© 1995 American Heart Association, Inc.
Articles |
Glibenclamide, an ATP-Sensitive K+ Channel Blocker, Inhibits Cardiac cAMP-Activated Cl- Conductance
Presented as preliminary data in abstract form (Circulation. 1992;86[suppl I]:I-695).
From the Department of Cellular and Molecular Physiology (M.T., Y.O.), National Institute for Physiological Sciences, Okazaki, Japan, and The Third Department of Internal Medicine (M.H., S.S.), Faculty of Medicine, Kyoto University, Japan.
Abstract Stimulation of the ß-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.
Key Words: cardiac myocytes • Cl- channels • guinea pigs • phosphorylation
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