bay-60-4552 and Erectile-Dysfunction

Overall efficacy rates of phosphodiesterase type 5 inhibitors (PDE5-i) for erectile dysfunction (ED) are 60-70%. PDE5-i treatment failures currently have to resort to invasive treatment options for restoration of erectile function. AIMS.: To assess changes in the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/protein kinase (PKG) pathway in human corpus cavernosum (HCC) of PDE5-i nonresponders compared with healthy controls. To evaluate the effects of BAY 60-4552, a stimulator of soluble guanylate cyclase (sGC), and vardenafil on relaxation of HCC strips from PDE5-i nonresponders.. mRNA expression, morphological localization of the NO/cGMP/PKG pathway, and relaxant capacity of both compounds alone or combined. Analysis of variance, t-test or Mann-Whitney test based upon number of groups and normality of data.. HCC tissues were harvested after consent from individuals undergoing penile prosthesis implantation (patients) and potent patients undergoing transurethral surgery (healthy controls, needle biopsy). HCC tissues of patients were compared with those of healthy controls for the expression of mRNA coding for PDE5A, eNOS, PKGα1, PKG2, sGCα1, sGCα2, sGCβ1, sGCβ2, α-smooth muscle actin (aSMA) and β-actin by quantitative polymerase chain reaction (qPCR). The respective proteins were localized using immunofluorescence. Tissue strips of patients were precontracted with phenylepinephrine followed by incubation with 1 μM of either vardenafil or BAY 60-4552, or both simultaneously.. The main targets in the NO/cGMP/sGC pathway were downregulated in PDE5-i nonresponders. The pathway was morphologically located to HCC smooth muscle, of which the overall content was preserved in ED patients based on aSMA expression. BAY 60-4552 and vardenafil have synergistic effects on relaxation of HCC of PDE5-i nonresponders. The main limitation is the small amount of control tissue precluding functional testing on these samples.. Despite downregulation of the NO/cGMP/PKG pathway, combining BAY 60-4552 with vardenafil significantly enhanced relaxation HCC strips of PDE5-i nonresponders.

Topics: Actins; Cyclic GMP; Drug Synergism; Erectile Dysfunction; Guanylate Cyclase; Humans; Imidazoles; Male; Middle Aged; Muscle, Smooth; Penile Erection; Penis; Phosphodiesterase 5 Inhibitors; Piperazines; Pyrazoles; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Sulfones; Triazines; Vardenafil Dihydrochloride

Radical prostatectomy (RP) is frequently responsible for erectile dysfunction (ED). Post-RP patients often show a failure to respond to phosphodiesterase type 5 (PDE5) inhibitors.. The acute effect of BAY 60-4552, the soluble guanylate cyclase (sGC) stimulator, and vardenafil were evaluated alone or in combination on erectile responses to electrical stimulation of the cavernous nerve (ES CN) in rats with cavernous nerve (CN) crush injury-induced ED.. Male adult Sprague-Dawley rats underwent laparotomy (sham, n=10) or bilateral CN crush injury (n=56). After 3 wk of recovery, erectile function was evaluated under urethane anaesthesia following ES CN at different frequencies.. The acute effects of intravenous (IV) injection of vehicle, vardenafil 0.03 mg/kg, BAY 60-4552 0.03 mg/kg or 0.3 mg/kg, or a BAY 60-4552 0.03 mg/kg plus vardenafil 0.03 mg/kg combination were evaluated in CN-crushed rats.. Bilateral CN crush injury followed by a 3-wk recovery period decreased erectile responses to ES CN by about 50%. In CN-crushed rats, IV vardenafil 0.03 mg/kg and BAY 60-4552 (0.03 or 0.3 mg/kg) increased erectile responses to ES CN to the same extent: Δ intracavernosal pressure/mean arterial pressure (ICP/MAP) at 10 Hz ES CN was 21±1% after vehicle, 25±3% (p<0.001) after vardenafil, and 26±5% and 27±5% after BAY 60-4552 0.03 mg/kg (p<0.01) and 0.3 mg/kg (p<0.001), respectively. The combination of vardenafil with BAY 60-4552 in CN-crushed rats totally restored erectile responses to ES CN equivalent to sham rats (ΔICP/MAP at 10 Hz ES CN: 34±4% after BAY 60-4552/vardenafil combination vs 39±4% in sham rats; not significant).. The present study supports the concept that the combined administration of a sGC stimulator, BAY 60-4552, and vardenafil provides synergistic beneficial effects and might therefore salvage patients who experience treatment failures with PDE5 inhibitors after RP.

Topics: Animals; Blood Pressure; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Electric Stimulation; Enzyme Activation; Enzyme Activators; Erectile Dysfunction; Guanylate Cyclase; Imidazoles; Male; Nerve Crush; Penis; Phosphodiesterase 5 Inhibitors; Piperazines; Pyrazoles; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Sulfones; Time Factors; Treatment Failure; Triazines; Vardenafil Dihydrochloride

Topics: Animals; Enzyme Activators; Erectile Dysfunction; Imidazoles; Male; Penis; Phosphodiesterase 5 Inhibitors; Piperazines; Pyrazoles; Pyrimidines; Sulfones; Triazines; Vardenafil Dihydrochloride