BACKGROUND: 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. METHODS AND RESULTS: 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%. CONCLUSIONS: 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.
BACKGROUND: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. METHODS AND RESULTS: 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%. CONCLUSIONS: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.
Authors: Garrett J Gross; Anna Hsu; Eric R Gross; John R Falck; Kasem Nithipatikom Journal: J Cardiovasc Pharmacol Ther Date: 2012-03-09 Impact factor: 2.457
Authors: Tanner M Fullmer; Shaobo Pei; Yi Zhu; Crystal Sloan; Robert Manzanares; Brandon Henrie; Karla M Pires; James E Cox; E Dale Abel; Sihem Boudina Journal: J Mol Cell Cardiol Date: 2013-08-30 Impact factor: 5.000
Authors: S B Kristiansen; B Løfgren; N B Støttrup; D Khatir; J E Nielsen-Kudsk; T T Nielsen; H E Bøtker; A Flyvbjerg Journal: Diabetologia Date: 2004-10-07 Impact factor: 10.122