The novel ATP-sensitive potassium channel opener iptakalim prevents insulin resistance associated with hypertension via restoring endothelial function

Abstract

AIM: To investigate the effects of iptakalim on endothelial dysfunction induced by insulin resistance (IR) and to determine whether iptakalim improved IR associated with hypertension in fructose-fed rats (FFRs) and spontaneously hypertensive rats (SHRs). METHODS: Human umbilical vein endothelial cells (HUVECs) were used for in vitro study. The levels of endothelial vasoactive mediators and eNOS protein expression were determined using radioimmunoassays, ELISAs, colorimetric assays or Western blotting. Sprague-Dawley rats were fed with a high-fructose diet. In both FFRs and SHRs, tail-cuff method was used to measure systolic blood pressure (SBP), and hyperinsulinemic- euglycemic clamp was used to evaluate IR states. RESULTS: (1) Cultured HUVECs incubated with the PI3-kinase inhibitor wortmannin (50 nmol/L) and insulin (100 nmol/L) induced endothelial dysfunction characterized by significantly reduced release of NO and expression of eNOS protein, and significantly increased production of ET-1. Pretreatment with iptakalim (0.1-10 mumol/L) could prevent the endothelial dysfunction. (2) In FFRs, the levels of SBP, fasting plasma glucose and insulin were significantly elevated, whereas the glucose infusion rate (GIR) and insulin sensitive index (ISI) were significantly decreased, and the endothelium-dependent vascular relaxation response to ACh was impaired. These changes could be prevented by oral administration of iptakalim (1, 3, or 9 mg.kg(-1).d(-1), for 4 weeks). The imbalance between serum NO and ET-1 was also ameliorated by iptakalim. (3) In 2-4 month-old SHRs (IR was established at the age of 4 months), oral administration of iptakalim (1, 3, or 9 mg.kg(-1).d(-1), for 8 weeks) significantly ameliorated hypertension and increased the GIR to the normal level. CONCLUSION: These results demonstrate that iptakalim could protect against IR-induced endothelial dysfunction, and ameliorate IR associated with hypertension, possibly via restoring the balance between NO and ET-1 signaling.