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)

Vasoactive intestinal peptide (VIP) was originally isolated from porcine duodenum and considered to be a gut hormone. Recent evidence indicates that it may also be involved in reproductive functions. In this study, a possible action of VIP on steroidogenesis by cultured testicular cells was investigated. Neonatal testicular cells were treated in vitro with hormones for 3 days and medium steroid or cAMP content was measured by radioimmunoassay. Treatment of cultured cells with VIP (10(-9) to 10(-6) M) increased the production of testosterone, progesterone, and pregnenolone in a dose-dependent fashion. Testosterone production in response to 10(-6) M VIP was about 5-10% of that maximally induced by LH. Addition of methyl-isobutyl-xanthine, a phosphodiesterase inhibitor, to the VIP-containing cultures significantly enhanced production of testosterone by 13-fold, of progesterone by 9-fold, and of pregnenolone by 2.5-fold as compared to treatment with VIP alone. Additional experiments also showed a dose-dependent stimulation of cAMP production by VIP. The VIP-related hormones PHM-27, secretin, and glucagon also stimulated progesterone and testosterone production with a potency order (PHM-27 greater than secretin greater than glucagon) consistent with that observed for other VIP receptor-mediated actions. A direct stimulatory effect of VIP on Leydig cells was indicated in studies on steroidogenesis by testicular cells separated on a metrizamide density gradient. In these studies, VIP stimulated androgen production in an LH-responsive subpopulation of testis cells but failed to affect steroid production in non-LH-responsive cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vasoactive intestinal peptide stimulates androgen biosynthesis by cultured neonatal testicular cells. 243 Aug 45

We have studied the regulation of inhibin secretion by rat Sertoli cells grown on extracellular matrix-impregnated porous filters in a twin chamber assembly. Previous studies have established that rat Sertoli cells cultured under these conditions reproduce the morphological and functional polarization observed in the Sertoli cell in situ. Sertoli cells isolated from 18- to 22-day-old Wistar rats were cultured for up to 8 days with daily changes of fully defined supplemented Eagle's Minimum Essential Medium (MEM). Rat inhibin was measured by RIA and pituitary cell bioassay, and transferrin by RIA. Inhibin measured by immunoassay or bioassay was always readily detectable in the upper, but not the lower, chamber. Inhibin secretion into the upper chamber exhibited a dose-dependent stimulation of up to 3.7-fold by ovine FSH, with a medium effective dose of 2.2 micrograms/liter and a constant bio- to immunoreactive ratio (3.6 +/- 0.4). Apically directed secretion accounted for over 80% of inhibit output under basal conditions and over 94% with FSH stimulation. Insulin also stimulated upper chamber inhibin secretion at a high dose (5 mg/liter) but not at lower doses or in conjunction with FSH exposure of Sertoli cells. Testosterone augmented FSH-induced stimulation of inhibin secretion, but was ineffective without FSH exposure. In contrast to inhibin secretion, for which FSH is the principal regulator, transferrin secretion by Sertoli cells is more evenly bidirectional (overall mean upper to lower chamber ratio of 1.5) and requires exposure to other stimuli (insulin, retinoic acid, and testosterone) in addition to FSH to achieve maximal secretion. Both submaximal and maximal FSH stimulation of inhibin output were augmented by a phosphodiesterase inhibitor, isobutylmethylxanthine, and these effects were fully reproduced by forskolin, which suggests the involvement of cAMP in the vectorial secretion of inhibin. The marked polarization of Sertoli cell inhibin secretion in vitro could not be explained by restricted transmembrane passage of inhibin. It is, therefore, suggested that the bulk of inhibin secretion by the immature rat Sertoli cell in vivo may be directed primarily into the seminiferous tubular lumen. Thus, in addition to its role in endocrine negative feedback signaling to the pituitary, inhibin may also have important functions in seminiferous tubular function and the support of spermatogenesis.
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PMID:Highly polarized secretion of inhibin by Sertoli cells in vitro. 254 46

Testosterone, progesterone, and estradiol-17 beta each inhibit cAMP phosphodiesterase activity of mouse oocyte extracts in a concentration-dependent manner. This finding provides an explanation for the inhibitory effect of steroid hormones on germinal vesicle breakdown (GVBD) of mouse oocytes in vitro. Furthermore, it raises the possibility that steroid hormones present in follicular fluid participate in maintaining meiotic arrest in vivo by acting in a nonclassical manner.
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PMID:Inhibition of mouse oocyte cyclic AMP phosphodiesterase by steroid hormones: a possible mechanism for steroid hormone inhibition of oocyte maturation. 282 57

The effects of different atrial natriuretic peptides on cyclic GMP formation and steroidogenesis have been studied in Percoll-purified mouse Leydig cells. Rat atrial peptides rANP (rat atrial natriuretic peptide), rAP-I (rat atriopeptin I) and rAP-II (rat atriopeptin II), in the presence of a phosphodiesterase inhibitor, stimulated cyclic GMP formation in a concentration-dependent manner. In the presence of saturating concentrations of the peptides, a 400-600 fold stimulation of cyclic GMP accumulation was observed. Among the peptides, rAP-II appeared to be the most potent. ED50 values (concentration causing half-maximal effect) for rAP-II, rANP and rAP-I were 1 X 10(-9) M, 2 X 10(-9) M and 2 X 10(-8) M respectively. A parallel stimulation of cyclic GMP formation and testosterone production by the cells was observed after incubation of the cells with various concentrations of rAP-II. In the presence of a saturating concentration of rAP-II (2 X 10(-8) M), maximum stimulation of intracellular cyclic GMP content was obtained within 5 min of incubation. Testosterone production by mouse Leydig cells could be stimulated by 8-bromo cyclic GMP in a concentration-related manner. At a 10 mM concentration of the cyclic nucleotide, steroidogenesis was stimulated to a similar extent as that obtained with a saturating concentration of human chorionic gonadotrophin (5 ng/ml). On the basis of these results we conclude that cyclic GMP acts as a second messenger in atrial-peptide-stimulated steroidogenesis in mouse Leydig cells. The steroidogenic effect of atrial peptides appears to be species-specific, since none of these peptides stimulated testosterone production by purified Leydig cells of rats, though in these cells a 40-60-fold stimulation of cyclic GMP formation in response to each of the three peptides was observed. However, 8-bromo cyclic GMP could stimulate testosterone production in rat Leydig cells. Therefore we conclude that the lack of steroidogenic response in rat Leydig cells to atrial-natriuretic-factor-stimulation results from an insufficient formation of cyclic GMP in these cells. This species difference would appear to result from a lower guanylate cyclase activity in rat Leydig cells.
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PMID:Steroidogenic effect of atrial natriuretic factor in isolated mouse Leydig cells is mediated by cyclic GMP. 302 72

We investigated, in a rabbit model, the effects of castration and testosterone replacement on: 1) the hemodynamics of the corpus cavernosum; 2) alpha-1 adrenergic receptor protein expression; 3) neural NO synthase protein expression and activity; 4) phosphodiesterase type 5 activity; and 5) trabecular smooth muscle/connective tissue balance. One week after bilateral orchiectomy, animals were treated for 7 days with vehicle alone, testosterone, or estradiol. Intact control animals received vehicle only. Systemic arterial blood and intracavernosal pressures (ICP) were measured in each animal before and after electrical stimulation of the cavernosal nerve. Alpha1-adrenergic receptor protein expression was determined by ligand binding studies. NO synthase expression and activity were determined by Western blot analyses and conversion of L-arginine to citrulline, respectively. Phosphodiesterase type 5 activity was determined by hydrolysis of guanosine 3',5'-cyclic monophosphate (cGMP) in tissue extracts in the absence or presence of 100 nM sildenafil. Smooth muscle content was assessed by Masson's trichrome staining and computer-assisted histomorphometry. Castration significantly reduced ICP, but it did not alter systemic arterial blood pressure during stimulation of the cavernosal nerve. Testosterone, but not estradiol, treatment prevented the effects of castration and restored ICP to values similar to those obtained in intact animals. Castration reduced expression of alpha1-adrenergic receptor, and this reduction was prevented or reversed by testosterone replacement. Neural NO synthase protein expression and total activity were not altered significantly by castration or after testosterone replacement. However, phosphodiesterase type 5 activity increased in castrated animals treated with testosterone. Castration significantly reduced trabecular smooth muscle content, and this reduction was restored by testosterone (but not estradiol) treatment. The results of this study demonstrate that androgen deprivation alters the functional responses and structure of erectile tissue.
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PMID:Effects of castration and androgen replacement on erectile function in a rabbit model. 1009 25

Erectile dysfunction (ED) is a common problem with a prevalence of approximately 50% in men aged 40 to 70. There are several etiologies for ED including vasculogenic, neurogenic, hormonal and/or psychogenic factors; one-fourth of ED cases can be drug-related. Penile erection involves a complex interaction between the CNS and local factors. It is a neurovascular event modulated by psychological and hormonal factors. Pharmacologically, neural modulation and endocrine status are very important to attaining penile erection. There have been several significant advances for the pharmacologic treatment of ED. Treatments include agents that are not only orally effective, but possess either local or central acting mechanisms of action. Apomorphine, a centrally-acting agent, is effective in the treatment of ED. Sildenafil, another orally effective agent, acts by inhibiting cyclic GMP-specific phosphodiesterase Type V. Testosterone can be effective transdermally. Non-orally active agents include alprostadil and papaverine. Phentolamine and trazodone are effective in selected cases. Some agents can interact with other medications. Several pharmacological agents, some with central-acting mechanisms and some with Iocally-acting vascular effects, are therapeutically useful in the treatment of ED.
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PMID:Pharmacological aspects of erectile dysfunction. 1212 Jul 51

Male sexual activity is characterized by a synchronization of sexual desire arising in the brain and its transmission to the periphery, resulting in penile tumescence necessary for sexual intercourse. Testosterone (T) has been claimed for so long as a pivotal hormone in regulating male sexual function, acting both at central and peripheral level. We believe that T is indeed the main synchronizer of sexual activity regulating libido and enzymes as nitric oxide synthase (NOS) and phosphodiesterase type 5 (PDE5), which are crucial for the erectile process. In fact, NOS increases cyclic guanosine monophosphate (cGMP) levels, while PDE5 reduces it. Because T positively controls both the initiation and the end of the penile erection, its net effect on erection is null. In fact, penile erections are often present even without T. The main action of T is to timely adjust the erectile process as a function of sexual desire, therefore finalizing erections to sex.
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PMID:Testosterone and sexual activity. 1604 59

Hypogonadism (low serum testosterone) is commonly associated with erectile dysfunction (ED). However, many urologists may lack appreciation of the relative merits of treating hypogonadism compared with oral phosphodiesterase inhibitors for sexual dysfunction. Testosterone-replacement therapy (TRT) may be the best treatment for men with ED when the presentation includes diminished libido or other sexual symptoms or when non-sexual symptoms such as depressed mood, decreased sense of vitality, and increased fatigue also exist. The health benefits of TRT also include improvements in body composition, bone density, cognition, and sense of well-being. Thus, there may be good reasons to use TRT as first-line therapy for the man with ED. Concerns regarding prostatic and cardiovascular risks of TRT have not been supported by the literature. Nevertheless, men receiving TRT must be monitored at regular intervals with digital rectal examination and blood testing for prostate-specific antigen. Hematocrit or hemoglobin also should be obtained regularly due to the risk of erythrocytosis. Awareness of the benefits of TRT in the man with ED may improve clinical outcomes.
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PMID:Hypogonadism in the man with erectile dysfunction: what to look for and when to treat. 1623 23

Aging in men is accompanied by a decrease in libido and sexual activity. Recently, it has been demonstrated that a significant proportion of men >60 yr of age has biochemical hypogonadism. Hypoandrogenism, which is associated with other conditions that negatively influence erectile activity, may be an important cofactor in the induction of erectile dysfunction and in the response to phosphodiesterase type 5 (PDE5) inhibitors in aging. In these patients, administration of 50 mg sildenafil or 3 mg apomorphine has no influence on erectile function. Recently we showed that, in hypogonadal subjects, testosterone treatment might stimulate endothelial and neuronal production of vasoactive substances like nitric oxide (NO). Furthermore it can improve endothelial repair mechanisms by increasing bone marrow-derived endothelial progenitor cell (EPC) number in the peripheral circulation. Finally, the normal response to pharmacological stimulation with apomorphine or sildenafil, observed in hypogonadal men treated with testosterone, indicates a positive role of this hormone in the central and peripheral control of erection, confirming the possible positive influence on endothelial function and PDE5 expression. Therefore, we suggest measuring plasma testosterone levels in aged men with erectile dysfunction and recommend treating them barring clinical contraindications. Testosterone plus PDE5 inhibitors may be beneficial in improving erectile function in hypogonadal men with erectile dysfunction who were unresponsive to PDE5 inhibitors alone.
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PMID:Erectile dysfunction in aging men: testosterone role in therapeutic protocols. 1676 Jun 37

Hypogonadism may play a significant role in the pathophysiology of erectile dysfunction (ED). A threshold level of testosterone may be necessary for normal erectile function. Testosterone replacement therapy is indicated in hypogonadal patients and is beneficial in patients with ED and hypogonadism. Monotherapy with testosterone for ED is of limited effectiveness and may be most promising in young patients with hypogonadism and without vascular risk factors for ED. A number of laboratory and human studies have shown the combination of testosterone and other ED treatments, such as phosphodiesterase type 5 (PDE5) inhibitors, to be beneficial in patients with ED and hypogonadism, who fail PDE5 inhibitor therapy alone. There is increasing evidence that combination therapy is effective in treating the symptoms of ED in patients for whom treatment failed with testosterone or PDE5 inhibitors alone. Testosterone replacement therapy has potentially evolved from a monotherapy for ED in cases of low testosterone, to a combination therapy with PDE5 inhibitors. Screening for hypogonadism may be useful in men with ED who fail prior PDE5 inhibitors, especially in populations at risk for hypogonadism such as type 2 diabetes and the metabolic syndrome.
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PMID:The evolving role of testosterone in the treatment of erectile dysfunction. 1693 38


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