Biomedical subjects

Christian G Stief

Publications and source records attributed to Christian G Stief.

At least 19 recordsLinked to original sources

PubMed2006

The complex structure of the smooth muscle layer of spermatic veins and its potential role in the development of varicocele testis.

OBJECTIVES: Varicocele, a dilatation of the pampiniform venous plexus, is considered to cause male infertility. The exact mechanism of varicocele development is not clarified yet. This study focused on the structure of varicocele veins, compared with normal spermatic veins, and its potential role in varicocele development. METHODS: Morphologic and immunohistochemical studies using antibodies against vWF and neurofilament-200 (NF-200) were performed on spermatic vein fragments of 20 varicocele patients and 40 normal spermatic cords. Casting preparation of veins was performed on five normal spermatic cords. RESULTS: Casting preparation frequently revealed circular constrictions of normal spermatic vein lumina. Histologic evaluation showed a strong longitudinal smooth muscle layer in the adventitia of large veins in addition to the circularly organised tunica media. Serial sections showed smooth muscle fibres branching from the outer longitudinal into the inner circular layer. Immunostaining for vWF revealed high vascularisation of this outer layer. Interestingly, the number of nerve fibres marked by NF-200 immunostaining was considerably higher in large veins compared to the testicular artery. The longitudinal smooth muscle layer was significantly degraded in the presence of varicocele grades I and II, and did not even exist in varicocele grade III. Correspondingly, the number of vasa vasorum and nerve fibres was reduced in varicocele veins. CONCLUSIONS: Our data show a complex smooth muscle organisation of spermatic veins, which serves the basis for a contractile mechanism, providing an effective blood transport through pampiniform plexus. This mechanism is obviously damaged in the varicocele. Molecular processes behind this impairment remain to be clarified.

Adolescent↗

PubMed2006

In vitro effects of PDE5 inhibitors sildenafil, vardenafil and tadalafil on isolated human ureteral smooth muscle: a basic research approach.

Cyclic nucleotide phosphodiesterase (PDE) isoenzymes are key proteins regulating intracellular cyclic nucleotide turnover and thus smooth muscle tension. Several in vitro studies have indicated that the cyclic GMP and cyclic AMP-mediated signaling may play a role in the control of human ureteral muscle. The aim of the present study was to evaluate the functional effects of PDE5 inhibitors sildenafil (Sil), vardenafil (Var) and tadalafil (Tad), as well as nitric oxide (NO)-donating agent sodium nitroprusside (SNP) and non-selective muscarinic antagonist butylscopolamine (BSC) on the tension induced by KCl and the turnover of cyclic nucleotides in isolated human ureteral smooth muscle. In vitro relaxant responses of human ureteral smooth muscle to the PDE5 inhibitors mentioned above were investigated using the organ bath technique. Cyclic nucleotides cAMP and cGMP were determined by means of specific radioimmunoassay following incubation of the tissue with Sil, Var, Tad and SNP. The tension induced by KCl of the ureteral tissue was dose dependently reversed by the drugs with the following rank order of efficacy: SNP > Var >or= Sil > Tad > BSC. R(max) values ranged from 25 +/- 9% (SNP) to 5 +/- 3% (BSC). Relaxant responses were paralleled by threefold to fourfold increase in tissue levels of cGMP. Our results indicate that PDE5 inhibitors can reverse the tension of isolated human ureteral smooth muscle via cGMP-mediated pathways. Nevertheless, further studies are indicated in order to evaluate as to whether there might be a use for PDE5 inhibitors in the treatment of ureteral stone disease.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed2006

Risk stratification in penile carcinoma: 25-year experience with surgical inguinal lymph node staging.

OBJECTIVES: In penile carcinoma, the most reliable staging method for lymph node involvement remains radical dissection with its associated high morbidity. However, the patient's prognosis is closely associated with lymph node status, and radical dissection is potentially curative. We report our experience with surgical lymph node staging and evaluate which group of patients could be assigned to a wait-and-see strategy or dynamic sentinel node biopsy and which group should undergo groin dissection. METHODS: From 1979 to 2004, 56 consecutive patients with penile cancer underwent surgical inguinal lymph node staging. On the basis of the histopathologic results, we defined risk stratification into low, high, and intermediate-risk groups according to the clinical examination findings, stage, and grade. RESULTS: Tumor stage (P = 0.019) and tumor grade (P <0.001) correlated significantly with lymph node status. Stratification into low (pT1G1, pT1G2), high (all G3 tumors), and intermediate-risk (all others) groups found 7.7% of low-risk patients with metastases. In the intermediate and high-risk groups, 28.6% and 75.0% had nodal metastases, respectively. Correlation with nodal involvement according to risk group was R2 = 0.608 (P <0.001). CONCLUSIONS: Risk stratification might enable a modified staging strategy for lymph node status according to stage, grade, and clinical examination findings. Highly motivated low-risk patients could be included in a surveillance program; however, high-risk patients should undergo bilateral inguinal dissection. Dynamic sentinel lymph node biopsy might be encouraged for intermediate-risk patients in the future.

Adult↗

PubMed2006

Safety and effectiveness of photoselective vaporization of the prostate (PVP) in patients on ongoing oral anticoagulation.

OBJECTIVES: Ongoing oral anticoagulation (OA) contraindicates transurethral electroresection of the prostate. We evaluated the safety and effectiveness of photoselective vaporization of the prostate (PVP) in patients on ongoing OA with coumarin derivatives, aspirin, or clopidogrel, complaining of symptomatic benign prostatic hyperplasia (BPH). METHODS: We evaluated perioperative parameters, functional outcome, and adverse events up to 24 mo postoperatively of patients on OA, and compared results with 92 men at normal risk without anticoagulant therapy undergoing PVP for the same indication (control). RESULTS: Within 40 mo, 116 men on OA were included, with 31% (n=36) receiving coumarin derivatives; 61% (n=71), aspirin; and 8% (n=9), clopidogrel. Mean prostate volume (62+/-34ml vs. 57+/-25ml; p=0.289) and mean operation time (67+/-28min vs 63+/-29min; p=0.313) were comparable with control. We observed no bleeding complications necessitating blood transfusions. Average postoperative decrease of haemoglobin was 8.6% for patients on OA versus 8.8% for control. At 3, 6, 12, and 24 mo postoperatively, improvement of the International Prostate Symptom Score ranged from 60-70%; postvoid residual volume, 80-88%; and average maximum urinary flow rate, 116-140%, respectively. Postoperative complications were low and comparable with control. CONCLUSIONS: PVP is characterized by excellent haemostatic properties and very low intraoperative complication rate even in patients on OA. On the basis of our perioperative results, we recommend PVP as first-line procedure for patients with symptomatic BPH at high risk of bleeding.

Administration, Oral↗

PubMed2006

Validation of the diagnostic value of NMP22 BladderChek test as a marker for bladder cancer by photodynamic diagnosis.

OBJECTIVES: The aim of the present study was to validate the sensitivity and specificity of the new "point-of-care" NMP22 BladderChek test compared to photodynamic diagnosis (PDD). METHODS: Voided urine samples from 100 patients with suspicion of bladder cancer were collected to perform the NMP22 BladderChek test and voided urinary cytology. The nuclear matrix protein 22 (NMP22) levels were measured by a lateral flow immunochromatographic qualitative assay, using 10 U/ml as the cut-off value. Subsequently patients underwent PDD, using 5-aminolevulinic acid or hexyl-aminolevulinate; previous bladder washings for cytology were collected. Sensitivity and specificity of the NMP22 BladderChek test were compared with cytology and PDD. RESULTS: Forty of the 100 patients had urothelial malignancies (22 pTa, 4 pT1, 3 pT2, 9 carcinoma in situ, 2 pTx; 16 G1, 6 G2, 18 G3). The sensitivity was 65% for the NMP22 BladderChek test, 44% for voided cytology, 75% for washing cytology, and 93% for PDD. Specificity rates were 40%, 78%, 62%, and 43%, respectively. Positive predictive values were 0.42, 0.58, 0.53, and 0.52 and the negative predictive values 0.63, 0.68, 0.82, and 0.9, respectively. CONCLUSIONS: The results demonstrate that the NMP22 BladderChek is an easily applied test, giving diagnostic findings within 30 min. However, validated by the highly sensitive PDD, the NMP22 BladderChek test demonstrates poor specificity and sensitivity and, therefore, cannot be recommended for screening or surveillance in daily clinical routine use. Further studies with careful patient selection are necessary to identify the patient population that might benefit from the NMP22 BladderChek test.

Aged↗

PubMed2006

How painful is donor nephrectomy? Retrospective analysis of early pain and pain management in open versus laparoscopic versus retroperitoneoscopic nephrectomy.

BACKGROUND: The aim of this study was to evaluate the early postoperative pain and pain management after standard open (ODN), hand-assisted laparoscopic (HLDN) and retroperitoneoscopic (RDN) donor nephrectomy. METHODS: The visual analogue scale (VAS) was determined twice a day in 203 donors during the first five days after nephrectomy. RESULTS: Mean VAS was significantly lower after RDN and HLDN than after ODN on day 2 (p=0.004) and days 3-5 (p<0.001). After RDN, "no pain" (VAS=0) was reported significantly earlier than after ODN. Irrespective of the technique used and the pain management, all donors reported significantly higher VAS in the morning. Opiates were administered for a significantly shorter average time period after RDN than after ODN (p=0.005). Cumulative morphine equivalent doses were higher after ODN than after RDN (p=0.001). Mean VAS reported after HLDN and RDN was similar. CONCLUSIONS: In summary, RDN and HLDN were clearly associated with much less early pain than ODN, independently of the used pain management.

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

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

Catheter-based intraluminal optical coherence tomography (OCT) of the ureter: ex-vivo correlation with histology in porcine specimens.

Intraluminal optical coherence tomography (OCT) applies coherent light to provide cross-sectional images with a spatial resolution of 10-25 microm. We compared OCT and matching whole-mount histology microscopy sections of porcine upper ureters ex vivo for visualization and delineation of different tissue layers of the ureteral wall. Porcine ureters (six specimens, 24 quadrants) were flushed with normal saline solution prior to insertion of the OCT catheter (diameter, 0.014 inch, OCT wavelength, 1,300+/-20 nm). Cross-sectional OCT images were obtained in marked locations before specimens were fixed in 4% formalin, cut at marked locations, whole-mounted, and stained with hematoxilin and eosin. Visualization and delineation of different tissue layers of the ureteral wall by OCT was compared with matching histology by two independent observers (O1,O2). OCT distinguished tissue layers of the ureteral wall in all quadrants. In OCT images, O1/O2 delineated urothelium and lamina propria in 23/24 quadrants, lamina propria and muscle layer in 19/16 quadrants, inner and outer muscle layer in 13/0 quadrants, and urothelial cell layers in 13/2 quadrants, respectively. Intraluminal OCT provides histology-like images of the ureter in porcine specimens ex vivo and reliably distinguishes between urothelium and deeper tissue layers of the ureteral wall.

Animals↗

PubMed2006

Techniques and long-term results of surgical procedures for BPH.

OBJECTIVE: To provide an overview on the current status of the long-term outcomes of instrumental treatment options for patients with lower urinary tract symptoms that are suggestive of bladder outlet obstruction. METHODS: Based on MEDLINE database searches, we performed a systematic review of the literature with a focus on peer-reviewed articles about surgical benign prostatic hyperplasia (BPH) therapy published between 2000 and 2005. Special emphasis was given to randomized controlled trials on long-term outcome with a minimum follow-up of five years. RESULTS: Data on clinical outcome with a follow-up of more than 10 years are available for open prostatectomy (OP), transurethral resection of the prostate (TURP), and transurethral microwave therapy. Studies with a follow-up of at least five years are obtainable for transurethral incision of the prostate, transurethral vaporisation of the prostate, transurethral needle ablation of the prostate, Holmium:YAG laser enucleation of the prostate, potassium-titanyl-phosphate laser vaporization of the prostate, and interstitial laser coagulation of the prostate. Among these long-term reports, OP and TURP provide the most durable results. CONCLUSIONS: The most substantial long-term data on surgical procedures for BPH are available for conventional therapy, namely TURP. Concerning the techniques that have emerged within the last decade, there is clear evidence that the outcomes are more sustainable for truly ablative and thus deobstructing procedures.

Humans↗

PubMed2006

Preliminary results on the off-label use of duloxetine for the treatment of stress incontinence after radical prostatectomy or cystectomy.

OBJECTIVES: Stress urinary incontinence (SUI) is a common compliant of patients after pelvic surgery. To date, no pharmacotherapy for men is available, but duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, has been successfully introduced and tested for SUI in women. The aim of our study was to evaluate if duloxetine is safe and effective for men with stress incontinence after radical prostatectomy or cystectomy. METHODS: Twenty patients were included in our study, 15 after radical prostatectomy and 5 after radical cystectomy and orthotopic ileal neobladder reconstruction. Each patient reported at least 3 wk of SUI despite doing consequent pelvic floor exercises. After exclusion of a urinary tract infection, we administered 40 mg duloxetine twice daily for a mean of 9.4 wk (range: 1-35 wk). RESULTS: After duloxetine, the average daily use of incontinence pads was lowered significantly (p < 0.001) from 8.0 (+/-6.5) to 4.2 (+/-5.9). Seven patients were completely dry or used one pad daily at most. Most patients reported mild side effects such as fatigue or a dry mouth, but these symptoms vanished after a short time. Six patients, however, had severe side effects, mainly massive fatigue or insomnia, and discontinued using duloxetine. CONCLUSIONS: Our preliminary results suggest that duloxetine is effective in men with SUI after prostatectomy or cystectomy. Further prospective studies with more patients included and a longer follow-up are recommended.

Aged↗

PubMed2006

Retroperitoneoscopic donor nephrectomy: donor outcome and complication rate in comparison with three different techniques.

Four surgical techniques for living donor nephrectomy were analyzed retrospectively in terms of perioperative outcome and early complication rate. A total of 182 donor nephrectomies including 69 open (OLDN), 14 fully laparoscopic (LDN), 34 hand-assisted laparoscopic (HLDN) and 65 retroperitoneoscopic (RLDN) nephrectomies were analyzed. There was a significant difference in mean operating time (OPT) between the OLDN (160 min) and RLDN (150 min) as compared to the LDN (212 min) and HLDN group (192 min) (P < 0.001). Mean warm ischemia time (WIT) was significantly shorter with OLDN (114 s), RLDN (121 s) and HLDN (128 s) when compared to LDN (238 s) (P < 0.001). Major complication rate was comparable among the groups. Independent of the preferred technique, donor nephrectomy is associated with complication rates. RLDN is comparable to OLDN in terms of OPT, WIT. Learning endoscopic donor nephrectomy could be associated with a higher complication rate.

Adult↗

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

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

High-level virtual reality simulator for endourologic procedures of lower urinary tract.

OBJECTIVES: To analyze the limitations of existing simulators for urologic techniques, and then test and evaluate a novel virtual reality (VR) simulator for endourologic procedures of the lower urinary tract. Surgical simulation using VR has the potential to have a tremendous impact on surgical training, testing, and certification. Endourologic procedures seem to be an ideal target for VR systems. METHODS: The URO-Trainer features genuine VR, obtained from digital video footage of more than 400 endourologic diagnostic and therapeutic procedures, as well as data from cross-sectional imaging. The software offers infinite random variations of the anatomy and pathologic features for diagnosis and surgical intervention. An advanced haptic force feedback is incorporated. Virtual cystoscopy and resection of bladder tumors were evaluated by 24 medical students and 12 residents at our department. RESULTS: The system was assessed by more than 150 international urologists with varying experience at different conventions and workshops from March 2003 to September 2004. Because of these evaluations and constant evolutions, the final version provides a genuine representation of endourologic procedures. Objective data are generated by a tutoring system that has documented evident teaching benefits for medical students and residents in cystoscopy and treatment of bladder tumors. CONCLUSIONS: The URO-Trainer represents the latest generation of endoscopy simulators. Authentic visual and haptic sensations, unlimited virtual cases, and an intelligent tutoring system make this modular system an important improvement in computer-based training and quality control in urology.

Computer Simulation↗

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

Phosphodiesterase inhibitors in female sexual dysfunction.

Based on the increasing knowledge on both the physiology of penile erection and the pathophysiology of erectile dysfunction, selective phosphodiesterase (PDE) inhibitors have been successfully introduced in the oral treatment of male erectile dysfunction. Because of their central role in smooth muscle tone regulation, PDEs remain an attractive target for drug development in urology. Since the distribution and functional significance of PDE isoenzymes vary in different tissues, selective inhibitors of the isoenzymes have the potential to exert at least partially specific effects on the target tissue. Currently, PDE inhibitors are under investigation with potential uses in urinary stone disease, overactive bladder and the so-called benign prostatic syndrome. The convincing clinical data on the use of the orally active PDE5 inhibitors sildenafil (VIAGRA), vardenafil (LEVITRA) and tadalafil (CIALIS) in the treatment of erectile dysfunction are accompanied by boosting research activities on intracellular signal transduction and PDE characterisation in female genital tissues with the aid of immunohistochemistry and immunocytochemistry and molecular biology. The expression of various PDE isoforms in the human clitoris, vagina and labia minora was shown by means of immunohistochemistry and RT-PCR analyses and it was concluded from functional studies that an increase in cGMP or cAMP might be involved in the regulation of female genital blood flow and the control of genital non-vascular smooth muscle. As a consequence, the efficacy and safety of the PDE5 inhibitor sildenafil in the treatment of symptoms of female sexual dysfunction (FSD), including female sexual arousal disorders (FSAD), have been evaluated. Although the experiences from these early clinical studies have so far not been conclusive, they suggest that, after appropriate evaluation of patients, inhibition of PDE5 might be of benefit for selected individuals with FSAD. Such research efforts will possibly allow the identification of efficacious and diagnostic tools for erectile dysfunction and of even more selective drugs in its therapy.

Female↗