Hyperglycemia Impairs Isoflurane-Induced Adenosine Triphosphate-Sensitive Potassium Channel Activation in Vascular Smooth Muscle Cells

In Brief BACKGROUND: Isoflurane activates vascular adenosine triphosphate sensitive potassium (KATP) channels, and may induce vasodilation. In the present study, we investigated whether hyperglycemia modifies isoflurane activation of vascular KATP channel. METHODS: We used a cell-attached patch-clamp configuration to test the effects of isoflurane on KATP 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 KATP channel activity. In addition, a PKC activator, PMA, mimicked the effects of HG. Superoxide release was significantly increased in arteries incubated in HG (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 HG inhibition of isoflurane-induced KATP channel activity. CONCLUSIONS: Our results suggest that the metabolic stress of hyperglycemia can impair isoflurane-induced vascular KATP 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. IMPLICATIONS: The present study demonstrated that acute hyperglycemia impaired isoflurane-induced vascular adenosine triphosphate-sensitive potassium channel activity via activation of protein kinase C. These results indicated that hyperglycemia may contribute to perioperative risk by impairing isoflurane-induced cardiovascular protective mechanisms via activation of vascular adenosine triphosphate-sensitive potassium channels.