DUAL EFFECT OF GLYBURIDE, AN ANTAGONIST OF K-ATP CHANNELS, ON METABOLIC INHIBITION-INDUCED CA2+ LOADING IN CARDIOMYOCYTES

Whether sulfonylurea therapy, which blocks ATP-sensitive K+ (K-ATP) ch annels, impedes endogenous cardioprotective mechanisms during cellular metabolic impairment remains controversial. Therefore, the effect of glyburide, a prototype sulphonylurea drug, on cytosolic Ca2+ concentra tion and K-ATP channel activity, was measured in 2-4-dinitrophenol-tre ated guinea-pig cardiomyocytes, using epifluorescent digital-imaging a nd cell-attached patch-clamp electrophysiology. Dinitrophenol (200 mu M), which uncouples oxidative phosphorylation, induced opening of K-AT P channels and Ca2+ loading. Glyburide (6 mu M) which reduced the open ing of K-ATP channels, aggravated Ca2+ loading only when applied to di nitrophenol pretreated myocytes but not when applied with dinitropheno l treatment. We conclude that a blocker of K-ATP channels has differen tial effects upon dinitrophenol-induced intracellular Ca2+ loading, wh ich appear to depend upon the stage of metabolic insult.