cyclic-gmp and Prostatic-Hyperplasia

To provide a systematic review of epidemiological data regarding the association between erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) in men.. A research has been conducted on the Medline database using the keywords: ("erectile dysfunction" or "sexual dysfunction") and ("benign prostatic hyperplasia" or "lower urinary tract symptoms"). The eligibility of studies was defined using the PICOS method in accordance with the PRISMA statement. Cross-sectional studies and prospective cohorts assessing the association between LUTS and ED in the primary care setting or in general practice (i.e. exclusion of patients seen in outpatient urology or andrology) were included.. Among 898 reports assessed, seven studies were included in this systematic review (whole cohort: 1,196,393 men). There were five cross-sectional studies and two prospective cohorts. The whole seven studies reported an association between LUTS and ED (range of odds-ratio: 1.52-4.03). Four common pathogenic mechanisms were found in the literature, all of them being somewhat related with metabolic syndrome and cardiovascular risk factors: reduced nitric oxide (NO) pathway signalling, increased RhoA-Rho kinase signalling, autonomic nervous system hyperactivity and pelvic atherosclerosis.. The main limitations of this review were: a possible publication bias, the relatively low number of included studies and the lack of assessment of potential confounders such as factors related to sexual partner.. The close epidemiological and pathogenic links between LUTS and ED have given rise to a new nosological entity: the erectile urogenital dysfunction, which should be assessed globally with special considerations to frequently associated comorbidities such as metabolic syndrome and cardiovascular risk factors.

Topics: Atherosclerosis; Autonomic Nervous System; Cardiovascular Diseases; Comorbidity; Cross-Sectional Studies; Cyclic GMP; Endothelium, Vascular; Erectile Dysfunction; Humans; Impotence, Vasculogenic; Lower Urinary Tract Symptoms; Male; Metabolic Syndrome; Muscle, Smooth; Nitric Acid; Prospective Studies; Prostatic Hyperplasia; rho-Associated Kinases; rhoA GTP-Binding Protein; Risk Factors; Signal Transduction

Phosphodiesterase-5 (PDE5) inhibitors, such as sildenafil, tadalafil and vardenafil are first line treatment for erectile dysfunction (ED). These PDE5 inhibitors are known to increase cyclic guanosine monophosphate (cGMP) concentrations in the smooth muscle cells of the corpora cavernosa penis by inhibiting PDE5, leading to smooth muscle relaxation. This mode of action is also believed to result in prostatic smooth muscle relaxation and to improve lower urinary tract symptoms (LUTS). Randomized controlled trials have shown beneficial effects on LUTS and on objective parameters such as maximum urinary flow rate (tadalafil). Based on these data tadalafil was recently approved for treatment of patients with male LUTS; however, the mechanisms leading to improvement of symptoms are still under debate.

Topics: Carbolines; Controlled Clinical Trials as Topic; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Humans; Imidazoles; Lower Urinary Tract Symptoms; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Prostatic Hyperplasia; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Urodynamics; Vardenafil Dihydrochloride

Benign prostatic hyperplasia (BPH) is a common disease in older men that can lead to lower urinary tract symptoms (LUTS). Male sexual dysfunction is also an age-related condition. Epidemiological studies have confirmed an association between BPH/LUTS and sexual dysfunction in ageing men that is independent of the effects of age, other co-morbidities and lifestyle factors. Proposed pathophysiological mechanisms for BPH/LUTS-associated sexual dysfunction include the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway, rho-kinase and endothelin-1 activity, autonomic nervous system overactivity and the metabolic syndrome, and pelvic organ atherosclerosis. Both BPH/LUTS and sexual dysfunction can have a substantial negative impact on a man's quality of life. However, urologists and primary care physicians appear to under-recognise sexual dysfunction in men with BPH/LUTS. Current guidelines recommend alpha-blockers and 5-alpha reductase inhibitors, either alone or in combination, among appropriate medical treatment options for BPH/LUTS. Randomised, controlled trials demonstrate that these therapies can be associated with sexual adverse effects (AEs) such as loss of libido, erectile dysfunction and ejaculatory disorders. Sexual dysfunction should be fully evaluated in men requiring treatment for BPH/LUTS using validated questionnaires. Management of sexual dysfunction in men treated for BPH/LUTS should involve assessment of co-morbidities and concomitant medications, consideration of lifestyle interventions such as weight loss and increased physical activity to improve risk factors and, if necessary, introduction of pharmacotherapies. In addition, physicians should provide patients with proper counselling on the possible sexual AEs of medical therapies for BPH/LUTS and their impact on sexual satisfaction, while being aware of the possibility that counselling in itself is likely to influence reported rates of sexual dysfunction.

Topics: 5-alpha Reductase Inhibitors; Adrenergic alpha-Antagonists; Adult; Aged; Atherosclerosis; Autonomic Nervous System Diseases; Cyclic GMP; Drug Combinations; Endothelin-1; Humans; Male; Metabolic Syndrome; Middle Aged; Nitric Oxide; Prostatic Hyperplasia; Prostatism; rho-Associated Kinases; Sexual Dysfunction, Physiological

This review focuses on the relationship among sexual dysfunction (SD), lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH), and related therapies.. We reviewed the current literature to provide an overview of current data regarding epidemiology and pathophysiology of SD and LUTS. Moreover, we analysed the impact of currently available therapies of LUTS/BPH on both erectile dysfunction (ED) and ejaculatory dysfunction and the effect of phosphodiesterase type 5 inhibitors (PDE5-Is) in patients with ED and LUTS.. We conducted a Medline search to identify original articles, reviews, editorials, and international scientific congress abstracts by combining the following terms: benign prostatic hyperplasia, lower urinary tract symptoms, sexual dysfunction, erectile dysfunction, and ejaculatory dysfunction.. We conducted a comprehensive analysis of more relevant general population-based and BPH/LUTS or SD clinic-based trials and evaluated the common pathophysiologic mechanisms related to both conditions. In a further step, the overall impact of current BPH/LUTS therapies on sexual life, including phytotherapies, novel drugs, and surgical procedures, was scrutinized. Finally, the usefulness of PDE5-Is in LUTS/BPH was critically analysed, including preclinical and clinical research data as well as possible mechanisms of action that may contribute to the efficacy of PDE5-Is with LUTS/BPH.. Community-based and clinical data demonstrate a strong and consistent association between LUTS and ED, suggesting that elderly men with LUTS should be evaluated for SD and vice versa. Pathophysiologic hypotheses regarding common basics of LUTS and SD as discussed in the literature are (1) alteration of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway, (2) enhancement of RhoA-Rho-kinase (ROCK) contractile signalling, (3) autonomic adrenergic hyperactivity, and (4) pelvic atherosclerosis. The most important sexual adverse effects of medical therapies are ejaculation disorders after the use of some α-blockers and sexual desire impairment, ED, and ejaculatory disorders after the use of α-reductase inhibitors. Minimally invasive, conventional, and innovative surgical treatments for BPH may induce both retrograde ejaculation and ED. PDE5-Is have demonstrated significant improvements in both LUTS and ED in men with BPH; combination therapy with PDE5-Is and α1-adrenergic blockers seems superior to PDE5-I monotherapy.

Topics: Adrenergic alpha-1 Receptor Antagonists; Atherosclerosis; Clinical Trials as Topic; Cyclic GMP; Drug Therapy, Combination; Humans; Lower Urinary Tract Symptoms; Male; Meta-Analysis as Topic; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Prevalence; Prostatic Hyperplasia; rho-Associated Kinases; Sexual Dysfunction, Physiological

During the last decades it turned out that the NO/cGMP signaling cascade is one of the most prominent regulators of a variety of physiological and pathophysiological processes in a broad range of mammalian tissues. Thus cGMP is a key second messenger and targeting this pathway by increasing intracellular cGMP levels is a very successful approach in pharmacology as shown for nitrates, PDE5 inhibitors and more recently for stimulators of the guanylate cyclase. Besides the beneficial effects of cGMP elevation in cardiac, vascular, pulmonary, renal or liver disorders the launch of PDE5 inhibitors for the treatment of erectile dysfunction 10 years ago, has directed a lot of attention to the NO/cGMP signaling in the lower urinary tract. Triggered by the use of PDE5 inhibitors in ED it turned out that cGMP is a common regulatory mechanism for lower urinary tract function also beyond ED. In recent years intense research and development efforts were undertaken to elucidate the role of the NO/cGMP and to fully exploit the therapeutic implications of cGMP elevation in urological disorders in ED and beyond. Therefore we have summarized the effects of cGMP elevation for treatment of erectile dysfunction in males and in females. We have also reviewed the recent pre-clinical and clinical lines of evidence for treatment options of benign prostatic hyperplasia and lower urinary tract symptoms in male patients and overactive bladder and urinary incontinence in female patients. In addition we also touch more speculative concepts using cGMP elevating drugs for the treatment of premature ejaculation, peyornies disease and stone disease.

Topics: Animals; Cyclic GMP; Erectile Dysfunction; Female; Humans; Male; Nephrolithiasis; Nitric Oxide; Penile Induration; Prostatic Hyperplasia; Sexual Dysfunction, Physiological; Signal Transduction; Urinary Bladder, Overactive; Urinary Incontinence

To review the current literature regarding the relationship between lower urinary tract symptoms (LUTS) and erectile dysfunction (ED), and the role of phosphodiesterase-5 (PDE5) inhibitors for the treatment of LUTS. Review of recently published (1990-2009) data regarding epidemiologic and pathophysiologic mechanisms are involved in LUTS-ED, focusing on PDE5 inhibitors particularly evidenced from level 1 clinical trials. Search terms included phosphodiesterase inhibitors, nitric oxide, autonomic hyperactivity, Rho-kinase, atherosclerosis, LUTS, benign prostatic hypertrophy, and ED. Results of several epidemiologic studies show a possible causal relationship between LUTS and ED. Four possible mechanisms have been proposed to explain this association. Multiple large clinical trials have shown a benefit in LUTS after PDE5-inhibitors treatment. PDE5 inhibitors show promise as a future treatment for LUTS, either in conjunction with existing therapies or as a primary treatment.

Topics: Aged; Aging; Animals; Atherosclerosis; Autonomic Nervous System; Clinical Trials as Topic; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Erectile Dysfunction; Humans; Male; Middle Aged; Nitric Oxide; Nitric Oxide Synthase; Phosphodiesterase Inhibitors; Prostate; Prostatic Hyperplasia; Prostatism; rho-Associated Kinases

Topics: Cyclic GMP; Humans; Male; Muscle Relaxation; Nitric Oxide; Nitric Oxide Donors; Phosphodiesterase Inhibitors; Prostatic Hyperplasia; Urinary Bladder Neck Obstruction

Treatment with alpha-adrenoceptor antagonists that reduce the tone of prostatic stromal and urethral smooth muscle has beneficial effects in patients with benign prostatic hyperplasia (BPH) and lower urinary tracts symptoms (LUTS) and has brought attention to regulatory mechanisms of smooth muscle contractility of the outflow region. The prostate, urethra and bladder neck are densely supplied by nitric oxide (NO)-synthase-containing nerves that cause relaxation upon activation. In various experimental models, altered function or activity of the NO/cGMP pathway of the bladder neck and urethra may be related to inappropriate or un-coordinated functions of the bladder outlet and detrusor, but causal connections between alterations in this signaling system, a dysfunctional bladder outlet, and the development of LUTS are not established for humans. The present review focuses on regulatory functions of smooth muscle contractility by the NO/cGMP-pathway in the bladder neck, urethra, and prostate. Disease-related alterations in the NO/cGMP-pathway, and putative options for pharmacological modification of this signaling pathway in the out-flow region are briefly discussed.

Topics: Cyclic GMP; Humans; Male; Muscle Contraction; Muscle, Smooth; Nitric Oxide; Prostate; Prostatic Hyperplasia; Urethra; Urinary Bladder

Metabolic syndrome (MetS) and benign prostate hyperplasia (BPH)/low urinary tract symptoms (LUTS) are often comorbid. Chronic inflammation is one of the putative links between these diseases. Phosphodiesterase type 5 inhibitors (PDE5i) are recognized as an effective treatment of BPH-related LUTS. One proposed mechanism of action of PDE5 is the inhibition of intraprostatic inflammation. In this study we investigate whether PDE5i could blunt inflammation in the human prostate.. Evaluation of the effect of tadalafil and vardenafil on secretion of interleukin 8 (IL-8, a surrogate marker of prostate inflammation) by human myofibroblast prostatic cells (hBPH) exposed to different inflammatory stimuli. We preliminary evaluate histological features of prostatic inflammatory infiltrates in BPH patients enrolled in a randomized, double bind, placebo controlled study aimed at investigating the efficacy of vardenafil (10 mg/day, for 12 weeks) on BPH/LUTS.. In vitro treatment with tadalafil or vardenafil on hBPH reduced IL-8 secretion induced by either TNFα or metabolic factors, including oxidized low-density lipoprotein, oxLDL, to the same extent as a PDE5-insensitive PKG agonist Sp-8-Br-PET-cGMP. These effects were reverted by the PKG inhibitor KT5823, suggesting a cGMP/PKG-dependency. Treatment with tadalafil or vardenafil significantly suppressed oxLDL receptor (LOX-1) expression. Histological evaluation of anti-CD45 staining (CD45 score) in prostatectomy specimens of BPH patients showed a positive association with MetS severity. Reduced HDL-cholesterol and elevated triglycerides were the only MetS factors significantly associated with CD45 score. In the MetS cohort there was a significant lower CD45 score in the vardenafil-arm versus the placebo-one.

Topics: Aged; Aged, 80 and over; Carbolines; Cyclic GMP; Double-Blind Method; Humans; Imidazoles; Inflammation; Interleukin-8; Lower Urinary Tract Symptoms; Male; Middle Aged; Myofibroblasts; Phosphodiesterase 5 Inhibitors; Pilot Projects; Piperazines; Prostate; Prostatic Hyperplasia; Sulfones; Tadalafil; Treatment Outcome; Triazines; Vardenafil Dihydrochloride

To investigate whether 7-[2-[4-(2-chlorophenyl) piperazinyl] ethyl]-1,3-di-methylxanthine (KMUP-1) inhibits the effects of testosterone on the development of benign prostatic hyperplasia and sensitizes prostate contraction.. A benign prostatic hyperplasia animal model was established by subcutaneous injections of testosterone (3 mg/kg/day, s.c.) for 4 weeks in adult male Sprague-Dawley rats. Animals were divided into six groups: control, testosterone, testosterone with KMUP-1 (2.5, 5 mg/kg/day), sildenafil (5 mg/kg/day) or doxazosin (5 mg/kg/day). After 4 weeks, the animals were killed, and prostate tissues were prepared for isometric tension measurement and western blotting analysis. KMUP-1, Y27632, zaprinast, doxazosin or tamsulosin were used at various concentrations to determine the contractility sensitized by phenylephrine (10 μmol/L).. KMUP-1 inhibited testosterone-induced phosphorylation of extracellular signal-regulated phosphorylated protein kinase and mitogen-activated protein kinase kinase and Rho kinase-II activation. Sildenafil and doxazosin significantly decreased benign prostatic hyperplasia-induced mitogen-activated protein kinase kinase and Rho kinase-II activation. The decreased expressions of soluble guanylate cyclase α1 was reversed by KMUP-1, doxazosin and sildenafil. Soluble guanylate cyclase β1 and protein kinase G were increased by KMUP-1, doxazosin, and sildenafil in the testosterone-treated benign prostatic hyperplasia group. Phosphodiesterase-5A was increased by testosterone and inhibited by KMUP-1 (5 mg/kg/day) or sildenafil (5 mg/kg/day). KMUP-1 inhibited phenylephrine-sensitized prostate contraction of rats treated with testosterone.. Mitogen-activated protein kinase 1/extracellular regulated protein kinases kinase, soluble guanylate cyclase/cyclic guanosine monophosphate, protein kinase/protein kinase G and Rho kinase-II are related to prostate smooth muscle tone and proliferation induced by testosterone. KMUP-1 inhibits testosterone-induced prostate hyper-contractility and mitogen-activated protein kinase 1/extracellular regulated protein kinases kinase-phosphorylation, and it inactivates Rho kinase-II by cyclic guanosine monophosphate, protein kinase and α1A-adenergic blockade. Thus, KMUP-1 might be a beneficial pharmacotherapy for benign prostatic hyperplasia.

Topics: Animals; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Disease Models, Animal; Guanylate Cyclase; Male; MAP Kinase Signaling System; Piperidines; Prostatic Hyperplasia; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; rho-Associated Kinases; Soluble Guanylyl Cyclase; Xanthines

Topics: Animals; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Guanylate Cyclase; Male; MAP Kinase Signaling System; Piperidines; Prostatic Hyperplasia; Receptors, Cytoplasmic and Nuclear; rho-Associated Kinases; Soluble Guanylyl Cyclase; Xanthines

Doxazosin (Doxa) is an α1-selective adrenergic receptor (ADR) antagonist widely used, alone or in combination, to treat high blood pressure, benign prostatic hyperplasia symptoms, and recently has been suggested as a potential drug for prostate cancer prevention/treatment. This study was designed to evaluate the effect of in vivo Doxa po-application, in clinically relevant dose, on: (i) steroidogenic machinery homeostasis; (ii) cAMP/cGMP signalling; (iii) transcription profile of ADR in Leydig cells of adult rats. The results showed that po-application of Doxa for once (1×Doxa), or for two (2×Doxa) or 10 (10×Doxa) consecutive days significantly disturbed steroidogenic machinery homeostasis in Leydig cells. Doxa po-application significantly decreased circulating luteinizing hormone and androgens levels. The level of androgens in testicular interstitial fluid and that extracted from testes obtained from 1×Doxa/2×Doxa rats decreased, although it remained unchanged in 10×Doxa rats. Similarly, the ex vivo basal androgen production followed in testes isolated from 1×Doxa/2×Doxa rats decreased, while remained unchanged in 10×Doxa rats. Differently, ex vivo testosterone production and steroidogenic capacity of Leydig cells isolated from 1×Doxa/2×Doxa rats was stimulated, while 10×Doxa had opposite effect. In the same cells, cAMP content/release showed similar stimulatory effect, but back to control level in Leydig cells of 10×Doxa. 1×Doxa/2×Doxa decreased transcripts for cAMP specific phosphodiesterases Pde7b/Pde8b, whereas 10×Doxa increased Pde4d. All types of treatment reduced the expression of genes encoding protein kinase A (PRKA) regulatory subunit (Prkar2b), whereas only 10×Doxa stimulated catalytic subunit (Prkaca). Doxa application more affected cGMP signalling: stimulated transcription of constitutive nitric oxide synthases (Nos1, Nos3) in time-dependent manner, whereas reduced inducible Nos2. 10×Doxa increased guanylyl cyclase 1 transcript and PRKG1 protein in Leydig cells. Orally applied Doxa significantly disturbed the transcriptional 'signature' of steroidogenic machinery, cAMP/cGMP signalling and ADRs and β-ADRs kinases in Leydig cells, thus giving new molecular insights into the role of cAMP/cGMP/adrenalin signalling in Leydig cells homeostasis.

Topics: Adrenergic alpha-1 Receptor Antagonists; Androgens; Animals; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; Cyclic GMP; Doxazosin; Guanylate Cyclase; Homeostasis; Hypertension; Leydig Cells; Luteinizing Hormone; Male; Organ Culture Techniques; Prostatic Hyperplasia; Prostatic Neoplasms; Rats; Receptors, Adrenergic; Receptors, Adrenergic, alpha-1; Signal Transduction; Steroids; Testosterone; Transcription, Genetic

Benign prostatic hyperplasia (BPH) is characterized by tissue overgrowth and stromal reorganization primarily due to cellular proliferation and fibroblast-to-myofibroblast trans-differentiation. To evaluate the potential of phosphodiesterase type 5 (PDE5) inhibitors like tadalafil for prevention and treatment of BPH, we analyzed the role of the nitric oxide/cyclic GMP (cGMP)/PDE5 pathway for cellular proliferation and TGFbeta1-induced fibroblast-to-myofibroblast trans-differentiation in primary prostate stromal cells. Inhibition by tadalafil of PDE5, which is mainly expressed in the stromal compartment of the prostate, reduced proliferation of primary prostate stromal cells and to a lesser extent of primary prostate basal epithelial cells. Attenuated proliferation due to elevated intracellular cGMP levels was confirmed by inhibition of the cGMP-dependent protein kinase G by its inhibitor KT2358. Moreover, tadalafil strongly attenuated TGFbeta1-induced fibroblast-to-myofibroblast trans-differentiation. The inhibitory effect on trans-differentiation was also observed after small interfering RNA-mediated PDE5 knockdown. As confirmed by the MAPK kinase 1 inhibitor PD98059, this effect was mediated via MAPK kinase 1 signaling. We conclude that BPH patients might benefit from adjuvant therapies with PDE5 inhibitors that inhibit stromal enlargement due to cell proliferation, as well as TGFbeta1-induced trans-differentiation processes.

Topics: Carbolines; Cell Proliferation; Cell Transdifferentiation; Cells, Cultured; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Down-Regulation; Drug Evaluation, Preclinical; Gene Expression Regulation, Enzymologic; Gene Knockdown Techniques; Humans; Male; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Prostate; Prostatic Hyperplasia; RNA, Small Interfering; Stromal Cells; Tadalafil; Treatment Outcome

Topics: Actins; Adrenergic alpha-Antagonists; Aged; Animals; Blotting, Western; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Doxazosin; Humans; Immunohistochemistry; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Purines; Sildenafil Citrate; Sulfones

Topics: Cyclic AMP; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Endothelin-1; Humans; Isometric Contraction; Male; Muscle Tonus; Muscle, Smooth; Nitric Oxide Donors; Organ Culture Techniques; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Prostate; Prostatic Hyperplasia

This study investigates the effect of protein kinase G (PKG) activation upon proliferation of human cultured prostatic stromal cells. The PKG II activator (8-pCPT-cGMP; IC50 of 113+/-42 nM) and the phosphodiesterase inhibitor, zaprinast (up to 50 microM), but not the PKG I isoform activators (APT-cGMP and PET-cGMP), reduced foetal calf serum-stimulated proliferation. The effect of 8-pCPT-cGMP (30 microM) was blocked by Rp-8-Br-cGMPS (5 microM) and Rp-8-pCPT-cGMP (5 microM), but not Rp-cAMPS (5 microM). 8-pCPT-cGMP (30 microM) and zaprinast (50 microM), but not PET-cGMP (30 microM), caused a significant increase in atypical nuclei and an increase in annexin-V staining. These data indicate that activation of PKG II induces apoptosis of human cultured prostatic stromal cells.

Topics: Aged; Apoptosis; Azides; Cell Division; Cell Nucleus; Cells, Cultured; Cyclic AMP; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Enzyme Inhibitors; Humans; Isoenzymes; Male; Phosphoric Diester Hydrolases; Prostate; Prostatic Hyperplasia; Purinones; Serum; Stromal Cells; Thionucleotides

The endogenous substance lysophosphatidic acid (LPA) has been found to generate proliferation of cultured smooth muscle cells (SMC). Therefore, the effect of LPA on human benign prostate hyperplasia (BPH) could be of interest.. The proliferative effect of LPA on cultured human prostatic SMC from specimens obtained at trans-urethral resection of the prostate (TURP) because of BPH, was analyzed by [3H]-thymidine and [35S]-methionine incorporation. In addition, LPA stimulated BPH SMC were treated with papaverin, forskolin, sildenafil or zaprinast, well known to increase the intracellular level of cAMP or cGMP.. LPA produced a dose-dependent increase in BPH SMC, both regarding DNA- and protein-synthesis with EC50 values of 3 and 10 microM, respectively. Furthermore, both papaverin, a general phosphodiesterase inhibitor regarding cAMP hydrolyzes, and forskolin, an adenylyl cyclase stimulating agent, inhibited the LPA-stimulated DNA replication in a dose dependent manner with IC50 = 2.5, and 0.35 microM, respectively. cGMP increasing agents, such as the NO-donors SIN-1 and SNAP, produced a weak anti-proliferative response. However, both phosphodiesterase 5 inhibitors sildenafil (Viagra) and zaprinast efficiently blocked DNA replication. In addition, when the protein synthesis was examined, we found that the LPA response was significantly inhibited by forskolin and papaverin.. The major conclusion of this investigation is that the endogenous serum component LPA, is able to promote human BPH SMC growth. In addition, our study indicates that cyclic nucleotides can inhibit this effect. Future clinical studies will be needed to determine if different specific phosphodiesterase inhibitors per se or in combination could represent a new therapeutic possibility for the treatment of BPH.

Topics: Cell Division; Cells, Cultured; Colforsin; Cyclic AMP; Cyclic GMP; DNA; Dose-Response Relationship, Drug; Growth Inhibitors; Humans; Lysophospholipids; Male; Muscle, Smooth; Papaverine; Phosphodiesterase Inhibitors; Piperazines; Prostatic Hyperplasia; Protein Biosynthesis; Proteins; Purines; Purinones; Sildenafil Citrate; Stimulation, Chemical; Sulfones

Melatonin, the hormone secreted nocturnally by the pineal gland, binds to epithelial cells from the human benign prostate, and can reduce their growth and viability. The possible involvement of GTP binding proteins cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in melatonin responses in these cells were investigated.. The effects of melatonin on cAMP and cGMP were assessed in prostate cells untreated or pretreated with pertussis toxin (PTX) or cholera toxin (CTX).. Melatonin augmented cAMP but reduced cGMP in the epithelial cells (maximal responses at 10 nM). The increase in cAMP was attenuated by PTX, but not by CTX, whereas the decrease in cGMP was attenuated by CTX, but not by PTX. CTX, but not PTX, abolished the melatonin-mediated suppression of 3H-thymidine incorporation. In addition, melatonin facilitated the CTX- and PTX-mediated ADP ribosylation of 44- and 41-kilodalton proteins, respectively. The cGMP analogue 8-bromo-cGMP, negated the melatonin-mediated decrease in 3H-thymidine incorporation, whereas H89, a protein kinase A inhibitor, did not inhibit melatonin's effect.. Melatonin receptors in the human benign prostate epithelial cells enhance cAMP and inhibit cGMP through PTX- and CTX-sensitive G proteins, respectively. The decrease in DNA synthesis may be secondary to the melatonin-mediated decrease in cGMP.

Topics: Adenosine Diphosphate Ribose; Aged; Aged, 80 and over; Cells, Cultured; Cholera Toxin; Cyclic AMP; Cyclic GMP; DNA; Epithelial Cells; GTP-Binding Proteins; Humans; Male; Melatonin; Middle Aged; Pertussis Toxin; Prostate; Prostatic Hyperplasia; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear; Receptors, Melatonin; Signal Transduction; Virulence Factors, Bordetella