TNF-α infusion impairs corpora cavernosa reactivity

Introduction. Erectile dysfunction (ED), as well as cardiovascular diseases (CVDs), is associated with endothelial dysfunction and increased levels of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α). Aim. We hypothesized that increased TNF-α levels impair cavernosal function. Methods. In vitro organ bath studies were used to measure cavernosal reactivity in mice infused with vehicle or TNF-α (220 ng/kg/min) for 14 days. Gene expression of nitric oxide synthase isoforms was evaluated by real-time polymerase chain reaction. Main Outcome Measures. Corpora cavernosa from TNF-α-infused mice exhibited decreased nitric oxide (NO)-dependent relaxation, which was associated with decreased endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) cavernosal expression. Results. Cavernosal strips from the TNF-α-infused mice displayed decreased nonadrenergic-noncholinergic (NANC)-induced relaxation (59.4 ± 6.2 vs. control: 76.2 ± 4.7; 16Hz) compared with the control animals. These responses were associated with decreased gene expression of eNOS and nNOS (P < 0.05). Sympathetic-mediated, as well as phenylephrine (PE)-induced, contractile responses (PE-induced contraction; 1.32±0.06 vs. control: 0.9±0.09, mN) were increased in cavernosal strips from TNF-α-infused mice. Additionally, infusion of TNF-α increased cavernosal responses to endothelin-1 and endothelin receptor A subtype (ET_A) receptor expression (P < 0.05) and slightly decreased tumor necrosis factor-alpha receptor 1 (TNFR1) expression (P = 0.063). Conclusion. Corpora cavernosa from TNF-α-infused mice display increased contractile responses and decreased NANC nerve-mediated relaxation associated with decreased eNOS and nNOS gene expression. These changes may trigger ED and indicate that TNF-α plays a detrimental role in erectile function. Blockade of TNF-α actions may represent an alternative therapeutic approach for ED, especially in pathologic conditions associated with increased levels of this cytokine.