Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium : Two paradoxes revisited

Patients receiving oral hypoglycemic agents for diabetes mellitus are at increased risk of cardiovascular mortality. Oral hypoglycemic agents are inhibitors of the ATP-sensitive potassium (KATP) channel. Ischemic preconditioning is mediated by KATP channel activation. We therefore hypothesized that myocardium from patients taking long-term oral hypoglycemic agents would be resistant to the protection by ischemic preconditioning. Isolated human right atrial trabeculae were suspended in an organ bath at 37 degrees C, with field stimulation at 1 Hz. Control trabeculae were then subjected to 45 minutes of simulated ischemia (hypoxic, glucose-free buffer with pacing at 3 Hz) and 120 minutes of reperfusion. Ischemic preconditioned (IPC) trabeculae from patients without oral hypoglycemic therapy and from patients taking insulin (Ins+IPC) were given 5 minutes of simulated ischemia before this injury. Trabeculae (Oral Hypo+IPC) were obtained from patients taking long-term oral hypoglycemic agents and were also exposed to 5 minutes of simulated ischemia before this injury. Developed force (DF) was recorded. Recovery of DF relative to preischemic values was 28 +/- 4% in control trabeculae, whereas IPC trabeculae showed 52 +/- 5% recovery (P < .05 versus control). In patients receiving long-term oral hypoglycemic agents (Oral Hypo+IPC), recovery of DF was 27 +/- 3%, but in trabeculae from insulin-treated patients (Ins+IPC), it was 45 +/- 6%. Human myocardium from patients without long-term exposure to oral hypoglycemic agents is functionally protected by preconditioning. Long-term oral hypoglycemic intake blocks the protection by preconditioning. These data suggest that ischemic preconditioning in human myocardium relies on KATP channels, and long-term inhibition of KATP channels with oral hypoglycemic agents may explain the excess cardiovascular mortality in these patients.