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

Abstract

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.