Glibenclamide prevents hypoglycemia-induced fatal cardiac arrhythmias in rats

Sulfonylureas increase the incidence of severe hypoglycemia in people with type 2 diabetes and might increase the risk of sudden cardiac death. Sulfonylureas stimulate insulin secretion by closing pancreatic ATP-sensitive potassium ion (KATP) channels. To investigate the role of KATP channel modulators on cardiac arrhythmias and mortality in the setting of severe hypoglycemia, adult Sprague-Dawley rats underwent hyperinsulinemic (0.2 U/kg/min) severe hypoglycemic (10 to 15 mg/dL) clamps with continuous electrocardiography. The rats were randomized for treatment with intravenous vehicle (VEH), the sulfonylurea glibenclamide (GLIB; K_ATP channel blocker; 5 mg/kg/h), or diazoxide (DIAZ; K_ATP channel opener; 5 mg/kg/h). The results demonstrated that GLIB completely prevented first-degree heart block compared with VEH (0.18 6 0.09/min) and DIAZ (0.2 6 0.05/min). Second-degree heart block was significantly reduced with GLIB (0.12 6 0.1/min) compared with VEH (0.6 6 0.2/min) and DIAZ (6.9 6 3/min). The incidence of third-degree heart block was completely prevented by GLIB compared with VEH (67%) and DIAZ (87.5%). Hypoglycemiainduced mortality was completely prevented by GLIB compared with VEH (60%) and DIAZ (82%). In conclusion, although GLIB increases the risk of hypoglycemia by increasing insulin secretion, these results have demonstrated a paradoxical protective role of GLIB against severe hypoglycemiainduced fatal cardiac arrhythmias.