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Udo Jonas

Publications and source records attributed to Udo Jonas.

At least 19 recordsLinked to original sources
PubMed2006

Diagnostic accuracy of noninvasive tests to evaluate bladder outlet obstruction in men: detrusor wall thickness, uroflowmetry, postvoid residual urine, and prostate volume.

OBJECTIVES: The aim of this prospective study was to compare the diagnostic accuracy of detrusor wall thickness (DWT), free uroflowmetry, postvoid residual urine, and prostate volume (index tests) with pressure-flow studies (reference standard) to detect bladder outlet obstruction (BOO) in men. METHODS: During a 2-yr period, men older than 40 yr with lower urinary tract symptoms and/or prostatic enlargement had the following tests: ultrasound measurements of DWT, free uroflowmetry (Q(max), Q(ave)), postvoid residual urine, and prostate volume. Pressure-flow studies were used to divide obstructed from nonobstructed bladders. RESULTS: One hundred sixty men between 40-89 yr of age (median: 62 yr) were included in the study; 75 patients (46.9%) had BOO according to pressure-flow studies. The results of all investigated index tests differed significantly between obstructed and nonobstructed men. DWT was the most accurate test to determine BOO: the positive predictive value was 94%, specificity 95%, and the area under the curve of ROC analysis 0.93. There was an agreement of 89% between the results of DWT measurement and pressure-flow studies. CONCLUSIONS: Measurements of DWT can detect BOO better than free uroflowmetry, postvoid residual urine, or prostate volume. In clinical routine, DWT measurements can be used to judge BOO noninvasively.

Adult↗
PubMed2006

Immunohistochemical distribution of cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human vagina: a potential forensic value?

OBJECTIVES: Phosphodiesterase (PDE) isoenzymes are key proteins involved in the maintenance of the normal function of various tissues of the human body including those of the male and female urogenital tract. More recently, PDEs and their main substrates, cyclic GMP and cyclic AMP, have also been assumed to play a crucial role in the control of the human vagina. In order to elucidate the potential significance of phosphodiesterases as marker proteins in female genital organs, it was the aim of the present study to evaluate by means of immunohistochemistry the distribution of cGMP- and cAMP-PDE isoenzymes in specimens of the human vagina. METHODS: Conventional immunohistochemical techniques (double antibody technique, laser fluorescence microscopy) were applied to sections of the human vaginal wall in order to evaluate the presence of the PDE isoenzymes 1, 2, 3, 4, 5 and 10. RESULTS: Immunoreactivities (IR) specific for PDE1 (cAMP/cGMP-PDE, Ca(2+)/Calmodulin-dependent), PDE2 (cAMP-PDE, cGMP-dependent) and PDE5 (cGMP-PDE) were exclusively registered in the smooth musculature of vaginal arterial vessels, whereas no signals were detected in non-vascular tissue. IR indicating the expression of the cAMP-degrading PDE4 was mainly observed in the vaginal epithelium. Vaginal epithelial cells also presented immunosignals specific for PDE3 (cAMP-PDE, inhibited by cGMP) and PDE10 (dual substrate PDE), nevertheless, these stainings were less abundant than those related to the PDE4. IR for PDE10 was also registered in inflammatory cells located in the subepithelial region of the vaginal wall. CONCLUSION: Our study revealed the presence of IR specific for PDE1, PDE2, PDE4, PDE5 and PDE10 in sections of the human vagina and demonstrated that these enzymes are not evenly distributed in the tissue. Especially, the prominent expression of the cyclic AMP-PDE4A in the vaginal epithelium may give hint to a potential significance of this isoenzyme as a forensic marker protein. The findings give a rationale to investigate further as to whether the immunohistochemical detection of PDE4 may represent a new forensic tool in order to identify human vaginal epithelial cells.

Adolescent↗
PubMed2006

Complications of endoscopic extraperitoneal radical prostatectomy (EERPE): prevention and management.

Endoscopic extraperitoneal radical prostatectomy (EERPE) is a further advancement of minimal invasive surgery as it overcomes the limitations of laparoscopic (transperitoneal) RPE by the strictly extraperitoneal route of access combining the advantages of minimal invasive surgery with the advantages of an extraperitoneal procedure. Endoscopic extraperitoneal radical prostatectomy has many advantages but is not without complications. The aim of this review article is to describe the most common complications of this procedure. Complications associated with endoscopic extraperitoneal radical prostatectomy are: vascular injury--bleeding--haematoma, bowel injury, lymphocele, injury to the bladder--ureter, port site hernia, anastomotic leakage--stricture, obturator nerve injury--paralysis, gas embolism, catheter blockage, and miscellaneous like perineal pain, pubic osteitis, infection- urosepsis. The present review paper focuses on the identification and management of these complications The incidence of most complications directly correlates with the surgeons' experience, and the various complications are related to technical errors rather than to the technique itself. The laparoscopist performing endoscopic/ laparoscopic radical prostatectomy should be aware of all these complications. He should be able to recognise promptly, treat efficiently, and ideally prevent these complications.

Endoscopy↗
PubMed2006

p16INK4a expression and clinicopathologic parameters in renal cell carcinoma.

OBJECTIVES: The tumour suppressor gene p16INK4a is a cyclin-dependent kinase inhibitor, for which inactivation attributable to promoter hypermethylation or homozygous deletion has been described in malignancies. Little is known about p16INK4a protein levels in renal cell carcinoma (RCC) and its association with clinicopathologic parameters or disease progression. METHODS: The expression of the p16INK4a gene was analysed with the use of immunohistochemistry and tissue microarrays (TMA). Tissue cores were obtained from the primary tumour itself, the tumoural invasion front, and histologically benign peritumoural tissue of 397 nephrectomies. For statistical analysis, sections were classified into four groups according to the relative amount of positively stained cells: negative (0%), low (1-10%), intermediate (11-50%), and high positivity (>50%). Follow-up data were analyzed for 198 patients (follow-up period: 2-240 mo; median: 138 mo). RESULTS: Absent or low expression of p16INK4a was observed in 82% of tumour samples. No statistically significant association was found between protein levels detected in tumour, invasion front, or normal renal tissues and any of the clinicopathologic variables. Survival analysis by Kaplan-Meier revealed a significant association between high expression (>50%) of p16INK4a in tumours and better disease-specific survival (p=0.03, log-rank test). Cox regression analysis showed that p16INK4a expression is an independent covariate in disease-specific survival (p<0.01). CONCLUSIONS: The absence of p16INK4a expression in most tumour cells indicates that p16INK4a could be involved in the tumourigenesis of RCC. Immunohistochemically detected positivity for p16INK4a is a positive prognosticator for specific survival in both uni- and multivariate analyses.

Carcinoma, Renal Cell↗
PubMed2006

Alteration of subcellular and cellular expression patterns of cyclin B1 in renal cell carcinoma is significantly related to clinical progression and survival of patients.

Cyclin B1, identified as a regulator of late cell cycle, is involved in the development and progression of a variety of human malignancies. To clarify the role of cyclin B1 in the pathogenesis and prognosis of renal cell carcinoma (RCC), protein expression was compared with clinicopathological characteristics of patients as well as the long-term survival after surgical therapy. Expression analysis was carried out by immunohistochemistry and tissue microarray analysis. The microarrays that represented the primary tumors, their invasion front and normal peritumoral renal parenchyma contained 753 tissue cores obtained from 251 randomly selected nephrectomy specimens. Immunopositivity within the primary tumors was significantly associated with tumor stage (pT) (p < 0.01), lymph node status (pN) (p < 0.01) as well as the presence of systemic metastatic disease (p = 0.01). Subcellular expression in the cytoplasm of tumor cells significantly correlated with pT (p = 0.02) and pN (p = 0.03). When peritumoral tissue samples exhibited a relative amount of <10% of positively reacting epithelial cells, cyclin B positivity was identified to predict long-term survival of patients in univariate analysis (p < 0.01) whereas borderline significance was observed in multivariate statistical analysis (p = 0.05). Increased intratumoral cyclin B1 positivity and aberrant localization of signals within the cytoplasm of tumor cells is positively correlated with the tendency towards tumor progression, indicating the significant role of cyclin B1 in the development and pathogenesis of RCC. The result of uni- and multivariate statistical analysis suggests the prognostic value of cyclin B1 for RCC patients.

Adult↗
PubMed2006

Update on phosphodiesterase (PDE) isoenzymes as pharmacologic targets in urology: present and future.

OBJECTIVES & METHODS: Diseases of the human urinary tract represent common morbidities characterized by a high prevalence in the population of most westernized countries. The existence of a significant number of affected patients and the recent increase in scientific attention has resulted in various experimental and clinical efforts in order to evaluate the mechanisms controlling the function of urinary tract organs. This review attempts to describe the physiology and pharmacology of phosphodiesterase (PDE) isoenzymes with special regard to their (potential) use in disorders of the human urogenital tract. RESULTS: The promising clinical data for the orally active phosphodiesterase (PDE) inhibitors sildenafil, vardenafil and tadalafil, used in the treatment of male erectile dysfunction (MED), has boosted research activities on the significance of the cyclic GMP- and cyclic AMP pathway in other genitourinary tract tissues, such as the bladder, prostate, ureter, urethra, as well as female genital tissues. Based on the more extensive understanding of the pathways controlling the function of the male and female urogenital tract, orally administered phosphodiesterase inhibitors are considered a logical and straightforward approach for treating urological diseases. Due to the unending charge to conceive advanced first-line treatments, new therapeutic options taking into consideration the cyclic nucleotide signaling have been introduced or might be launched in the near future. Upcoming strategies will not only focus on the nitric oxide (NO)/cGMP cascade but also on compounds modulating signal transduction mediated by cyclic adenosine monophosphate, as well as combined agents in order to affect multiple peripheral intracellular targets. CONCLUSIONS: The article highlights cGMP- and cAMP-pathways, PDE subtypes and their present or putative future clinical significance in urological practice.

Female↗
PubMed2006

In vitro functional responses of isolated normal human prostatic tissue to compounds interacting with the cyclic guanosine monophosphate pathway.

OBJECTIVES: To examine the effects of some nitric oxide-donating agents, as well as the C-type natriuretic peptide (CNP), on isolated human prostatic tissue. To date, guanylyl cyclases and cyclic guanosine monophosphate (cGMP)-degrading phosphodiesterases represent important target proteins for the development of new drugs for the treatment of lower urinary tract symptoms and benign prostatic hyperplasia. METHODS: Using the organ bath technique, the effects of sodium nitroprusside, S-nitrosoglutathione, S-nitrosocysteine, linsidomine, and CNP (1 nM to 1.0/10 microM) on the tension induced by norepinephrine of prostatic tissue strips were investigated. The tissue was also exposed to three different concentrations of the drugs, and the production of cGMP and cyclic adenosine monophosphate (cAMP) was determined. RESULTS: The tension induced by 40 microM norepinephrine of the isolated prostatic tissue was dose dependently reversed by the drugs. The rank order of potency was sodium nitroprusside more than S-nitrosoglutathione more than linsidomine more than S-nitrosocysteine, which was equal to CNP (1 microM). The reversal of tension induced by the greatest drug concentrations ranged from 50% relaxation with sodium nitroprusside to 42% relaxation with CNP. The relaxing effects of the drugs were paralleled by a 2-fold to 40-fold and 2-fold to 45-fold increase in tissue levels of cAMP and cGMP, respectively. CONCLUSIONS: Our results provide further evidence that cGMP and cAMP are involved in the control of the normal function of human prostatic smooth muscle. Our findings may provide new strategies for future therapeutics used in the treatment of lower urinary tract symptoms and bladder outlet obstruction secondary to benign prostatic hyperplasia.

Aged↗
PubMed2006

Expression of cAMP and cGMP-phosphodiesterase isoenzymes 3, 4, and 5 in the human clitoris: immunohistochemical and molecular biology study.

OBJECTIVES: Only a little research has focused on the evaluation of female sexual function. With sexual stimulation, the clitoris becomes engorged with blood and tumescent. Nevertheless, only little is known about the significance of the cyclic nucleotide-mediated signal transduction in the control of this process. We sought to elucidate the presence of the phosphodiesterase (PDE) isoenzymes 3, 4, and 5 in the human clitoris using immunohistochemical and molecular biology methods. METHODS: Thin sections of clitoral specimens were incubated with primary antibodies directed against PDE isoenzymes 3, 4, and 5. Next, the sections were incubated with either Texas red or fluorescein isothiocyanate-labeled secondary antibodies, and visualization was done using laser microscopy. The expression of mRNA encoding for various PDE isoenzymes was evaluated using reverse transcriptase polymerase chain reaction. RESULTS: Immunofluorescence indicating the presence of PDE4 (cyclic adenosine monophosphate-PDE) was observed in the nonvascular smooth musculature of the corpus cavernosum clitoris, sinusoidal endothelial and subendothelial layers, and nerve fibers innervating the tissue. Immunoreactivity specific for PDE5 (cyclic guanosine monophosphate-PDE) was limited to the smooth muscle of the clitoral erectile tissue. The fluorescein isothiocyanate reaction indicating the expression of PDE3 (cyclic adenosine monophosphate-PDE) was registered to a certain degree only in the clitoral epidermis. In the reverse transcriptase polymerase chain reaction studies, a predominant expression of mRNA encoding for PDE1A was registered, but only small amounts of mRNA encoding for PDE4 and PDE5 were detected. CONCLUSIONS: Our results have demonstrated the presence of cyclic adenosine monophosphate-PDE and cyclic guanosine monophosphate-PDE in the human clitoris and may indicate a regulatory function of these enzymes in the cyclic nucleotide-mediated control of smooth muscle tone.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2006

Immunohistochemical distribution of cAMP- and cGMP-phosphodiesterase (PDE) isoenzymes in the human prostate.

OBJECTIVES: With the introduction of sildenafil citrate (Viagra), the concept of phosphodiesterase (PDE) inhibition has gained tremendous interest in the field of urology. Cyclic nucleotide second messengers cGMP and cAMP have been assumed to be involved in the control of the normal function of the prostate. The aim of the present study was to evaluate by means of immunohistochemistry the expression and distribution of some cAMP- and cGMP-PDE isoenzymes in the prostate. MATERIAL & METHODS: Cryostat sections (10 microM) of formaldehyde-fixated tissue segments excised from the transition zone of human prostates were incubated with primary antibodies directed against the PDE isoenzymes 3, 4, 5, and 11. Then, sections were exposed to either fluorescein isothiocyanate- (FITC) or Texas Red- (TR) labeled secondary antibodies and visualization was commenced by means of laser fluorescence microscopy. RESULTS: TR-immunofluorescence indicating the presence of PDE4 (cAMP-PDE) was abundantly observed in the fibromuscular stroma as well as in glandular structures of the transition zone. In contrast to the distribution of PDE4, immunoactivity indicating PDE5 (cGMP-PDE) and 11 (dual substrate PDE) was mainly observed in glandular and subglandular areas. No immunostaining for PDE3 (cGMP-inhibited PDE) was detected. CONCLUSION: Our results confirm the presence of PDE isoenzymes 4, 5 and 11 in the transition zone of the human prostate and present evidence that these isoenzymes are not evenly distributed. These findings are in support of the hypothesis that there might be a rationale for the use of PDE inhibitors in the pharmacotherapy of BPH and LUTS.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2006

Categorisation of complications of endoscopic extraperitoneal and laparoscopic transperitoneal radical prostatectomy.

The aim of the present review is to focus on the various attempts of categorisation of complications after endoscopic extraperitoneal and laparoscopic transperitoneal radical prostatectomy. Several classifications of complications and adverse events have been proposed in the literature but none is widely accepted or applied so far. We thus present a review of the existing literature and the complications of our series of 900 patients treated with endoscopic extraperitoneal radical prostatectomy (EERPE). We applied the recently revised Clavien classification system to grade EERPE complications.

Age Distribution↗
PubMed2006

Ultrasound measurement of detrusor wall thickness in healthy adults.

AIMS: Measurements of detrusor wall thickness (DWT) are used to diagnose bladder outlet obstruction (BOO). No values of DWT exist in healthy adults so far. These values, however, are necessary to judge DWT in patients with suspected BOO correctly. The aim of this study was to determine DWT in healthy adults and to investigate if bladder filling, gender, age, or body-mass index (BMI) influences DWT. MATERIALS AND METHODS: In 55 healthy adult volunteers between 15 and 40 years of age, DWT was measured at the anterior bladder wall with a 7.5 MHz ultrasound probe and with a full bladder. In nine of those volunteers, an urodynamic investigation was performed additionally during which DWT was measured in steps of 50 ml until 300 ml and in steps of 100 ml until the maximum bladder volume. RESULTS: DWT decreases rapidly during the first 250 ml of bladder filling but, thereafter, remains almost stable until maximal bladder capacity. No statistical difference was found between DWT at 250 ml and DWT at a higher bladder filling. Men had a greater DWT compared to women (1.4 vs. 1.2 mm, P < 0.001). The age and BMI did not have a significant impact on DWT. CONCLUSIONS: DWT remains stable at a bladder filling of 250 ml. At this state of bladder filling, DWT between different groups are comparable. Men have to be evaluated separately from women.

Adolescent↗
PubMed2006

Long-term results of interstitial brachytherapy (LDR-Brachytherapy) in the treatment of patients with prostate cancer.

Permanent interstitial brachytherapy represents the most conformal form of radiation therapy of the prostate and the number of patients with prostate cancers treated with permanent radioactive implants is increasing world wide. In the meanwhile long-term data on tumor control and treatment morbidity become available. Biochemical and clinical tumor control appears to be as effective as after radical prostatectomy or external beam radiation therapy in early prostate cancer. The risk of postreatment urinary incontinence and bowel dysfunction is low and erectile function can be preserved in the majority of patients. However, prostate brachytherapy requires a careful selection of patients as pretreatment factors predict for long-term outcome. The need for combined modality approaches in intermediate and high-risk patients remains controversely discussed. The continous refinement of intraoperative planning techniques and the elucidation of the etiology of urinary, sexual, and bowel dysfunction should result in further improvements in biochemical outcomes and decreased morbidity. Improved and standardized postimplantation evaluation will make outcome data more reliable and comparable.

Brachytherapy↗
PubMed2006

Potential future options in the pharmacotherapy of female sexual dysfunction.

Female sexual dysfunction (FSD) is considered a common medical problem estimated to affect millions of women in the westernized countries. FSD has been classified into four different categories including sexual arousal disorder (FSAD), sexual desire disorder (HSDD), orgasmic disorder and sexual pain disorder. The focus of this article is the potential role of pharmacological compounds currently under development, in the treatment of sexual arousal and orgasmic disorders in order to enhance the sexual response in adult females. While a number of potential therapeutic options are available to date, not one of the pharmacological treatment regimens has been yet considered the Gold standard in the management of symptoms of FSD. This article reviews the rationale and potential benefits of using distinct drug formulations in the treatment of FSD.

Adrenergic alpha-Antagonists↗
PubMed2006

Early photo-illustration of a hermaphrodite by the French photographer and artist Nadar in 1860.

As early as 1860 the French photographer Gaspard Félix Tournachon, called Nadar (1820-1910), took a series of nine photographs depicting a young intersex patient. These illustrations were not published at their time and little is known about the patient and the role of the physicians involved in this case. The article discusses the available information on these artworks that today belong to the photographic collection of the Musée d'Orsay in Paris.

Disorders of Sex Development↗
PubMed2005

Distribution and functional significance of phosphodiesterase isoenzymes in the human lower urinary tract.

To date, it is widely accepted that several disorders of the male and female urogenital tract, such as erectile dysfunction, bladder overactivity, urinary stone disease and the benign prostatic syndrome, can be therapeutically approached by influencing the function of the smooth musculature of the respective organs. In order to achieve a pronounced drug effect without significant adverse events, especially on the cardiovascular system, a certain degree of tissue selectivity is mandatory. Selective intervention in intracellular pathways regulating smooth muscle tone has become a promising strategy to modulate tissue function. Since the concept of taking a pill as a cure for an illness or the relief of symptoms has become widely accepted by the consumers, the pharmacological treatment of urological diseases has focused on selective, orally available drugs, acting via influencing intracellular regulatory mechanisms, thus combining a high response rate and the advantage of an on-demand intake. PDEs play a central role in controlling the levels of cyclic nucleotides (i.e. cAMP and/or cGMP), which are important second messengers in many transmitter pathways involved in the regulation of biological processes of urogenital tissues. Specifically, the use of isoenzyme selective phosphodiesterase (PDE) inhibitors offers great hope in the medical treatment of various genitourinary diseases. These agents are regarded efficacious, having a fast onset of drug action in the target tissue and an improved effect-to-side-effect ratio. The growing experience with the use of this class of compounds in urology is mainly based on basic research efforts and this field will remain the most exciting and innovative subject in genitourinary physiology and pharmacology for the next few years. These tremendous research efforts may lead to a vast pharmacological armamentarium of possible new treatment options. The purpose of this review is to summarize the current knowledge on the distribution and potential functional significance of PDE isoenzymes in the human lower urinary tract.

Humans↗
PubMed2005

Cyclic AMP-specific and cyclic GMP-specific phosphodiesterase isoenzymes in human cavernous arteries--immunohistochemical distribution and functional significance.

OBJECTIVES: It has been well established that male erectile dysfunction is frequently associated with vascular diseases. The normal function of cavernous arteries is considered a prerequisite to maintain sufficient blood flow to the trabecular spaces in order to enable penile erection. Contractility of cavernous arteries is regulated by the peripheral autonomic nervous system and endogenous factors released from the endothelial cell layer. A significant increase of blood flow in the central cavernous arteries is the initial event leading to penile tumescence and rigidity. Besides the significance of the nitric oxide/cyclic guanosine monophosphate (cGMP)-mediated mechanisms, the cyclic AMP (cAMP) signalling pathway is also involved in the regulation of tone of the erectile tissue, and interactions between cGMP- and cAMP-mediated mechanisms have been demonstrated. The aim of the present study was to investigate by means of immunohistochemistry the presence of the phosphodiesterase (PDE) isoenzymes 3, 4 (cAMP-specific PDEs) and 5 (cGMP-specific PDE) in thin sections of human central cavernous arteries (HCA) and their functional significance in the mechanism of vessel tone regulation. METHODS: Functional experiments were performed using circular segments of HCA and strip preparations of the human corpus cavernosum (HCC). Relaxant effects induced by the cumulative addition of the PDE inhibitors milrinone (PDE3 inhibitor), rolipram (PDE4 inhibitor) and sildenafil (PDE5 inhibitor; 0.01, 0.1, 1 and 10 M) were studied in preparations of HCA and HCC challenged by 1 M norepinephrine (NE). Moreover, immunohistochemistry was carried out in order to evaluate the expression of PDE3, PDE4 and PDE5 in thin sections of HCA. RESULTS: Milrinone, rolipram and sildenafil dose-dependently reversed the NE-induced tension of the isolated vascular segments and HCC strips with sildenafil being the most effective drug. Neither rolipram nor milrinone reached an EC50 value. Abundant immunoreactivities specific for PDE3, PDE4 and PDE5 were observed in the entire smooth musculature of the wall of HCA and resistance arteries. In addition, immunoreactivity for PDE4 was also detected in the cytoplasm of endothelial cells lining the cavernous arteries. CONCLUSIONS: The cGMP-dependent relaxation of cavernous arteries is not only dependent on the normal function of the peripheral autonomic nervous system but also on the functional integrity of the vascular endothelium. The expression of the cGMP-specific PDE5 and the ability of the PDE5 inhibitor sildenafil to reverse the adrenergic tension of isolated segments of HCA underline the important role of the NO/cGMP pathway in the control of smooth muscle tone of human trabecular smooth musculature and penile cavernous arteries. Our results also suggest a significance of the cAMP-dependent signaling mechanisms in the regulation of tension of central HCAs. The present findings are also in support of the hypothesis of interactions between the cGMP- and cAMP-mediated signaling pathways in HCAs. Further investigations are indicated in order to outline potential differences between central HCAs and helicine resistance arteries. This may help to understand better the relations between structural and functional changes in the penile erectile tissue in patients with cardiovascular diseases and endothelial dysfunction.

Arteries↗
PubMed2005

In vitro functional responses of isolated human vaginal tissue to selective phosphodiesterase inhibitors.

Only little is known as to the significance of the cyclic nucleotide-mediated signal transduction in the control of the function of human vaginal smooth musculature. Recently, the presence of the phosphodiesterase (PDE) isoenzymes 4 (cAMP-PDE) and 5 (cGMP-PDE) in the human vagina was reported. Thus, it was the aim of the study to elucidate the effects of some PDE inhibitors on the tension induced by endothelin 1 (ET-1), as well as on levels of cGMP and cAMP in isolated human vaginal wall tissue. Using the organ bath technique, the ability of norepinephrine (NE), carbachol, serotonin (5-HT), oxytocin and ET-1 to contract isolated vaginal wall muscle strips was evaluated. In another set-up, the effects of the PDE4 inhibitor rolipram and PDE5 inhibitors sildenafil and vardenafil (1 nM-10 microM) on the tension induced by 0.1 microM ET-1 of human vaginal wall tissue strips were investigated. In order to measure drug effects on tissue levels of cGMP and cAMP, vaginal tissue was exposed to different concentrations (0.1, 1 and 10 microM) of the compounds and the accumulation of cyclic nucleotides was determined. The adenylyl cyclase stimulating agents forskolin and nitric oxide donor sodium nitroprusside (SNP) (0.01, 0.1 and 1 microM) were used as reference compounds. While NE, carbachol and oxytocin failed to contract the vaginal tissue, ET-1 and, to a certain degree, 5-HT elicited contractile responses of the isolated strip preparations. The tension induced by 0.1 microM ET-1 was dose-dependently reversed by the drugs. The rank order of efficacy was sildenafil > forskolin > rolipram >or= vardenafil > SNP. Rmax values ranged from 24% (SNP) to 50% (sildenafil). With sildenafil being the only exception, none of the compounds reached an EC50 value. The relaxing effects of the drugs were paralleled by a fourfold to tenfold increase in tissue levels of cGMP and/or cAMP. Our results demonstrate that PDE inhibitors can relax human vaginal tissue and increase levels of cyclic nucleoside monophosphates. The findings with regard to the PDE5 inhibitors may indicate that the NO-cGMP pathway is, to a certain degree, involved in the control of vaginal smooth muscle tone. This might be of significance with regard to the pharmacological treatment of disorders connected with female sexual arousal and the ability to achieve orgasm.

Female↗