STIMULATION OF THE CYCLIC AMP/GMP SIGNALLING ENHANCES THE RELAXATION OF ISOLATED HUMAN DETRUSOR SMOOTH MUSCLE ACHIEVED BY PHOSPHODIESTERASE INHIBITORS.

Phosphodiesterase (PDE) enzymes are considered being key proteins in controlling the function of smooth musculature in the human urinary tract. The use of PDE inhibitors (PDE-Is) to treat erectile dysfunction and lower urinary tract symptomatology (LUTS) secondary to benign prostatic hyperplasia (BPH) is well established. It has been shown that PDE-Is can reverse the tension induced by means of muscarinergic agents of detrusor smooth muscle and enhance the production of cyclic nucleotides. In clinical settings, the PDE1 inhibitor vinpocetine had beneficial effects in patients presenting with voiding dysfunctions. This prompted us to evaluate further the mechanism of action of PDE-Is on bladder smooth musculature. Using the tissue bath technique, relaxant responses of human detrusor smooth muscle, challenged by acetylcholine (1 µM), to vinpocetine (PDE1-I), rolipram (PDE4-I), MY 5445 and sildenafil (PDE5-Is) (0.1 µM, 1 µM, and 10 µM) were investigated with and without pre-exposure of the tissue to threshold concentrations of the NO donor drug sodium nitroprusside (SNP) or adenylyl cyclase activator forskolin (0.02 µM). The non-specific PDE-I papaverine was used as a reference compound. The cumulative addition of forskolin or SNP exerted a pronounced reversion of the tension induced by means of ACh, starting at a concentration of 1 µM (forskolin, -25,6%) and 0.1 µM (SNP, -20%), respectively. There were marginal responses of the detrusor smooth musculature to the PDE-Is, the relaxation measured ranged from -12% (vinpocetine/sildenafil) to -19% (rolipram, MY 5445). Exposure of the tissue to a threshold concentration of SNP increased the reversion of tension induced by vinpocetine (-40%), rolipram (-50%) and MY 5445 (-45%). An enhancement in the potency of the drugs was also registered. A threshold concentration of SNP did not significantly affect the maximum reversion of tension brought about by sildenafil but added positively to the in vitro potency of the PDE5-I. PDE inhibitors may tend to be more effective in systems characterized by an enhanced production of cyclic AMP/GMP (such as urogenital tissues in vivo). Our findings may explain how PDE inhibitors can affect symptoms of the overactive bladder.

Endopeptidase inhibition attenuates the contraction induced by big endothelin-1 of isolated human penile erectile tissue.

Peptides, such as C-type natriuretic peptide (CNP), vasoactive intestinal polypeptide (VIP) and endothelin 1 (ET-1), are involved in the control of penile erectile tissue (corpus cavernosum = CC). Inhibiting the degradation of CNP and VIP or conversion of Big ET-1 into ET-1 by endopeptidase enzymes should result in an enhancement of CC smooth muscle relaxation. Using the tissue bath technique, responses of isolated CC, challenged by noradrenaline (NA, 1 µm), to increasing concentrations of the endopeptidase inhibitor KC 12615 (1 nm - 10 µm), CNP and VIP (0.1 nm - 1 µm), were investigated. Effects of CNP, VIP and Big ET-1 (0.1 nm - 100 nm) on the tissue tension were also evaluated following pre-exposure to 10 µm of KC 12615. Big ET-1 induced contraction of the CC amounting to a force generation of 1,200 mg. The contraction was attenuated in the presence of KC 12615 by 35% and 50%, respectively. The tension induced by NA was reversed by VIP and CNP to 38.7% ± 15.8% and 61% ± 13%, respectively, of the initial force. The findings might be of significance with regard to future pharmacological treatment options for male ED, where an endothelial dysfunction exists.

Expression and distribution of key proteins of the endocannabinoid system in the human seminal vesicles.

The endocannabinoid system (ECS), comprising the cannabinoid receptors (CBR), their ligands, and enzymes controlling the turnover of endocannabinoids, has been suggested to be involved in male reproductive function. As information is scarce on the expression of the ECS in human male reproductive tissues, this study aimed to investigate by means of molecular biology (RT-PCR) and immunohistochemistry/immunofluorescence the expression and distribution of CB1 and CB2, GPR55 (an orphan G protein-coupled receptor that recognises cannabinoid ligands) and FAAH (isoforms 1 and 2) in the human seminal vesicles (SV). The specimens expressed PCR products corresponding to CB1 (66 bp), CB2 (141 bp), GPR55 (112 bp), FAAH1 (260 bp) and FAAH2 (387 bp). Immumohistochemistry revealed dense expression of CB1, CB2 and GPR55 located to the pseudo-stratified columnar epithelium and varicose nerves (also characterised by the expression of vasoactive intestinal polypeptide and calcitonin gene-related peptide). Cytosolic staining for FAAH1 and FAAH2 was seen in cuboidal cells of all layers of the epithelium. No immunoreactivity was detected in the smooth musculature or nerve fibres. CB1, CB2, GPR55, FAAH1 and FAAH2 are highly expressed in the human SV. Considering their localisation, the ECS may be involved in epithelial homeostasis, secretory function or autonomic mechano-afferent signalling.

Expression and distribution of the transient receptor potential cationic channel A1 (TRPA1) in the human clitoris-comparison to male penile erectile tissue.

The transient receptor potential cationic channel ankyrin 1 (TRPA1) is a channel protein assumed to act in various human tissues as mechano- and pain sensor and play a role in neurotransmission. The expression of TRPA has already been investigated in the human prostate and urethra, however, only very few studies have addressed the expression and distribution in the male and female genital tract. The present study aimed to investigate by means of immunohistochemistry (double-labeling technique, laser fluorescence microscopy) in the human clitoris and penile erectile tissue the localization of TRPA1 in relation to nNOS, the vasoactive intestinal polypeptide (VIP) and vesicular acetylcholine transporter (VAChT). In the clitoral tissue, TRPA1 was observed in basal epithelial cells and slender nNOS-positive nerve fibers transversing the subepithelial space. To a certain degree, in the clitoral epithelial cells, TRPA1 was found co-localized with vimentin. In human corpus cavernosum, immunoreactivity for TRPA1 was seen in nerves transversing the cavernous sinusoidal space and running alongside small arteries, these nerves also displayed expression of the vesicular acetylcholine transporter protein (VAChT). Varicose nerves containing nNOS or VIP were not immunoreactive for TRPA1. It seems likely that TRPA1 is involved in nitric oxide-mediated afferent sensory transmission in the clitoris while, in penile erectile tissue, a role for TRPA1 in cholinergic signaling might be assumed.

Protein kinase enzymes in the human vagina-relation to key mediators of the cyclic AMP and cyclic GMP pathways.

Aside from phosphodiesterase (PDE) isoenzymes, protein kinases (cAK=cyclic AMP-binding protein kinase, cGK=cyclic GMP-binding protein kinase) have also been identified as important receptors for cyclic nucleotides. A significance of protein kinases in the control of the function of the male and female reproductive tract has been suggested; however, up until today, only a few approaches have addressed these enzymes in female genital tissues. The present study aimed to investigate by means of biochemical and immunohistochemical methods the expression of cAK and cGK. The distribution of cAK(I) and cGK(I) in relation to the vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP) and PDE type 4 (PDE4) was also evaluated. Cytosolic supernatants prepared from specimens of vaginal wall smooth muscle or epithelium were subjected to anion exchange chromatography and the activities of cAK and cGK(I) measured. To evaluate the distribution of cAK(I) and cGK(I) in relation to VIP, CGRP and PDE4, immunohistochemistry was conducted in sections of the human vaginal wall (full-wall specimens). Activities representing cGK(I) and cAK(I) were resolved from the chromatography column. Staining specific for cAK(Iα) was identified in both vascular and non-vascular vaginal smooth musculature, immunoreactivity for cGK(Iß) was observed in the smooth muscle and endothelium of small arteries interspersing the sections. cAK(Iα)-positive vessels were found innervated by slender varicose nerve fibers presenting the expression of VIP and CGRP. These arteries also expressed PDE4. Localization of cAK and cGK in close relation to key mediators of the cyclic AMP (PDE4, VIP) and cyclic GMP (CGRP) pathways indicate that both signaling systems may synergistically work together in human vaginal tissue.

Effects of endopeptidase inhibition on the relaxation response of isolated human penile erectile tissue to vasoactive peptides.

Peptides, such as CNP, CGRP and VIP, are involved in the function of male penile erectile tissue. Tissue levels of said peptides are controlled by the endopeptidase enzymes. Theoretically, the inhibition of the degradation of CNP, CGRP and/or VIP should result in an enhancement in penile smooth muscle relaxation. The effects were investigated of CNP or VIP (0.1 nm-1 µm), without and following pre-exposure of the tissue to a threshold concentration of the endopeptidase inhibitor KC 12615 (10 µm, for 20 min), on the reversion of tension induced by means of electrical field stimulation. Drug effects on the production of cyclic AMP/GMP were also evaluated. Neither KC 12615, CNP and VIP nor the combination of CNP plus KC 12615 or VIP plus KC 12615 increased the response of the tissue to EFS. While no effects were observed of a pre-exposure of the tissue to KC 12615 on the production of cyclic AMP in the presence of VIP, an enhancement was registered in the accumulation of cyclic AMP in the presence of CNP plus KC 12615. Further studies are indicated to investigate whether endopeptidase inhibitors might tend to be more effective in tissues affected by a decreased local production of vasoactive peptides.

Expression and distribution of the transient receptor potential cationic channel ankyrin 1 (TRPA1) in the human vagina.

The transient receptor potential cationic channel type A1 (TRPA1), belonging to a superfamily of cationic membrane channels, has been suggested to act as mechano- and pain sensor and, thus, to play a role in neurotransmission in the human body, including the urogenital tract. While the expression of TRPA1 has been investigated in a variety of tissues, up until today, no study has addressed the expression and distribution in the female genital tract. The present study aimed to investigate the expression and distribution of TRPA1 protein in human vaginal tissue. Reverse transcriptase PCR (RT-PCR) was applied in order to identify messenger ribonuleic acid specifically encoding for TRPA/A1. The distribution of TRPA1 in relation to the neuronal nitric oxide synthase (nNOS) and the signaling peptide calcitonin gene-related peptide (CGRP) was examined by means of immunohistochemical methods (double-antibody technique, laser fluorescence microscopy). RT-PCR analysis revealed the expression of mRNA encoding sequences specific for TRPA in the vaginal wall and epithelium. Immunostaining related to TRPA1 was observed in the basal epithelium and in slender varicose nerve fibers transversing the subepithelial and stromal space of the vaginal sections. In addition, these fibers presented immunoreactivity specific for nNOS or CGRP. The smooth musculature of the vaginal wall and small vessels interspersing the tissue did not present signals related to TRPA1. The findings indicate that TRPA1 might be involved in afferent neurotransmission in the vagina and work synergistically together with the nitric oxide/cyclic guanosine monophosphate pathway.

[Induratio penis plastica and the capability of vaginal penetration in the context of forensic evaluation]. / Induratio Penis Plastica und Vaginale Penetrationsfähigkeit im Kontext der Forensischen Begutachtung.

The so-called Induratio penis plastica (IPP), also known as Peyronie Disease or Morbus Peyronie, is the most common cause for deviation of the male penis. In most cases, the deviation is directed to the dorsal side. In face of a lawsuit related to a sexual offence, the opponent might argue that, due to an existing IPP, he is generally unable to insert his penis into a female's vagina. The aim of the present study was to examine the clinical files of thirty (30) consecutive patients who presented with IPP. Particular attention was given to the individual degree of penile deviation and the ability of the subjects to conduct vaginal intercourse. Subjects who had a dorsal penile deviation of 800 to 900, or a lateral deviation of 600, were unable to commence vaginal coitus. In contrast, three (3) subjects who presented with a ventral deviation of 30° to 40° had no difficulties in performing vaginal penetration. The medicolegal aspects of these findings are being discussed.

[Rehabilitation of erectile function after nerve-sparing radical prostatectomy: therapeutic concepts in Germany]. / Rehabilitation der erektilen Funktion nach nervenschonender radikaler Prostatektomie : Therapiekonzepte in Deutschland.

OBJECTIVE: Despite objective published data regarding rehabilitation of erectile function (EF) after nerve-sparing radical prostatectomy (nsRP) the gold-standard treatment is still under debate. The aim of this study was to evaluate the distribution of the different treatment options in Germany. PATIENTS AND METHODS: Between October 2010 and May 2012 a questionnaire was sent to urologists in outpatient, general and university hospitals and rehabilitation hospitals in Germany. The survey consisted of various questions concerning, e.g. if and what kind of therapy urologists choose to support rehabilitation of EF after nsRP. Further questions dealt with the frequency, duration and optimal start of the chosen therapy. RESULTS: Currently 188 urologists have completed and returned the questionnaire. The distribution was urologists in hospitals n=79 and outpatient/ambulatory n=106, with 24 % performing surgical treatment and urologists in rehabilitation hospitals n=3. The question about the rehabilitation concept showed 39 different forms of treatment within this group. To increase EF after nsRP PDE5 inhibitors were mostly administered (88 %) with 45 % on request compared to 55 %on a daily or regular basis ≥ 3 times/week. The use of penile injection therapy, medicated urethral system for erection (MUSE) and vacuum constriction devices (VCD) was prescribed by 32 %, 6 % and 30 % of urologists, respectively. Only 14 % of the urologists did not choose any active kind of rehabilitation treatment for EF recovery after nsRP. CONCLUSION: Many different therapeutic concepts are currently performed in Germany to increase EF recovery after nsRP. The use of PDE5 inhibitors is the most commonly chosen treatment option. Despite published data regarding effectiveness, the optimal treatment seems to be still unknown.

Is there a significance of histamine in the control of the human male sexual response?

Although histamine has been suggested to be involved in the control of male sexual function, including the induction of penile erection, its role in the human corpus cavernosum penis is still poorly understood. The aim of our study was to evaluate the course of histamine plasma levels through different stages of sexual arousal in the systemic and cavernous blood of healthy male subjects. Thirty four (34) healthy men were exposed to erotic stimuli to elicit penile erection. Blood was aspirated from the corpus cavernosum and a cubital vein during the penile conditions flaccidity, tumescence, rigidity and detumescence. Blood was also collected in the post-ejaculatory period. Plasma levels of histamine (ng ml(-1)) were determined by means of a radioimmunoassay. Histamine slightly decreased in the cavernous blood when the penis became tumescent. During rigidity, histamine decreased further but remained unaltered in the phase of detumescence and after ejaculation. In the systemic circulation, no alterations were observed with the initiation or termination of penile erection, whereas a significant drop was registered following ejaculation. Results are not in favour of the hypothesis of an excitatory role of histamine in the control of penile erection. Nevertheless, the amine might mediate biological events during the post-ejaculatory period.

Systemic and cavernous plasma levels of neuropeptide Y during sexual arousal in healthy males.

Neuropeptide Y (NPY) has been shown to induce contraction of isolated human penile erectile tissue and potentiate the response to noradrenaline. The purpose of our study was to measure in the cavernous and systemic blood of healthy male volunteers the course of NPY through different stages of sexual arousal. Whole blood was drawn simultaneously from the corpus cavernosum and the cubital vein of 16 healthy male volunteers during penile flaccidity, tumescence, rigidity and detumescence. Tumescence and erection were induced by applying audiovisual and tactile stimulation. Plasma levels of NPY (given in pmol l(-1)) were determined by means of an enzyme-linked immunoassay. NPY significantly decreased in the cavernous blood on sexual arousal, when the flaccid penis became tumescent and, finally, rigid (F: 88.8 ± 35.8, T: 62.4 ± 22.7, R: 62.3 ± 19.7), and only slightly rose in the phase of detumescence (64.8 ± 23). In the systemic circulation, no pronounced alterations in the concentration of NPY were registered (F: 64.4 ± 27, T: 65.8 ± 19, R: 59.6 ± 25, D: 67.6 ± 29.3). Our findings are in favour of the hypothesis that NPY could contribute to the maintenance of the resting state of cavernous smooth muscle.

Expression and distribution of key enzymes of the cyclic GMP signaling in the human clitoris: relation to phosphodiesterase type 5 (PDE5).

The clitoris contributes to the normal female sexual response cycle. A significance of cyclic guanosine monophosphate (GMP) has been assumed in the control of clitoral vascular smooth muscle. As only a few investigations on the physiology of the vascular and non-vascular clitoral tissue have been carried out, knowledge on the mechanisms controlling this particular female genital organ is still vague. It has been suggested that human clitoral corpus cavernosum smooth muscle is regulated by nitric oxide (NO)/cyclic GMP and related key enzymes, such as NO synthases (NOSs) and the phosphodiesterase type 5 (PDE5). The present study evaluated in the human clitoris, by means of immunohistochemistry, the expression and distribution of key enzymes of the cyclic GMP pathway, such as the endothelial NOS, PDE2, PDE11 and cyclic GMP-dependent protein kinase type I (cGKI) in relation to the PDE5. Immunohistochemistry revealed the presence of PDE2, PDE5 and cGKI in the smooth muscle wall of blood vessels transversing the supepithelial and stromal space. Immunosignals specific for PDE2 were also identified in interstitial-like cells located in the basal epithelial layer. Staining for PDE11A was observed in single nerve trunks located in the clitoral stroma. The results are in favor of a role of the cyclic GMP signaling in the control of clitoral blood flow. It seems likely that PDE2 and PDE11 are also involved in the mechanism of local (neuro)transmission in the clitoris.

C-kit-positive multipolar cells in human penile erectile tissue: expression of connexin 43 and relation to trabecular smooth muscle cells.

The aim of this study was to evaluate the hypothesis that interstitial cells might play a role in controlling and synchronizing via gap junctions the electrical activity of smooth muscle cells. The expression and distribution of interstitial cells in human penile erectile tissue was evaluated to determine whether or not cavernous interstitial cells express the gap junction protein connexin 43. Specimens of human corpus cavernosum were excised from full preparations of human penises. Cryostat sections (10 microm to 15 microm) of formaldehyde-fixated tissue segments were incubated using a double-labelling technique with antibodies directed against smooth muscle alpha-actin, c-kit, and connexin 43. Then, sections were exposed to secondary antibodies. Visualization was commenced by means of laser fluorescence microscopy. Double-staining techniques revealed immunosignals specific for c-kit (transmembrane receptor protein) and connexin 43 (gap junction protein) in multipolar cells located adjacent to smooth muscle cells. The number of c-kit-positive cells was significantly lower within the smooth musculature than within bundles of connective tissue surrounding smooth muscle cells of corpus cavernosum or cavernous arteries. Our findings demonstrate the distribution of c-kit- and connexin 43-positive interstitial cells in the connective tissue and smooth musculature of the corpus cavernosum. Additional studies are needed in order to evaluate further the ultrastructure of human penile erectile tissue and enable the identification of gap junctions mediating direct cell-to-cell communication.

[Significance of phosphodiesterase isoenzymes in the control of human detrusor smooth muscle function. An immunohistochemical and functional study]. / Bedeutung von Phosphodiesteraseisoenzymen in der Kontrolle der humanen Detrusormuskulatur. Eine immunhistochemische und funktionelle In-vitro-Studie.

OBJECTIVES: The use of inhibitors of phosphodiesterase (PDE) isoenzymes 1 and 5 to treat overactive bladder has been suggested. To further evaluate the significance of PDE isoenzymes in detrusor smooth muscle relaxation, we investigated the effects of selective PDE inhibitors on the tension induced by carbachol of isolated human detrusor tissue. Using immunohistochemical methods, the expression of PDE1, PDE4, and PDE5 in human detrusor was also investigated. MATERIAL AND METHODS: The expression of PDE1, PDE4, and PDE5 was evaluated by means of conventional immunohistochemistry (IHC). Using the organ bath technique, the effects of the PDE inhibitors vinpocetine, rolipram, sildenafil, tadalafil, and vardenafil on the tension induced by the muscarinic agonist carbachol (1 microM) were investigated. RESULTS: The tension induced by carbachol was dose-dependently reversed by the PDE inhibitors; the maximum reversal of tension ranged from 7% (tadalafil) to 34% (vardenafil). IHC revealed that the expression of PDE isoenzymes was limited to the smooth musculature of the detrusor. While there was prominent expression of PDE4 and PDE5, immunoreactions indicating the presence of PDE1 were less abundant. CONCLUSION: Despite the fact that inhibitors of PDE1, PDE4, and PDE5 exerted only a weak relaxant response on detrusor strips precontracted by carbachol, our findings indicate that both the cAMP and cGMP pathways might be involved in the relaxation mechanism of human detrusor smooth muscle.

[In vitro effects of a novel class of nitric oxide donating compounds on isolated human urinary bladder]. / In vitro-Effekte einer neuen Klasse Stickstoffmonoxid (NO) freisetzender Substanzen auf die glatte Muskulatur des humanen Detrusors.

Nitric oxide (NO) has been identified an important neurotransmitter involved in the control of the human urinary tract. It has been suggested that NO is one of the factors keeping the bladder relaxed during the filling phase. This function might be mediated by the NO-induced elevation of intracellular cyclic GMP. Prostaglandins (PG) are known to exert contractile effects on the bladder smooth musculature, especially in pathological conditions. The aim of the present study was to examine the effects of a new class of NO donor drugs, combining both anti-phlogistic and NO-donating activity (NCX 2111 and HCT 1026), on the contraction induced by PG or electrical field stimulation (EFS) of isolated human detrusor. Effects were compared to those of sodium nitroprusside (SNP), forskolin, tolterodine, and oxybutynin. Using the organ bath technique, drug effects on the contraction induced by PG ((F2 alpha)) or EFS of isolated human detrusor smooth muscle were investigated. Detrusor strips were also exposed to increasing concentrations of the compounds (0.1 microM - 10 microM) and the accumulation of cyclic GMP and cyclic AMP was determined by means of radioimmunoassays. The tension induced by PG was dose-dependently reversed by the drugs. The rank order of efficacy was: forskolin > SNP > NCX 2111 > HCT 1026. R(max) values ranged from 57% (forskolin) to 24% (HCT 1026). Compounds also dose-dependently reduced the amplitudes of contraction induced by EFS (tolterodine > oxybutynin > NNP = forskolin > HCT 1026 > 2111). The effects of forskolin, HCT 1026, NCX 2111 and SNP were paralleled by an increase in cyclic AMP or cyclic GMP. Our results provide evidence that the NO-cGMP pathway is not of utmost significance in the control of human detrusor smooth muscle. In vitro, the combination of NO-donating with anti-phlogistic activity does not seem to be of functional advantage with regard to the facilitation of detrusor relaxation.

[Is medical therapy useful in the management of stress urinary incontinence?]. / Wie sinnvoll ist die medikamentöse Therapie der Belastungsinkontinenz?

In Germany, only duloxetine is registered for treating stress urinary incontinence in adult women; duloxetine treatment for stress urinary incontinence in children or men is poorly investigated and still off-label. Trials in women based on the evidence level 1B and meta-analyses have demonstrated that duloxetine significantly reduced the frequency of incontinence episodes and increased incontinence-related quality of life. However, duloxetine must be used on a regular base to maintain these positive effects. Therefore, duloxetine seems to be especially indicated in women who refuse or cannot be subjected to physical or surgical treatment and are willing to accept the long-term use and possible side effects of the drug. Furthermore, duloxetine could be useful in women to support pelvic floor physiotherapy or in female patients awaiting incontinence surgery.

[The basics of phosphodiesterase type 5 (PDE5) inhibition in urology]. / Grundlagen der Phosphodiesterase-5- (PDE5-)Inhibitoren.

Phosphodiesterase (PDE) isoenzymes hold a central role in controlling levels of the cyclic nucleotide monophosphates cyclic AMP and cyclic GMP, which are important second messengers in many transmitter pathways involved in regulating biological processes in urogenital tissues. The development of the PDE5 inhibitors Sildenafil (Viagra), Vardenafil (Levitra), and Tadalafil (Cialis), combining a high response rate and the advantage of on-demand intake, is the result of the scientific characterization of the physiology of penile erectile smooth muscle.The introduction of these compounds as safe and well-tolerated orally active drugs for the treatment of erectile dysfunction has not only become a worldwide clinical success, but it provided the basis for the development and introduction of several new therapeutic modalities into the management of male and female sexual dysfunction. It has also brought further attention to cyclic nucleotide phosphodiesterases as putative pharmacological targets in a variety of disorders, such as pulmonary arterial hypertension, Raynaud's disease, Peyronie's disease, the so-called benign prostatic syndrome, endothelial dysfunction, disturbances of male ejaculatory function (premature ejaculation), and female sexual dysfunction.Because the concept of taking a pill to cure an illness or relieve disease symptoms has become widely accepted by consumers, pharmacological research and development is focusing primarily on selective orally available drugs that influence peripheral intracellular or central regulatory mechanisms. This review briefly describes the current and evolving advances in the field of PDE5 pharmacotherapy in urology and other fields of medicine.

[PDE5 inhibitors. A new option in the treatment of ureteral colic?]. / PDE-5-Inhibitoren. Ein neuer Therapieansatz in der Behandlung der Harnleiterkolik?

BACKGROUND: PDE5 inhibitors represent the gold standard in the medical therapy of erectile dysfunction (ED). Promising results have been published regarding further urological indications such as treatment of ureteral colic. The aim of the present study was to evaluate the functional effects of the PDE5 inhibitors sildenafil (SIL), vardenafil (VAR), and tadalafil (TAD) on tissue tension and cyclic nucleotide levels of human ureteral smooth muscle segments in vitro. METHODS: Relaxant responses of human ureteral smooth muscle were investigated in vitro using the organ bath technique. Cyclic nucleotides cAMP and cGMP were determined by specific radioimmunoassays. RESULTS: Relaxing effects of ureteral muscle tension were observed in the rank order VAR>SIL>TAD. While only VAR significantly elevated cGMP levels 3.3-fold over control, no increase for cAMP levels was observed. CONCLUSIONS: Our data provide evidence that cGMP is involved in the control of the normal function of the smooth musculature of the human ureter. Our findings suggest the potential of using selective inhibitors of PDE isoenzymes in the treatment of ureteral colic.

Adverse effects of drug therapies on male and female sexual function.

Sexual dysfunctions (SD) are adverse effects of common drug therapies that have rarely been considered in investigations so far. Possibly it is barely known that many widespread and frequently prescribed medications and drug therapies can have significant impact on vascular and nerval processes as well as on endocrinologic and psychoneuroendocrinologic systems and therefore can influence sexual functions. Impotence and disorders of the erectile function can mainly be caused by antidopaminergic mechanisms, whereas ejaculatory disorders and anorgasmia often can be explained by antiserotoninergic effects. Anticholinergic and adrenoloytic agents can also cause a particular impairment of erectile functions. The following considerations will show that the detection and treatment of SD (also in women!) should be given much more attention since drug-induced SDs occur predominantly in indications where a SD itself can be a symptom of the disease.