Effects of ATP-dependent K+ channel modulators on an ischemia-reperfusion rabbit isolated heart model with programmed electrical stimulation.

The effects of glibenclamide and BRL-38227 were studied in isolated rabbit hearts subjected to ischemia and programmed electrical stimulation. Coronary artery occlusion over 24 min decreased the ventricular effective refractory period in the ischemic zone. BRL-38227 (0.1 microM) showed significant coronary vasodilator effects, but failed to modify the ventricular effective refractory period under these conditions. A higher concentration (5 microM) of BRL-38227 potentiated the ischemia induced ventricular effective refractory period shortening effects. Glibenclamide (0.1 and 1 microM) delayed the onset of the ischemia-induced ventricular effective refractory period shortening. Glibenclamide (1 microM) inhibited the potentiated ventricular effective refractory period shortening effects of BRL-38227 (5 microM) during ischemia, but failed to antagonise the coronary vasodilator effects of BRL-38227 (5 microM). A higher incidence of ventricular fibrillation was inducible when an extra beat was applied in the ischemic zone through programmed electrical stimulation. The incidence of programmed electrical stimulation induced ventricular fibrillation was increased by BRL-38227 (5 microM) and antagonised by glibenclamide (1 microM). The results suggest that high concentrations of KATP-activators can accentuate ischemia-induced decreases in refractory period and increase the susceptibility of hearts to ventricular fibrillation when an extra beat is applied to the ischemic myocardium. These effects did not occur at lower coronary vasodilating concentrations of BRL-38227.