endothelin-1 and fructose-1-6-diphosphate

Phosphodiesterase type 5 inhibitors are potent in relieving erectile dysfunction (ED), however, they are less satisfactory in diabetic patients, probably due to the pro-inflammatory biomarkers caused by diabetes. Therefore, it was interesting to compare the effects of sildenafil with strontium fructose 1,6-diphosphate (FDP-Sr) on cavernosal vascular activity and expressions of pro-inflammatory biomarkers in diabetic rats.. Male Sprague-Dawley rats were injected with streptozocin (60 mg/kg, i.p.) to develop diabetes. The animals were diabetic for eight weeks with sildenafil (12 mg/kg per day) or FDP-Sr (200 mg/kg per day) being administered for the last four of those eight weeks.. Sildenafil was more effective in relieving reduced vascular dilatation (relevant to ED), but less in attenuating over-expressions of NADPH oxidase p22, p47 and p67 subunits, and ET(A/B) R (endothelin receptor type A and type B) in the diabetic cavernosum. In contrast, FDP-Sr was less effective in improving ED, but more effective in normalizing the abnormal NADPH oxidase and ET(A/B) R.. The activated NADPH oxidase and upregulated ET(A) R and ET(B) R due to diabetic lesions played a minor or moderate role in ED. By offering extra ATP, FPD-Sr suppressed these abnormalities, however, sildenafil did not. A combined therapy of sildenafil with FDP-Sr may be more effective in relieving ED in diabetic patients through normalizing pro-inflammatory cytokines and improving the nitric oxide/cGMP pathway in the cavernosum.

Topics: Animals; Blood Glucose; Blotting, Western; Diabetes Mellitus, Experimental; Disease Models, Animal; Endothelin-1; Erectile Dysfunction; Fructosediphosphates; Male; Malondialdehyde; NADPH Oxidases; Piperazines; Protein Kinase C-epsilon; Purines; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sildenafil Citrate; Sulfones; Superoxide Dismutase; Up-Regulation; Vasodilator Agents

Diabetes is frequently associated with declining sexual function resulting from oxidative damage. NADPH oxidase is a major resource of reactive oxygen species (ROS) in the testes and is likely related to an activated endothelin-1 (ET-1) system. An activation of NADPH oxidase-ET-1 pathway was hypothesized in diabetic testopathy. We verified the hypothesis and tested if strontium fructose 1,6-diphosphate (FDP-Sr) could relieve these changes in diabetic testis as compared to testosterone propionate (TP) and sildenafil. Diabetes was produced in male Sprague-Dawley rats 8 weeks after a single injection of streptozotocin (STZ), and interventions with testosterone propionate (TP), sildenafil and FDP-Sr were conducted in the last 4 weeks. Blood glucose, testosterone, follicle stimulating hormone (FSH) , luteinizing hormone (LH) and expressions of NADPH oxidase subunits and the ET system were measured. Decreased insulin, FSH, LH and testosterone in serum were found associating with testicular oxidative stress in STZ-injected rats. Additionally, over-expressions of NADPH oxidase p22, p47, p67 subunits and the ET pathway were significant in the diabetic testis relative to normal and were completely abolished by FDP-Sr. Both TP and sildenafil were not beneficial to diabetic testopathy except serum androgen raised by TP. Activated NADPH oxidase and ET system are significant contributing to testis injury and are responded to FDP-Sr only, against both TP and sildenafil, by restoring the testis function and the hypothalamus-pituitary-testis axis. It is due to its extra-energy supply and an antioxidant activity of FDP-Sr.

Topics: Animals; Blood Pressure; Diabetes Mellitus, Experimental; Endothelin-1; Follicle Stimulating Hormone; Fructosediphosphates; Insulin; Luteinizing Hormone; Male; NADPH Oxidases; Oxidative Stress; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Testicular Diseases; Testis; Testosterone; Testosterone Propionate

1. Male hypogonadism is a major problem that starts to affect middle-aged men and has adversely effects on human sexual life. The aim of the present study was to investigate the effect of strontium fructose 1,6-diphosphate (FDP-Sr) on male hypogonadism in rats. 2. The pharmacological model of testis dysfunction was created by administration of adenine (200 mg/kg per day, i.g.) for 30 days. Three doses of FDP-Srs (200, 100 and 50 mg/kg per day, i.g.) were administered in parallel with adenine. Finally, mating behaviour index (the mounting latency and the number of mounting events), the total number of spermatozoa and sperm motility, related enzyme function and gene regulation and the mRNA levels of steroidogenic acute regulatory protein (StAR), cytochrome P450 side-chain cleavage enzyme (P450scc), 3beta-hydroxysteroid dehydrogenase (3beta-HSD), prepro-endothelin (ET)-1, endothelin-converting enzyme (ECE) and endothelin receptor A (ET(A)) were analysed. 3. The results showed that adenine significantly prolonged the mounting latency and decreased the number of mounting events, markedly reduced the total number of spermatozoa, slowed sperm motility and decreased testicular enzyme activity in the testes. At the mRNA level, adenine significantly downregulated serum testosterone, StAR, P450sc and 3beta-HSD. In parallel, adenine also targeted the ET-1 system, significantly downregulating mRNA levels of prepro-ET-1, ECE and ET(A). Administration of FDP-Sr dose-dependently reversed these effects. 4. In conclusion, adenine-induced testis dysfunction appears to be manifested as loss of sexual function in association with decreased spermatogenesis and reduced mRNA levels of steroidogenesis and the testicular ET-1 system. These abnormalities were significantly restored by FDP-Sr in a dose-dependent manner. These data indicate the possibility of using FDP-Sr to treat male hypogonadism.

Topics: 3-Hydroxysteroid Dehydrogenases; Adenine; Animals; Aspartic Acid Endopeptidases; Cholesterol Side-Chain Cleavage Enzyme; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Endothelin-Converting Enzymes; Fructosediphosphates; Gene Expression Regulation; Hypogonadism; Male; Metalloendopeptidases; Organ Size; Phosphoproteins; Rats; Receptor, Endothelin A; RNA, Messenger; Sexual Behavior, Animal; Signal Transduction; Sperm Count; Sperm Motility; Spermatogenesis; Strontium; Testis; Testosterone