Pre-clinical evidence for the use of phosphodiesterase-5 inhibitors for treating benign prostatic hyperplasia and lower urinary tract symptoms

OBJECTIVE: To evaluate the potential of sildenafil, vardenafil and tadalafil, all phosphodiesterase-5 (PDE-5) inhibitors used for treating erectile dysfunction, for treating benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). MATERIALS AND METHODS: The mRNA expression of the PDE-5 was determined in rat LUT tissues. The PDE-5 inhibitors were also tested in organ-bath experiments and in a partial bladder outlet obstruction (BOO) rat model in vivo. RESULTS: The highest PDE-5 mRNA expression was in the bladder, followed by the urethra and prostate. PDE-5 inhibitors dose-dependently reduced the contraction of the isolated bladder, urethral and prostate strips. The rank order of potency was vardenafil > sildenafil > tadalafil. In human prostate stromal cells vardenafil inhibited cell proliferation and was more effective than tadalafil and sildenafil. In the BOO model, there was a reduction in the non-voiding contractions after bolus intravenous administration of 3 mg/kg sildenafil and vardenafil. CONCLUSION: These results show that PDE-5 is expressed in LUT tissues. PDE-5 inhibitors induced significant relaxation of these tissues, inhibited the proliferation of human prostate stromal cells and reduced the irritative symptoms of BPH/LUTS in vivo. Therefore, PDE-5 inhibitors could be used as an effective treatment for BPH/LUTS.     

同期内使用3种PDE5抑制剂治疗ED的经验

目的:观察与比较同期内使用3种PDE5抑制剂治疗ED患者的疗效,满意情况和不良反应。分析影响患者疗效、接受度、倾向性的因素。方法:11个月在门诊应用3种PDE5抑制剂治疗ED患者331例。使用西地那非134例,他达拉非88例,及伐地那非109例。医师详细指导药物的应用,注意事项,观察的内容等,并互留电话,列表登记、随访。结果:复诊或电话随访时间,结果为:①获得良好的疗效及满意率为西地那非72例(79.12%),他达拉非52例(78.78%),伐地那非63例(81.81%)。②PDE5抑制剂单纯或交叉应用的资料分析显示:青年患者或新婚者,偏好伐地那非;③中青年患者倾向于他达拉非;中老年及较长期应用PDE5抑制剂的患者多选用西地那非。3种PDE5抑制剂用于早泄均有一定疗效。④对不能继续用此类药治疗ED的原因进行了分析,分别为:价高,不治本,效果差,耽心不良反应。结论:①同期3种PDE5抑制剂治疗ED的疗效基本相近。亦各有一些优势和特点。②3种PDE5抑制剂的安全性均好,一般、轻度不良反应相近,中度、特殊的不良反应少,严重不良反应均无发生。③PDE5抑制剂的疗效观察,目前众多的问卷、量表实际均仍以主观的感受为主。对同一个人以相同形式、相同问题、繁简一致阐述,获得的有关疗效满意情况、感受等简易回答是有可比性、可信度和实用性的。     

Oral phosphodiesterase-5 inhibitors: effect of heme oxygenase inhibition on cGMP signalling in rat cavernous tissue

This work postulated that heme oxygenase (HO) is partly responsible for controlling phosphodiesterase-5 inhibitor actions by modulating cyclic guanosine monophosphate (cGMP) cavernous tissue levels. Five hundred and four male Sprague-Dawley rats, divided into five groups, were investigated. Group 1 (n=72) included controls, group 2 (n=72) received sildenafil citrate (Viagra) orally, group 3 (n=72) received vardenafil hydrochloride (Levitra), group 4 (n=72) received tadalafil (Cialis). Group 5 (n=216), subdivided into three subgroups (A, B and C, 72 each), received the same dose of each drug with the HO inhibitor, Zn protoporphyrin. Eight rats from each group/subgroup were killed at 0.5, 1, 2, 3, 4, 6, 18, 24 and 36 h when cGMP levels in the cavernous tissues were estimated. Cavernous tissue cGMP levels increased significantly in sildenafil, vardenafil and tadalafil-treated rats compared to the controls with significant decreases after HO inhibition. It is concluded that the effects of these PDE-5 inhibitors in rat cavernous tissue are partly mediated through HO activity via the cGMP signalling pathway.     

Interactions between cGMP- and cAMP-pathways are involved in the regulation of penile smooth muscle tone

Nitric oxide (NO)/cyclic GMP (cGMP)-mediated mechanisms have a pivotal function in reducing the tone of the penile smooth musculature during normal erectile responses. The cyclic AMP (cAMP) signaling pathway is also involved in the adjustment of smooth muscle contractility, and suggestions for interactions between cGMP- and cAMP-mediated mechanisms have been presented. Using activators of the cGMP- or the cAMP-pathway, as well as inhibitors of protein kinase A (PKA; cAMP-dependent kinase) and protein kinase G (PKG; cGMP-dependent kinase), the present study was undertaken to further delineate the functional relation between these pathways in the penis. In addition, the distribution of PKA and some cAMP-binding phosphodiesterases (cAMP-PDEs) were investigated in human erectile tissue. Functional experiments were performed on isolated human corpus cavernosum (HCC). The effects of an inhibitor of the PKA, Rp-8CPT-cAMPS (10 µM), or the PKG, Rp-8-pCPT-cGMPS (10 µM), on relaxation induced by the cumulative administration of sodium nitroprusside (SNP), forskolin, sildenafil or tadalafil (IC351) were studied in preparations of HCC precontracted with 1 µM norepinephrine (NE). Using immunohistochemical procedures, the presence of immunoreactivity for cAMP-PDEs PDE3, PDE4, and PDE4A, as well as for PKA was investigated in specimens of HCC from which preparations were also used in the functional experiments. Forskolin, SNP, sildenafil, and IC 351 dose-dependently reversed NE-induced tension of isolated HCC preparations. The relaxing effects of SNP were significantly attenuated by Rp-8-pCPT-cGMPS, but not by Rp-8CPT-cAMPS. In contrast, relaxation induced by forskolin, sildenafil and tadalafil were significantly reversed by both Rp-8-pCPT-cGMPS and Rp-8CPT-cAMPS. Abundant immunoreactivity for PDE3 and PKA was observed in the corpus cavernosum smooth muscle cells. Immunoreactivity for PDE4 was also detected in the smooth musculature and in the cytoplasm of endothelial cells lining the cavernous sinusoids, as well as in nerve fibres interspersing the trabecular stroma. The present results support the hypothesis of interactions between cGMP- and cAMP-mediated signals in the HCC, and suggest that the effects of inhibitors of PDE5 on isolated erectile tissue may also partly or indirectly include actions of the cAMP second messenger system. The exact mechanism by which such an interaction occurs is not clear, but it may involve altered activity of the cGMP-inhibited PDE3 brought about by a change in the intracellular levels of cGMP by the inhibition of PDE5. This will in turn lead to increasing levels of cAMP, facilitating the interaction of cAMP with the PKA. The immunoreactivity specific for PDE3, PDE4, PDE4A and PKA registered in HCC section is also in support of an important role for the cAMP/PKA-system for penile smooth muscle function.     

The effects of chronic phosphodiesterase-5 inhibitor use on different organ systems

Phosphodiesterase-5 (PDE-5) inhibitors selectively inhibit PDE-5 enzymes that are present in various tissues like penile tissue, platelets, vascular, and smooth muscle tissue. The drug's actions on these tissues have lead to the successful therapeutic use in patients suffering from conditions such as erectile dysfunction (ED) and pulmonary hypertension. PDE-5 inhibitors (PDE-5i) act on the erectile tissue causing penile smooth muscle relaxation and vasodilatation leading to penile erection. In addition, in particular when used in conjunction with prostaglandin inhibitors, PDE-5i cause vasodilatation in pulmonary vasculature hence decreasing both the pulmonary arterial pressure and resistance. PDE-5i have also shown to mildly decrease blood pressure, increase cardiac index, and increase coronary blood flow in experimental animals as well as in human studies. The Food and Drug Administration (FDA) has approved three PDE-5i for the treatment of ED: sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) and one for pulmonary hypertension: sildenafil (Revatio). These agents are highly selective for PDE-5 enzymes as compared to other subclasses of PDE enzymes and have the almost identical pharmacological action but slightly different pharmacokinetics. Only little data exist about long-term use of PDE-5i and their effects on different organ system. This paper reviews the current information available on chronic PDE-5 inhibitor use.     

Molecular mechanisms and pharmacokinetics of phosphodiesterase-5 antagonists

The prominence of phosphodiesterase-5 (PDE-5) inhibitors in the treatment of male erectile dysfunction and other diseases related to vascular dysfunction mandates a comprehensive understanding of the properties and effects of these compounds. Three potent and selective PDE-5 inhibitors (sildenafil, tadalafil, and vardenafil) have been approved for clinical use. The clinical efficacy and safety profiles of these medications are related to their molecular mode of action, the selectivity for PDE-5, and the pharmacokinetic properties (absorption, bioavailability, time to onset of action, distribution, metabolism, and elimination). These PDE-5 inhibitors share some common properties with regard to mechanisms of action and selectivities for PDE-5. They also have distinctive characteristics that may impact their clinical use. This article focuses on the basic biochemistry of cyclic guanosine monophosphate signaling and the pharmacokinetic parameters that describe characteristics of drug action of these PDE-5 inhibitors in facilitating smooth muscle relaxation, leading to improved penile erectile response or causing side effects.     

Medikamentöse Therapie des benignen Prostatasyndroms mit Phosphodiesterase-5-Inhibitoren

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

Sildenafil inhibits the up-regulation of phosphodiesterase type 5 elicited with nicotine and tumour necrosis factor-alpha in cavernosal vascular smooth muscle cells: mediation by superoxide

OBJECTIVES: To determine whether there is an association between vascular phosphodiesterase type 5 (PDE-5) and NADPH oxidase (NOX) in cavernosal vascular smooth muscle cells (CVSMCs), and to study the actions of the PDE-5 inhibitor sildenafil; the pro-erectile actions of nitric oxide (NO) are reduced by PDE-5 which hydrolyses cGMP to inactive GMP, thus an up-regulation of PDE-5 and over-production of O(2)(-) derived from NOX might promote erectile dysfunction (ED). MATERIALS AND METHODS: To study the effects of nicotine and tumour necrosis factor-alpha (TNF-alpha) on superoxide (O(2)(-)) production and PDE-5 expression, CVSMCs from rabbit penis were incubated with nicotine or TNF-alpha, and superoxide dismutase (SOD), catalase, sildenafil citrate, or apocynin (NADPH inhibitor) for 16 h. The expression of PDE-5 and of glyceraldehyde-3-phosphate dehydrogenase (internal standard) was assessed using Western blotting. O(2)(-) was measured spectrophotometrically. RESULTS: After a 16-h incubation, both nicotine (maximal at 10 microm) and TNF-alpha (10 ng/mL) significantly increased O(2)(-) formation in CVSMCs; this effect was blocked by co-incubating with SOD, catalase, and sildenafil (1 microm). Apocynin also inhibited O(2)(-) formation when added after 16-h incubation with nicotine (10 microm) or TNF-alpha. PDE-5 expression was also significantly increased in CVSMCs incubated with nicotine and TNF-alpha. This effect was negated by 16-h co-incubation with SOD, catalase, apocynin, and sildenafil. CONCLUSIONS: Nicotine and TNF-alpha up-regulate PDE-5 expression in CVSMCs through an a priori up-regulation of NOX and formation of O(2)(-). As PDE-5 hydrolyses cGMP, this effect might 'blunt' the pro-erectile actions of NO. Sildenafil inhibits O(2)(-) formation, and 'normalizes' PDE-5 expression. This represents a novel pathogenic mechanism underlying ED, and a novel mechanism of action of sildenafil.     

Efficacy of PDE-5-inhibitors for erectile dysfunction. A comparative meta-analysis of fixed-dose regimen randomized controlled trials administering the International Index of Erectile Function in broad-spectrum populations

This meta-analytic study aims to estimate the likely improvements of erectile dysfunction (ED) measured by the International Index of Erectile Function (IIEF) at the highest fixed dosages of the three available PDE-5-inhibitors: sildenafil, tadalafil, and vardenafil. MEDLINE and the Cochrane Library were searched electronically for efficacy trials of PDE-5-inhibitors for treating ED. In addition drug manufacturers were contacted to provide unpublished or unrecorded congress proceedings. Randomized, double-blind, placebo-controlled, parallel-group, maximum fixed-dose, broad-spectrum efficacy trials using IIEF were included in the analysis. Data were independently extracted by two reviewers. The results were pooled using weighted mean differences. A formal indirect comparison (including Bonferroni-correction) was conducted to estimate the differences between agents. A total of 14 trials were included in the meta-analysis (three with 100 mg sildenafil, eight with 20-25 mg tadalafil, and three with 20 mg vardenafil). All trials were of good methodological quality. Overall heterogeneity was moderate: I(2)=33.2%, chi(2)=19.47, P=0.11. The funnel plot suggested moderate likelihood of publication bias. Pooled results of IIEF-improvement were for sildenafil 9.65 (95% CI: 8.50, 10.79) points, tadalafil 8.52 (7.61, 9.42) points, and vardenafil 7.50 (6.50, 8.50) points, respectively. Sildenafil proved to be significantly more effective than vardenafil (d=2.15, P=0.006), other pairwise comparisons showed no difference in efficacy. All PDE-5-inhibitors are highly effective in the treatment of ED. At maximum dosage they improve erectile function 7-10 points on the IIEF compared to placebo-treatment. There is evidence that sildenafil might be more efficacious than vardenafil, although this is to be interpreted with caution. To prove higher efficacy truly independent comparative trials are needed.     

Erectile dysfunction secondary to nerve-sparing radical retropubic prostatectomy: Comparative phosphodiesterase-5 inhibitor efficacy for therapy and novel prevention strategies

Postprostatectomy erectile dysfunction appears to be initiated by neuropraxia and perpetuated by cavernosal smooth muscle apoptosis. Phosphodiesterase-5 (PDE-5) inhibitor therapy is the current cornerstone of erectile dysfunction (ED) therapy in this population. Although no head-to-head trials have been performed with sildenafil, vardenafil, and tadalafil in this population, there are numerous studies in the general ED population. The results of these studies demonstrate that neither of the new PDE-5 inhibitors met statistical noninferiority to sildenafil. Sildenafil has been studied in a novel primary prevention modality using nightly administration after a bilateral nerve-sparing prostatectomy. In this novel approach, it effected a sevenfold improvement in return of spontaneous, normal erectile function 2 months after drug discontinuation. This effect appears to be mediated by properties unique to sildenafil that include improved endothelial function and neuronal regeneration and neuroprotection. In primary prevention, unlike ED therapy, one has only “one shot” by definition. Therefore, it is even more critical to apply evidence-based medicine.     

PDE-5-Inhibitoren

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.     

The phosphodiesterase inhibitory selectivity and the in vitro and in vivo potency of the new PDE5 inhibitor vardenafil

We investigated the potency and the selectivity profile of vardenafil on phosphodiesterase (PDEs) enzymes, its ability to modify cGMP metabolism and cause relaxation of penile smooth muscle and its effect on erections in vivo under conditions of exogenous nitric oxide (NO) stimulation. PDE isozymes were extracted and purified from human platelets (PDE5) or bovine sources (PDEs 1, 2, 3, 4 and 6). The inhibition of these PDEs and of human recombinant PDEs by vardenafil was determined. The ability to potentiate NO-mediated relaxation and influence cGMP levels in human corpus cavernosum strips was measured in vitro, and erection-inducing activity was demonstrated in conscious rabbits after oral administration together with intravenous doses of sodium nitroprusside (SNP). The effects of vardenafil were compared with those of the well-recognized PDE5 inhibitor, sildenafil (values for sildenafil in brackets). Vardenafil specifically inhibited the hydrolysis of cGMP by PDE5 with an IC50 of 0.7 nM (6.6 nM). In contrast, the IC50 of vardenafil for PDE1 was 180 nM; for PDE6, 11 nM; for PDE2, PDE3 and PDE4, more than 1000 nM. Relative to PDE5, the ratios of the IC50 for PDE1 were 257 (60), for PDE6 16 (7.4). Vardenafil significantly enhanced the SNP-induced relaxation of human trabecular smooth muscle at 3 nM (10 nM). Vardenafil also significantly potentiated both ACh-induced and transmural electrical stimulation-induced relaxation of trabecular smooth muscle. The minimum concentration of vardenafil that significantly potentiated SNP-induced cGMP accumulation was 3 nM (30 nM). In vivo studies in rabbits showed that orally administered vardenafil dose-dependently potentiated erectile responses to intravenously administered SNP. The minimal effective dose that significantly potentiated erection was 0.1 mg/kg (1 mg/kg). The selectivity for PDE5, the potentiation of NO-induced relaxation and cGMP accumulation in human trabecular smooth muscle and the ability to enhance NO-induced erection in vivo indicate that vardenafil has the appropriate properties to be a potential compound for the treatment of erectile dysfunction. Vardenafil was more potent and selective than sildenafil on its inhibitory activity on PDE5.     

Carbon monoxide relaxes the female pig urethra as effectively as nitric oxide in the presence of YC-1

PURPOSE: Nitric oxide (NO) and carbon monoxide (CO) have been suggested to relax smooth muscle by activating soluble guanylate cyclase (sGC), binding to the same site of the enzyme. 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1) (Cayman Co., Malm?, Sweden) increases the catalytic rate of sGC by binding to an allosteric site. We investigated whether YC-1 can modulate the relaxant responses of isolated urethral smooth muscle to exogenous CO, (NO) and electrical field stimulation. MATERIALS AND METHODS: In spontaneously active and noradrenaline (Sigma-Aldrich Chemie GmbH, Steinheim, Germany) pre-contracted preparations of circular urethral smooth muscle from female pigs relaxant responses were evoked by electrical field stimulation before and after incubation with 10(-5) M. YC-1. The concentration-response curves for CO and NO were investigated in noradrenaline pre-contracted strips before and after incubation with YC-1. The tissue contents of cyclic 3',5'-guanosine monophosphate (cGMP) and cyclic adenosine monophosphate after electrical field stimulation, and the administration of CO or NO was investigated in the absence and presence of YC-1. RESULTS: YC-1 significantly increased the amplitude of the relaxations evoked by electrical field stimulation, CO and NO, and simultaneously caused significant increases in the cGMP content in all preparations. The effect on CO induced relaxant responses was conspicuous. In the presence of YC-1 the potency and maximal relaxant effect of CO were similar to those of NO in the absence of YC-1. CONCLUSIONS: YC-1 enhances cGMP dependent relaxant responses of the female pig urethra in vitro. The finding that the response to CO was greatly increased after sensitizing sGC suggests a potential for CO as a relaxant mediator in urethral smooth muscle.     

Clinical update on phosphodiesterase type-5 inhibitors for erectile dysfunction

Erectile dysfunction (ED) affects the sexual lives of millions of men. The first-line oral pharmacotherapy for most ED patients is phosphodiesterase type-5 (PDE-5) inhibitors, of which three are available. Sildenafil is the most widely prescribed oral agent for ED and has a very satisfactory efficacy–safety profile in all patient categories. Tadalafil and vardenafil were introduced in the European Union and in the United States in 2003 and 2004, respectively. The three PDE-5 inhibitors share many pharmacological and clinical characteristics, and each has unique features. This review, which is based on the contemporary literature on PDE-5 inhibitors, describes the chemical, pharmacological, and clinical features of sildenafil, vardenafil, and tadalafil. The first section reviews the pathophysiology of penile erection and PDE-5 inhibitor pharmacology. The second section summarizes data regarding efficacy and safety of the three drugs in treating ED in the general population as well as in selected patient categories.     

High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodiesterase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patients

The physiological role of phosphodiesterase (PDE)11 is unknown and its biochemical characteristics are poorly understood. We have expressed human His-tagged PDE11A4 and purified the enzyme to apparent homogeneity. PDE11A4 displays K(m) values of 0.97 microM for cGMP and 2.4 microM for cAMP, and maximal velocities were 4- to 10-fold higher for cAMP than for cGMP. Given the homology between PDE11 and PDE5, we have compared the biochemical potencies of tadalafil (Cialis, Lilly-ICOS), vardenafil (Levitra, Bayer-GSK), and sildenafil (Viagra, Pfizer Inc.) for PDE11A4 and PDE5A1. PDE5A1/PDE11A4 selectivities are 40-, 9300-, and 1000-fold for tadalafil, vardenafil, and sildenafil, respectively. This suggests that none of these three compounds is likely to crossreact with PDE11A4 in patients.     

Phosphodiesterase type 5 inhibitors for erectile dysfunction

The cyclic nucleotide signalling pathway mediates the smooth-muscle relaxing effects of nitric oxide necessary for normal erectile function. Down-regulation of this pathway is central to the pathophysiology of many forms of erectile dysfunction (ED), which is often associated with other chronic diseases (e.g. hypertension, type 2 diabetes mellitus) and treatments (e.g. certain drugs, radical prostatectomy). Conversely, selective inhibition of the enzyme that catalyses the degradation of cGMP (phosphodiesterase type 5, PDE-5) promotes erectile responses to sexual stimulation. The successful launch and commercialization of the selective PDE5 inhibitor (PDE5I) sildenafil transformed the treatment of ED, not only by providing an effective, well tolerated oral ED therapy, but also by fostering greater candour about the problem among men. Sildenafil is highly effective in promoting erectile responses across a wide spectrum of severity and causes of ED, including patients with ED that is often refractory to treatment. The recent advent of vardenafil, which has the highest in vitro potency of all available PDE5Is, and tadalafil, which has a prolonged half-life that may enable couples to have sexual activity with less planning, represent further advances. Other PDE5Is offering further potential improvements are under active investigation.     

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 ≥ 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.     

Drug Insight: oral phosphodiesterase type 5 inhibitors for erectile dysfunction

Erectile dysfunction (ED) is a common medical condition that affects the sexual life of millions of men. At present, first-line oral pharmacotherapy for most patients with ED is a phosphodiesterase type 5 (PDE-5) inhibitor, of which three are currently available worldwide. Sildenafil (Viagra, Pfizer) has a very satisfactory efficacy-safety profile in all patient categories. The first PDE-5 inhibitor to reach the market, it is now the most widely prescribed oral agent for ED. Tadalafil (Cialis, Lilly ICOS) and vardenafil (Levitra, Bayer/GlaxoSmithKline) were introduced to the European Union and the US in 2003 and 2004, respectively. These three PDE-5 inhibitors share many characteristics, but each has unique features. This review describes the chemical, pharmacologic and clinical features of sildenafil, vardenafil and tadalafil as oral first-line treatments for ED. First, we describe the physiology of penile erection and PDE-5 inhibitor pharmacology, including chemistry, PDE selectivity, pharmacokinetics, and possible drug interactions. We then summarize data on the efficacy and safety profiles of the three PDE-5 inhibitors for the treatment of ED in the general population, in patients with diabetes mellitus and in men that have undergone bilateral nerve-sparing retropubic radical prostatectomy.     

Bedeutung von Phosphodiesteraseisoenzymen in der Kontrolle der humanen Detrusormuskulatur

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 µM) 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.