Glibenclamide, an ATP-Sensitive K + Channel Blocker, Inhibits Cardiac cAMP-Activated Cl − Conductance

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Abstract
Stimulation of the β-adrenoceptor activates a time-independent Cl− conductance that is known to be regulated via phosphorylation by cAMP-dependent protein kinase in guinea pig ventricular myocytes. Since epithelial cystic fibrosis transmembrane conductance regulator Cl− channels are known to be sensitive to an antidiabetic sulfonylurea, glibenclamide, we tested whether the drug modulates cardiac cAMP-activated Cl− conductance. Bath application of isoproterenol (1 μmol/L, n=11) or forskolin (1 μmol/L, n=17) or the intracellular application of cAMP (1 mmol/L, n=9) activated whole-cell Cl− currents recorded from single myocytes at 36°C. External glibenclamide (≥10 μmol/L, n=26) inhibited the Cl− current induced by either of the stimulants in a concentration-dependent manner. The half-maximal inhibition concentration (IC50) of glibenclamide and the Hill coefficient were 24.5 to 37.9 μmol/L and 1.6 to 2.2, respectively. During current-clamp experiments, forskolin was found to shorten the action potential significantly (250±45 to 201±52 milliseconds, P<.05) in 7 of 11 cells tested. Glibenclamide antagonized the forskolin-induced shortening (to 243±54 milliseconds, n=7, P<.05). Intracellular administration of sodium orthovanadate (0.5 to ≈1 mmol/L, n=6) brought about persistent activation of Cl− current after brief bath application of forskolin. This Cl− current was not affected by H-89 (100 μmol/L, n=3), a specific inhibitor of cAMP-dependent protein kinase, and was suppressed by glibenclamide similarly, with an IC50 of 29.7 μmol/L. Thus, it is concluded that glibenclamide inhibits cardiac cAMP-activated Cl− channels at some step(s) downstream from the phosphorylation/dephosphorylation process.