Chronic Treatment with Sildenafil Results in Diminished Adiposity and Increased Energy Expenditure in High Fat‐Fed Mice

Sildenafil is a highly selective PDE‐5 inhibitor that prevents the breakdown of nitric oxide (NO)‐induced cyclic GMP, resulting in arterial smooth muscle relaxation and increased blood flow. Here we report a novel effect of chronic sildenafil treatment on adiposity and energy expenditure (EE). Male C57BL/6J mice (n=10–13/group) were fed a high fat diet for 12 weeks, during which they received either a mixture of sildenafil (12 mg/kg/day)+L‐arginine (NO donor, 150 mg/kg/day) or saline. Sildenafil+L‐arginine treatment resulted in reduced weight (27 ± 1 vs 32 ± 1 g) and fat mass (5 ± 0.4 vs 9 ± 1 g) compared to saline treatment. There was no difference in muscle mass or food consumption. EE was higher in sildenafil+L‐arginine than saline treated mice (13 ± 1 vs 9 ± 1 kcal/kg lean mass/h). There was no difference in physical activity between groups. To determine whether NO production by L‐arginine was required for these effects, saline treated mice were compared to mice chronically treated with either sildenafil or L‐arginine alone. Sildenafil treatment resulted in decreased weight (37 ± 1 vs 42 ± 1 g) due to lower fat mass (11 ± 1 vs 16 ± 1 g) compared to saline treatment. L‐arginine treatment had no effect on weight or fat mass. EE (kcal/kg lean mass/h) was higher in sildenafil (8.8 ± 0.4) compared to both saline (6.5 ± 0.7) and L‐arginine (7.7 ± 0.3) treated mice. There were no differences in muscle mass, food consumption or physical activity between any groups. Thus, chronic treatment of high fat‐fed mice with sildenafil results in decreased weight gain due to loss of fat mass. This is a direct result of increased energy expenditure with sildenafil treatment.