Expression of Phosphodiesterase (PDE) Isoenzymes in the Human Male and Female Urethra.

Purpose: Although it has been supposed that the NO/cyclic GMP system produces inhibitory signals to reduce the resistance of the bladder outlet and urethra during the micturition phase, little is known on the mechanisms controlling the function of urethral smooth muscle. The aim of the present study was to examine in the male and female urethra the expression of phosphodiesterase (PDE) isoenzymes, known as key proteins of the cyclic GMP/AMP signaling.

Methods: Urethral tissue was obtained from 4 female cadavers and 7 male patients (who had undergone gender reassignment surgery).

The Use of Vasoactive Drugs in the Treatment of Male Erectile Dysfunction: Current Concepts.

It is widely accepted that disorders of the male (uro)genital tract, such as erectile dysfunction (ED) and benign diseases of the prostate (lower urinary tract symptomatology or benign prostatic hyperplasia), can be approached therapeutically by influencing the function of both the vascular and non-vascular smooth muscle of the penile erectile tissue or the transition zone/periurethral region of the prostate, respectively. As a result of the discovery of nitric oxide (NO) and cyclic guanosine monophosphate (GMP) as central mediators of penile smooth muscle relaxation, the use of drugs known to increase the local production of NO and/or elevate the intracellular level of the second messenger cyclic GMP have attracted broad attention in the treatment of ED of various etiologies. Specifically, the introduction of vasoactive drugs, including orally active inhibitors of the cyclic GMP-specific phosphodiesterase (PDE) 5, has offered great advantage in the pharmacotherapy of ED and other diseases of the genitourinary tract.

Emerging drugs to target lower urinary tract symptomatology (LUTS)/benign prostatic hyperplasia (BPH): focus on the prostate.

Objectives: The benign prostatic syndrome, comprising lower urinary tract symptomatology secondary to benign prostatic hyperplasia/enlargement, represents a major health care issue in westernized countries. The pharmacological management involves alpha-adrenoceptor antagonists, intervention into the hormonal control of prostate growth using inhibitors of the enzyme 5-alpha-reductase, and stimulation of the nitric oxide/cyclic GMP pathway by tadalafil, an inhibitor of the phosphodiesterase type 5.

Methods: This review summarizes the achievements which have been made in the development of drug candidates assumed to offer opportunities as beneficial treatment options in the management of the benign prostatic syndrome.

Arginase enzymes in the human prostate: A molecular biological and immunohistochemical approach.

The nitric oxide (NO) pathway plays a role in maintaining the function of the prostate. An impairment in the activity of the NO system may have an impact in the manifestation of lower urinary tract symptomatology and benign prostatic hyperplasia. Arginase enzymes (Arg) counteract the generation of NO by depleting the intracellular pool of L-arginine, known to be the substrate of the NO synthases.

Expression and distribution of phosphodiesterase isoenzymes in the human male urethra.

Objective: To investigate the expression and distribution of phosphodiesterase (PDE) isoenzymes PDE1A, PDE2A, PDE4A, PDE4B, and PDE5A in human urethral tissue.

Methods: Specimens of penile urethra were obtained from male subjects who had undergone male-to-female sex reassignment surgery. Using immunohistochemistry (immunofluorescence), the occurrence of PDE1A, PDE2A, PDE4A, PDE4B, and PDE5A, the neuronal nitric oxide synthase, calcitonin gene-related peptide, and vasoactive intestinal polypeptide was examined in urethral sections.

Phosphodiesterase isoenzymes in the human urethra: a molecular biology and functional study.

Experimental and clinical studies have suggested a role for phosphodiesterase (PDE) isoenzymes in the control of the human lower urinary tract. This study aimed to investigate the expression of PDE isoenzymes and the effects of PDE inhibitors (PDE-Is) in isolated human urethral smooth muscle (USM). The expression of messenger ribonucleic acid (mRNA) specifically encoding for PDE isoenzymes and isoforms (1A, 1B, 1C, 2A, 4A, 4B, 4C, 4D, 5A and 11A) was analyzed by means of reverse transcriptase polymerase chain reaction (RT-PCR).

Pharmacologic characterization of human male urethral smooth muscle: an in vitro approach.

Objective: To elucidate the functional responses of isolated human urethral smooth muscle to various agents known to exert smooth muscle contraction or relaxation.

Methods: Specimens of penile urethra were obtained from male patients who had undergone male-to-female gender reassignment surgery. Using the tissue bath technique, the contraction induced by increasing concentrations (1 nM-10 μM) of norepinephrine, phenylephrine, acetylcholine, carbachol, prostaglandin F2α, endothelin 1, angiotensin II, and oxytocin was measured.

Avanafil for the treatment of erectile dysfunction: initial data and clinical key properties.

Orally active, selective inhibitors of phosphodiesterase type 5 (PDE 5, cyclic GMP PDE), such as sildenafil, tadalafil and vardenafil, are currently the first-choice treatment options for the clinical management of erectile dysfunction (ED) of various etiologies and severities. However, a significant number of patients remain dissatisfied with the available therapies due a lack of efficacy or discomfort arising from adverse events. Several new PDE5 inhibitors, among which are avanafil (TA-1790), lodenafil, mirodenafil, udenafil, SLX-2101, JNJ-10280205 and JNJ-10287069, have recently been approved and introduced into the market or are in the final stages of their clinical development.

Arginase enzymes in the human prostate: expression of arginase isoenzymes and effects of arginase inhibitors on isolated human prostate tissue.

Unlabelled: What's known on the subject? and What does the study add? A previous study by Lexander et al. in 2005, using two-dimensional gel electrophoresis, demonstrated the expression of arginase type II in the different anatomical regions of the prostate; however, to date, no study has addressed, using an in vitro approach, the role of arginase isoenzymes in the human prostate. The results of the present study demonstrate that: both arginase isoenzymes, Arg I and Arg II, are expressed in the transition zone of the human prostate; the inhibition of arginase antagonized, to a certain degree, the tension brought about by noradrenaline in isolated human prostate tissue; exposure of human prostate tissue to arginase inhibitors enhanced the local production of cyclic GMP; and inhibition of arginase enzymes in the human prostate may augment the activity of the nitric oxide/cyclicGMP pathway.

Evaluating the significance of cyclic adenosine monophosphate-mediated signaling in human prostate: a functional and biochemical study.

Objective: To investigate further the potential significance of the cyclic adenosine monophosphate (cAMP) pathway in the control of prostate smooth muscle. The cAMP pathway has been assumed to be an alternative pharmacologic target to treat dysfunctions of the human lower urinary tract. To date, only a few studies have addressed the physiologic relevance of cAMP signal transduction in the control of human prostate function.

Exposure of human seminal vesicle tissue to phosphodiesterase (PDE) inhibitors antagonizes the contraction induced by norepinephrine and increases production of cyclic nucleotides.

Objectives: To investigate further the role of phosphodiesterase (PDE) isoenzymes in the control of human seminal vesicle (SV) smooth muscle contractility, we examined the functional responses of isolated SV tissue to various PDE inhibitors. It has been suggested that the application of inhibitors of the PDE type 5 may facilitate SV smooth muscle relaxation and, subsequently, retard ejaculatory response.

Methods: Using the organ bath technique, strip preparations of human SV were exposed for 5 minutes to 1 μM of the PDE inhibitors milrinone (PDE3 inhibitor), rolipram, Ro 20-1724 (PDE4 inhibitors), and sildenafil (PDE5 inhibitor).

Characterization of the effects of various drugs likely to affect smooth muscle tension on isolated human seminal vesicle tissue.

Objectives: To investigate the effects of different classes of drugs on the isometric tension of isolated human seminal vesicle (SV) tissue. The contractility of human SV contributes to the process of seminal emission during ejaculation. Different endogenous compounds, such as serotonin (5-HT), adenosine triphosphate (ATP), and nitric oxide, have been suggested to be involved in the control of contraction and relaxation of human SV smooth muscle.

Evaluating the role of the serotoninergic system in the control of human seminal vesicle smooth muscle-an in vitro approach.

Introduction: It has been suggested that serotonin re-uptake inhibitors (SRIs) may retard the ejaculatory response by acting directly on the seminal vesicle (SV) and ductus deferens smooth muscle. However, until now, only a very few experimental studies have investigated such potential local (peripheral) effects.

Aim: To elucidate the effects of serotonin (5-HT) and the SRIs clomipramine, fluoxetine and imipramine on the tension induced by norepinephrine (NE) of isolated human SV smooth muscle, as well as on the production of tissue cyclic AMP and cyclic GMP.

Effects of phosphodiesterase inhibitors on contraction induced by endothelin-1 of isolated human prostatic tissue.

Objectives: To study the effects of selective phosphodiesterase (PDE) inhibitors on the contraction induced by endothelin-1 (ET-1) of isolated human prostatic tissue.

Methods: Using the organ bath technique, the effects of the cumulative addition of the PDE1 inhibitor vinpocetine, PDE2 inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA), PDE4 inhibitor rolipram, and PDE5 inhibitors sildenafil, vardenafil, and tadalafil (1 nM to 10 microM) were investigated on the contraction brought about by the peptide ET-1 (1 microM) on normal human prostatic tissue isolated from the transition zone. In the present study, the nitric oxide donor drug sodium nitroprusside and adenylyl cyclase activator forskolin were used as reference compounds.

The nitric oxide pathway in the human prostate: clinical implications in men with lower urinary tract symptoms.

To date, there is an increasing interest in the nitric oxide (NO) pathway as a potential pharmacological target to treat male lower urinary tract symptomatology (LUTS). In the transition zone of the human prostate, a dense nitrinergic innervation has been shown of the fibromuscular stroma, glandular epithelium and blood vessels. The expression of key proteins of the NO pathway, such as the endothelial and neuronal nitric oxide synthase (eNOS, nNOS), cGMP-degrading phosphodiesterase type 5 (PDE5) and cGMP-binding protein kinase (cGK), has also been demonstrated.