802 INFLIXIMAB PROTECTS AGAINST DIABETIC ERECTILE DYSFUNCTION BY NEUTRALIZING TNF-α IN A RAT MODEL

INTRODUCTION AND OBJECTIVES: Patients with diabetesassociated erectile dysfunction (ED) often show an increase in circulating tumor necrosis factor-alpha (TNF). However, no studies have indicated whether TNFplays a role in the pathogenesis of ED associated with diabetes, and if so, how it does this. We examined the effects of infliximab (INF), a chimeric monoclonal antibody to TNF, on reactive oxygen species (ROS) generation in corpus cavernosum and ED in diabetic rats. METHODS: Four groups of male rats (n 8/group) were used: age-matched normal controls; diabetic rats induced by a high-fat diet (HFD) combined with a single streptozotocin (STZ) injection (35 mg/kg body weight, i.p.); non-diabetic rats receiving INF (5 mg/kg body weight/week, i.p.), and diabetic rats receiving INF. Erectile function was assessed with electrical stimulation of the cavernous nerve after 8 weeks. The blood and penile tissues were harvested for plasma biochemical determinations, assessment of serum TNFlevels, determination of penile ROS levels, and molecular assays of nicotinamide adenine dinucleotide phosphate (NADPH) subunits, nitric oxide synthase (phospho-eNOS) and neural nitric oxide synthase (nNOS) in the penile tissue. The effects of INF on HFD/STZ-induced diabetic ED and NADPH oxidase-mediated ROS generation in diabetic corpus cavernosum were observed. RESULTS: Untreated diabetic rats displayed significantly decreased erectile parameters in addition to increased plasma TNFlevels, penile ROS production, and p47 and gp91 expression compared with non-diabetic controls. INF neutralized circulating TNF, and significantly reduced ED in diabetic rats. In addition, INF appeared to induce marked decreases in p47 and gp91 expression and ROS generation in corpus cavernosum in diabetic animals compared with untreated diabetic rats. Expression of phospho-eNOS and nNOS in the penis were also significantly increased in INF-treated versus untreated diabetic rats. CONCLUSIONS: Our data suggest that increased TNFexpression associated with diabetes contributes to ED by promoting NAPDH oxidase-derived ROS generation in corpus cavernosum, and that administration of INF protects against diabetic ED by neutralizing TNF.