejaculation. This review also discusses the findings against the use of these agents in RE. In conclusion, a review of the literature suggests the potential usefulness of PDE5 inhibitors as a promising line of therapy in RE but further studies are needed.
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PMID:Phosphodiesterase 5 inhibitors in rapid ejaculation: potential use and possible mechanisms of action. 1472 56

Functional anatomy of the human penis involves various parameters: cavernous tissue, covering integument, prepuce foreskin, corpora cavernosa, corpus spongiosum, glans, facia, arterial supply, venous drainage, lymph drainage, musculature, and nerve supply. Several factors affect the expression/degree of erectile dysfunction (ED) endocrine profile, aging/senescence, demyelinating diseases, and surgery. Risk factors of ED are: age, vascular factors, metabolic diseases (diabetes mellitus), neurologic diseases, and HIV/AIDS. Several drugs are associated with ED: antiandrogenic, anticholinergic, antidepressants, antihypertensive, major tranquilizers, anxiolytics, and certain medicines/metabolites. The International Index of Erectile Function (IIEF) is a multidimensional scale for assessment of erectile dysfunction. The main structures mediating erection are the corpora cavernosa or "erectile bodies," which are fused distally for approximately three-quarters of their length. They separate proximally to fuse with each ischial tuberosity of the pelvis. On their ventral surface lies the corpus spongiosum, which surrounds the urethra. Coital dysfunction is classified into "erectile dysfunction" (psychosexual and endocrine/neuro-endocrine) and "ejaculatory dysfunction" (psychosexual, and genitourinary surgery). Vasculogenic impotence was evaluated by high-resolution ultrasonography and pulsed Doppler spectrum analysis. Cavernosal, alpha-blockade is a technique used to evaluate and treat ED. Another diagnostic procedure for ED involves color floro and spectural Doppler imaging after papaverine-induced erection in impotent men. Color Doppler and duplex ultrasonography are used to evaluate Peyronie's disease. Sildenafil cilrate (Viagra) is an effective therapy of ED in men. Vardenavil is a highly selective phosphodiesterase 5 (PDE5) inhibitor which improved ED. Prostagland E1, vasoactive intestinal polypeptide (VIP), and phentolamine mesylate (administered by autoinjectors) have been applied to treat ED in patients resistant to other intracavernosal agents. Clinical trials were conducted on self-injection of vasoactive drugs, apomorphine SL, and tadalafil in diabetic men. Medical therapy of ED includes: medicated urethral system for erection (MUSE), intravenous pharmacotherapy, arterial revascularization, vacuum devices, two- and three-component inflatable penile prosthesis, semi-rigid penile prosthesis in situ, and inflatable one-piece penile prosthesis. Surgical therapy include procedures to correct Peyronie's penile deformity and penile deformity, procedures to avoid inevitable shortening accompanying Nesbit's disease, and for penile lengthening.
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PMID:Erectile dysfunction: anatomical parameters, etiology, diagnosis, and therapy. 1576 14

Cyclic nucleotide levels are controlled through their synthesis from nucleotide triphosphates by cyclases and their degradation to 5'-monophosphates by phosphodiesterases (PDEs). Components controlling cyclic AMP-induced relaxation in the urinary tract include receptors, inhibitory and stimulatory G-proteins, isoforms of adenylyl cyclase and PDEs. The responsiveness of PDEs to a variety of physiological challenges is related to the presence of multiple families of isoenzymes with specific localization within tissues and within cells. At least 11 families of PDEs encode more than 50 PDE proteins produced in mammalian cells. In the urinary tract, characterization of PDE isoforms has lagged behind other systems and much of the literature was published prior to identification of PDE7, 8, 9, 10, 11. Specific PDE inhibitors regulate smooth muscle function in the bladder, urethra, prostate and ureter. The pharmacological potential of these inhibitors may include treatment of urge incontinence and the low compliance bladder, and treatment of prostate cancer. G-proteins also regulate cyclic AMP production. Changes in specific G- protein isoforms with aging, most prominently Gialpha2, cause decreased relaxation response in the aging bladder. As we have seen here with aging and certainly in other disease processes, levels of the components of adenylyl cyclase/phosphodiesterase/protein kinase can change and thus affect the relaxation response. By exploitation of differences in PDE expression in disease, such as the overexpression of PDEs in cancer, treatment options may present themselves.
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PMID:Regulation of cyclic nucleotides in the urinary tract. 1585 36

To date, there is no FDA-approved therapy for premature ejaculation (PE). Recently, phosphodiesterase 5 inhibitors (PDE5-Is) have been demonstrated to have encouraging results in the treatment of PE by a few studies. The aim of this review was to assess the updated manuscripts and thereafter present the practical recommendations and possible mechanisms concerning PDE5-Is for treating PE. Using MEDLINE, we searched and assessed the peer manuscripts published from 1 January 1996 to 1 September 2005 about PDE5-Is for treating PE. The results show that the number of patients in all the reports is very few and most of the studies do not employ double-blinded and placebo-controlled tests, though they are prospective and randomized. Therefore, the results and conclusions might be biased. PDE5-Is are suggested to be used in PE with old age or associated with erectile dysfunction (ED), or to be employed alone or in combination with selective-serotonin reuptake inhibitors (SSRIs) when SSRIs fail to treat PE; behavioural therapy is proposed to be used for preventing the recurrence of PE following withdrawal of PDE5-Is. In addition, for the PE patient with a definite aetiological cause, the aetiology should be cured first, if PE still exists, followed by PDE-Is prescription. Possible mechanisms that are involved include relaxing the smooth muscles of vas deferens, seminal vesicle, prostate and urethra; decreasing the central sympathetic output; inducing peripheral analgesia; prolonging the duration of erection; and increasing confidence, the perception of ejaculatory control, overall sexual satisfaction, and decreasing the post-orgasmic refractory time to achieve a second erection after ejaculation. Well-designed multicentre studies are urgently warranted to further elucidate the efficacies and safety as well as mechanisms of PDE5-Is in the treatment of PE.
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PMID:Phosphodiesterase 5 inhibitors in the treatment of premature ejaculation. 1657 7

Sildenafil citrate is a specific inhibitor of phosphodiesterase (PDE) type-5 and represents a powerful therapy for male erectile and fertility dysfunctions of different etiologies. Present study demonstrates whether sildenafil administration modifies seminal parameters in diabetic neuropathic patients. In this investigation 50 insulin dependent (IDDM) and 50 non insulin dependent (NIDDM) diabetic male patients with and without an objective evidence of neuropathy and 50 age matched non diabetic male controls were selected. Every male had age between 20 to 65 years with duration of diabetes distributed over 1 to 20 years. Treatment with 100 mg of oral sildenafil citrate on seminal parameters was evaluated by semen analysis in these patients. In both IDDM and NIDDM diabetic neuropathic patients, chronic sildenafil treatment exhibited a significant decrease in total sperm output and sperm concentration (p<0.001). On the other hand, sperm motility and semen volume were found to be increased by about 40% and 48% respectively in these patients, where as sperm morphology and quality of sperm motility remained unaffected. However both types of non neuropathic diabetics showed a non significant difference in all the above mentioned parameters when compared with the untreated groups and their respective control subjects. A comparison between IDDM and NIDDM neuropathic and non neuropathic diabetic groups further indicated a non significant difference in all the parameters of semen analysis. These findings suggest a chronic neuro physiological effect of sildenafil treatment on male fertility profile exclusively in diabetic neuropathic condition with an improvement in testicular function which was probably arrested due to some kind of testicular hyperplasia resulted by testicular necrosis and promoted spermatogenesis. Sildenafil seems to be associated with an improvement in the entire smooth musculature of reproductive tract and testicular morphology which was altered due to neuropathy like a reduction in excess accumulation of interstitial collagen and calcification in the smooth muscles of seminiferous tubules which made them rigid leading to atonia of bladder and urethra which resulted in partial or retrograde ejaculation associated with a decreased sperm motility. Sildenafil treatment returned back the spermatogenesis to normal with a positive influence on sperm motility and ejaculate volume in these neuropathic patients irrespective of the type of diabetes.
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PMID:Neurophysiological role of sildenafil citrate (Viagra) on seminal parameters in diabetic males with and without neuropathy. 1733 26

Lower urinary tract (LUT) smooth muscle can be relaxed by drugs that increase intracellular concentrations of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both of these substances are degraded by phosphodiesterases (PDEs), which play a central role in the regulation of smooth muscle tone. The distribution and functional significance of PDE enzymes vary in different tissues of the LUT. Targeting specific PDE isoenzymes should thus allow organ selectivity. PDE 4 and 5 appear to predominate in the prostate, PDE 1 and 4 are thought to influence detrusor smooth muscle function, and PDE 5 may be functionally important in the urethra and vasculature. Studies on the use of PDE inhibitors to treat various LUT symptoms (LUTS), have yielded favorable results. Thus, positive effects of the PDE 5 inhibitors sildenafil and tadalafil on symptoms and quality of life in men with LUTS, erectile dysfunction, and BPH have also been demonstrated. These effects may be due to effects on cGMP signaling and/or modification of afferent input from bladder, urethral, and prostate tissue. This review gives an update on the distribution of PDEs in structures relevant for LUT function, and discusses how inhibition of these enzymes can contribute to beneficial effects on LUTS. Information for the review was obtained from searches of the PubMed database, and from the authors' files.
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PMID:Phosphodiesterases (PDEs) and PDE inhibitors for treatment of LUTS. 1780 24

Diverticula of the male penile urethra are rare clinical entities. Urethral diverticula in males may be associated with trauma, infection, impacted calculi or stricture disease. Herein, we present an unusual case of a 57-year-old man with erectile dysfunction and a symptomatic urethral diverticulum after endoscopic urethrotomy for a pendulous urethral stricture. One year after surgical repair involving urethral stricture excision, end-to-end primary urethroplasty, and closure of the diverticular neck, the patient is voiding well but has persistent erectile dysfunction unresponsive to phosphodiesterase-5 inhibitors.
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PMID:Urethral diverticulum after endoscopic urethrotomy: case report. 1806 75


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