OPENINGS OF CARDIAC K-ATP CHANNEL BY OXYGEN-FREE RADICALS PRODUCED BYXANTHINE-OXIDASE REACTION

We examined the effects of oxygen free radicals (OFRs) on action poten tials and membrane currents of guinea pig ventricular myocytes. OFRs p roduced biphasic changes in the action potential duration, initial len gthening (30 s after exposure to OFRs) and subsequent shortening (with in 5 min). In voltage-clamp experiments, OFRs suppressed the L-type ca lcium current, the delayed rectifier K+ current, and the inward rectif ier K+ current. In addition, OFRs increased the time-independent outwa rd current (I-term) at potentials greater than -30 mV. The increase in I-term reflected activation of the ATP-sensitive K+ (K-ATP) channels, as glibenclamide (1 mu M) blocked this current. In inside-out patches , OFRs significantly increased the open probability of the channel at a relatively narrow range of ATP concentrations (0.2-2 mM), and this e ffect was enhanced in the presence of ADP (0.1 mM) and abolished in th e presence of either free radical scavengers or glibenclamide. These f indings are compatible with the notion that OFRs activate K-ATP channe ls by modulating ATP binding sites of the K-ATP channels, without affe cting ADP binding or glibenclamide binding sites.