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 IC 50 of 0.7 nM (6.6 nM). In contrast, the IC 50 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 IC 50 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 stimulationinduced 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 NOinduced 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.

Introduction Diabetic men with erectile dysfunction (ED) are less responsive to therapy with type 5 phosphodiesterase (PDE5) inhibitors. Although an impairment of the nitric oxide (NO)/cyclic guanosin-monophosphate (cGMP) pathway has been shown in diabetic ED vs. non-diabetic ED, the functionality of NO/cGMP pathway in non-diabetic and diabetic ED patients with respect to non-ED patients has not been established. Aim The aim of this study is to evaluate the function of NO/cGMP signalling in human erectile tissues from ED patients exploring the added impact of diabetes. Methods Corpus cavernosum strips (human corpus cavernosum [HCC]) and penile resistance arteries (HPRA) were collected from penile specimens from organ donors (OD) and from diabetic and non-diabetic men with ED undergoing penile prosthesis implantation. Main Outcome Measures Relaxations to acetylcholine, electrical field stimulation, sodium nitroprusside, and sildenafil were evaluated in phenylephrine-contracted HCC and norepinephrine-contracted HPRA. cGMP content in HCC was also determined. Results The impairment of endothelium-dependent relaxation in HCC and HPRA from ED patients was exacerbated by diabetes (Emax 76.1, 62.9, and 49.3% in HCC and 73.1, 59.8, and 46.0% in HPRA from OD, non-diabetic and diabetic ED, respectively). Hypertension, hypercholesterolemia, or aging did not exert a further impairment of endothelial relaxation among ED patients. Diabetes also causes a further impairment of neurogenic relaxation in HCC and HPRA. The basal and stimulated content of cGMP in HCC was significantly decreased in patients with ED, but specially reduced in diabetic patients. Diabetes clearly impaired PDE5 inhibitor-induced vasodilation of HPRA from ED patients. Conclusions ED is related to impaired vasodilation, reduced relaxant capacity, and diminished cGMP content in penile tissue. These alterations are more severe in diabetes and accompany reduced relaxant efficacy of PDE5 inhibition. Thus, an exacerbated reduction of nitric oxide/cGMP signaling could be responsible for ED in diabetic men and would explain their reduced response to treatment.

No abstract

Introduction Lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH-LUTSs) may be associated with erectile dysfunction (ED). Phosphodiesterase type 5 (PDE5) inhibitors used for treating ED have shown clinical benefit in patients with LUTS but their actions in human LUT tissues are not well defined. Aim To determine the effects of the long-acting PDE5 inhibitor, tadalafil, on smooth muscle tone in human prostate and bladder neck as well as to evaluate the influence of tadalafil on the efficacy of the α-adrenergic receptor antagonist, tamsulosin, in inhibiting contractile responses in these tissues. Methods Strips of human peripheral prostate (HPP), human internal prostate (HIP), and human bladder neck (HBN) were obtained from organ donors and patients with BPH. The strips were then disposed in organ baths to evaluate nitric oxide/cyclic guanosine monophosphate (cGMP)-mediated relaxation and cGMP kinetics in HPP and HIP, and electrical field stimulation (EFS)-induced neurogenic contractions in HPP and HBN. Main Outcome Measures Tadalafil-induced effects on sodium nitroprusside (SNP)-induced relaxation and cGMP accumulation in HPP and HIP and influence of tadalafil and tamsulosin on EFS-induced contractions of HPP and HBN. Results SNP-induced relaxation of HPP and HIP was significantly potentiated by tadalafil (30–60 nM). SNP-induced cGMP accumulation in HPP and HIP was enhanced by tadalafil (30–60 nM), but significant difference was only obtained in HPP. EFS-induced contractions sensitive to tetrodotoxin in HPP were significantly inhibited by tadalafil (30 nM) but not by tamsulosin (0.01–100 nM) or vehicle. Further inhibition of neurogenic responses in HPP was achieved by combining tadalafil and tamsulosin treatments. Tamsulosin, but not tadalafil, significantly reduced EFS-induced contractions in HBN, but the coadministration of both therapies resulted in additional inhibition of contractions. Conclusions While tadalafil enhances cGMP accumulation and potentiates prostate relaxation, tadalafil combined with tamsulosin results in enhanced inhibition of neurogenic contractions of HPP and HBN.

Secondary tumors of the penis are rare, with 266 cases having been reported. We describe 5 new cases studied by cavernosography. The primary tumors were bladder cancer in 3 patients and prostatic cancer in 2. Cavernosography suggested the diagnosis, which was confirmed by a guided biopsy or fine needle aspiration biopsy. The prognosis has been poor, with the average survival being less than 9 months.