Glibenclamide, an ATP-sensitive K+ channel blocker, inhibits cardiac cAMP-activated Cl- conductance.

Stimulation of the beta-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 mumol/L, n = 11) or forskolin (1 mumol/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 degrees C. External glibenclamide (> or = 10 mumol/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 mumol/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 approximately 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 mumol/L, n = 3), a specific inhibitor of cAMP-dependent protein kinase, and was suppressed by glibenclamide similarly, with an IC50 of 29.7 mumol/L.(ABSTRACT TRUNCATED AT 250 WORDS)