Dual effect of sulfonylurea drugs on Ca²⁺ loading in hypoxic cardiac cells

Whether antidiabetic sulfonylurea drugs, such as glyburide, have deleterious effects upon the hypoxic myocardium through blockade of cardioprotective K_ATP channels remains controversial. To investigate this, the effect of glyburide on cytosolic Ca²⁺ concentration, an index of cell injury, and on K_ATP channel activity was measured using epifluorescent digital-imaging and cell-attached patch-clamp electrophysiology in a single cell model of chemical hypoxia induced by 2-4-dinitrophenol. Dinitrophenol (200 μM), which uncouples oxidativephosphorylation, induced opening of K_ATP channels and Ca²⁺ loading in ventricular guinea-pig cardiomyocytes. Glyburide (6 μM) which reduced the opening of K_ATP channels, aggravated Ca²⁺ loading only when applied to dinitrophenol-pretreated myocytes but not when applied concomitantly with dinitrophenol. We conclude that glyburide has differential effects upon dinitrophenol-induced intracellular Ca²⁺ loading, which appear to depend upon the stage of metabolic insult. These findings indicate that sulfonylurea-therapy may impair endogenous cardioprotective mechanisms, and that their use after the onset of myocardial ischemia can lead to accelerated cell death.