Sildenafil enhances angiogenesis and blood flow in response to ischemia in Diabetic mice.

Abstract

We have shown in the past that sildenafil enhances angiogenesis in wild type mice by PKG and cGMP pathway independent of NO Purpose: To test the hypothesis that PDE5 inhibition with sild would enhance angiogenesis in Diabetic mice in permanent ischemia. Methods We used two models of Diabetes. Streptozotocin given once daily for 5 days at 40mg/kg induced type 1 DM. For type 2 DM, we used mutant mice that were leptin receptor deficient (dBdB). Hind limb ischemia was induced in mice by femoral artery ligation. For type 1 model, mice (n=20/group) were treated with sild (0.1 mg/kg/day) or control for 21 days. For type 2 model, 20 controls and 10 sild treated mice were used. Blood flow (ml/min/100g) was measured using laser Doppler at 0, 7, 14 and 21 days. Tissue nitrite, cGMP, and angiogenic index (AI) were measured on day 21 by chemiluminescent detection. Results In both models, blood flow was significantly higher in ischemic limb treated with sildenafil vs. control ischemic limb, (p<0.0001) at 7, 14 and 21 days. AI was significantly elevated in sildenafil treated limbs (day 7 buffer 0.4 sild 0.65 p<0.0015, day 21 buffer 0.3 sild 1.1, p<0.0001) There was no significant difference in nitrite and nitrate levels between any groups. Conclusions These data indicate that sildenafil treatment enhances blood flow in diabetes in response to ischemic insult. This has important implications in Diabetes and Peripheral artery disease