Abstract 12295: Vascular Response to the Sodium-Glucose Cotransporter Inhibitor in Type 2 Diabetic Mice
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral drugs for the treatment of type 2 diabetes (T2D) and they reduce plasma blood glucose levels by inhibiting renal glucose reabsorption. However, there are no data investigating the vascular response to the SGLT inhibitors. This study is designed to determine whether and how phlorizin (a non-specific SGLT1 and 2 inhibitor) and canagliflozin, a FDA-approved SGLT2-specific inhibitor, regulate vascular tone in pulmonary and coronary arteries of control and T2D mice. Both phlorizin and canagliflozin induced vascular relaxation in pre-contracted pulmonary and coronary arteries. In addition, pretreatment of SGLT inhibitors significantly attenuated NO-dependent vascular relaxation in pulmonary arteries (assessed by sodium nitroprusside, a NO donor), but not in coronary arteries. We further examined the downstream of NO-dependent relaxation in pulmonary artery using a cGMP analogue and a phosphodiesterase inhibitor as well as measured membrane potential using pulmonary arterial smooth muscle cells. Our data suggest that pretreatment of SGLT inhibitors decreases NO-dependent relaxation via attenuated NO-induced hyperpolarization instead of affecting cGMP cascade. Interestingly, our RT-PCR data demonstrate that neither SGLT1 nor SGLT2 express in endothelial and smooth muscle cells of human pulmonary and coronary artery, implying that the effect of SGLT inhibitors on vascular function might be led by SGLT-independent mechanisms. To examine the chronic effect of the SGLT inhibitor on vascular functions, we administrated canagliflozin in control and T2D mice for 4 weeks orally (30 mg/kg body weight). Chronic canagliflozin administration significantly improved the glucose tolerance and increased plasma insulin level in T2D mice. Chronic administration did not affect NO-dependent relaxation in pulmonary arteries, but it significantly increased NO-dependent relaxation in coronary arteries in T2D mice. These results indicate that acute treatment of SGLT inhibitors has an adverse effect on pulmonary arterial functions, whereas chronic treatment does not show any negative effect in pulmonary artery and has a beneficial effect in coronary artery in T2D mice.
Author Disclosures: Y. Han: None. Y. Cho: None. R. Ayon: None. M. Pan: None. A. Dai: None. J. Yuan: None. A. Makino: None.
- © 2014 by American Heart Association, Inc.