Chronic Treatment With Sildenafil Improves Energy Balance and Insulin Action in High Fat–Fed Conscious Mice

• DOI: 10.2337/db06-0883
• Publication Date: 2007-03-29T17:19:11Z
• Authors: Julio E. Ayala; Deanna P. Bracy; Brianna M. Julien; Jeffrey N. Rottman; Patrick T. Fueger; David H. Wasserman
• Keywords: Blood Glucose; Male; 0303 health sciences; Blood Pressure; Feeding Behavior; Arginine; Animal Feed; Dietary Fats; Piperazines; Sildenafil Citrate; Mitochondria, Muscle; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Echocardiography; Purines; Body Composition; Glucose Clamp Technique; Animals; Insulin; Sulfones; Energy Metabolism

Stimulation of nitric oxide–cGMP signaling results in vascular relaxation and increased muscle glucose uptake. We show that chronically inhibiting cGMP hydrolysis with the phosphodiesterase-5 inhibitor sildenafil improves energy balance and enhances in vivo insulin action in a mouse model of diet-induced insulin resistance. High-fat–fed mice treated with sildenafil plus l-arginine or sildenafil alone for 12 weeks had reduced weight and fat mass due to increased energy expenditure. However, uncoupling protein-1 levels were not increased in sildenafil-treated mice. Chronic treatment with sildenafil plus l-arginine or sildenafil alone increased arterial cGMP levels but did not adversely affect blood pressure or cardiac morphology. Sildenafil treatment, with or without l-arginine, resulted in lower fasting insulin and glucose levels and enhanced rates of glucose infusion, disappearance, and muscle glucose uptake during a hyperinsulinemic (4 mU · kg−1 · min−1)–euglycemic clamp in conscious mice. These effects occurred without an increase in activation of muscle insulin signaling. An acute treatment of high fat–fed mice with sildenafil plus l-arginine did not improve insulin action. These results show that phosphodiesterase-5 is a potential target for therapies aimed at preventing diet-induced energy imbalance and insulin resistance.