Hyperglycemia impairs isoflurane-induced adenosine triphosphate-sensitive potassium channel activation in vascular smooth muscle cells

BACKGROUND: Isoflurane activates vascular adenosine triphosphate sensitive potassium (K-ATP) channels, and may induce vasodilation. In the present study, we investigated whether hyperglycemia modifies isoflurane activation of vascular K-ATP channel. METHODS: We used a cell-attached patch-clamp configuration to test the effects of isoflurane on K-ATP channel activity in vascular smooth muscle cells (VSMCs) after incubation for 24 h in medium containing normal glucose (NG, 5.5 mM D-glucose), L-glucose (LG, 5.5 MM D-glucose plus 17.5 MM L-glucose), or high glucose (HG, 23 MM D-glucose). Superoxide levels in aortas were measured by the lucigenin-enhanced chemiluminescence technique. RESULTS: Isoflurane-induced open probabilities were significantly reduced in VSMCs from arteries incubated in HG (0.06 +/- 0.01) compared with NG (0.17 +/- 0.02; P < 0.05) and LG (0.15 +/- 0.02; P < 0.05). Pretreatment of VSMCs with protein kinase C (PKC) inhibitors, calphostin C and PKC inhibitor 20-28, greatly reduced HG inhibition of isoflurane-induced K-ATP channel activity. In addition, a PKC activator, PMA, mimicked the effects of HG. Superoxide release was significantly increased in arteries incubated in FIG (18.3 +/- 11.5 relative light units (RLU).s(-1).mg(-1); P < 0.05 versus NG). Coincubated with polyethylene glycol-superoxide dismutase (250 U/mL), a cell-permeable superoxide scavenger, greatly reduced the HG-induced increase of superoxide, but failed to reduce FIG inhibition of isoflurane-induced K-ATP channel activity. CONCLUSIONS: Our results suggest that the metabolic stress of hyperglycemia can impair isoflurane-induced vascular K-ATP channel activity mediated by excessive activation of PKC. This could impede the coronary vasodilation response to isoflurane, causing ischemia or hypoxia in patients with perioperative hyperglycemia.