M. Horie et al., Disopyramide and its metabolite enhance insulin release from clonal pancreatic beta-cells by blocking K-ATP channels, CARDIO DRUG, 15(1), 2001, pp. 31-39
Citations number
33
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
In an insulin-secreting pancreatic beta -cell line (MIN6), insulin release
was caused by disopyramide, an antiarrhythmic drug with Na-channel blocking
action, and its main metabolite mono-isopropyl disopyramide (MIP). Insulin
secretion, measured as immunoreactive insulin (IRI), was accelerated to 26
5.7% of the control by disopyramide and to 184.4% by MIP, with half-effecti
ve concentrations (EC50) of 30.9 +/- 1.5 muM and 92.4 +/- 2.2 muM. We teste
d the possibility that these drugs induce insulin release by inhibiting ATP
-sensitive K+ (K-ATP) channels of MIN6 cells. In the cell-attached or ATP-f
ree inside-out mode with patch membranes on MIN6 cells, K-selective channel
s were recorded with unitary conductance of 70.5 +/- 3.5 pS (150 mM externa
l K+ ions at room temperature). The channels were concluded to be MIN6-K-AT
P channels because they were closed by extracellular high glucose (11.0 mM)
or glibenclamide (200 nM) and were reversibly activated by diazoxide (50 m
uM). In the inside-out patch mode, they were inhibited by micromolar ATP. I
n both cell-attached and insideout mode, disopyramide and MIP inhibited sin
gle MIN6-K-ATP channels. In the inside-out mode, they produced a dose-depen
dent inhibition of channel activity: the half-blocking concentrations (IC50
) were 4.8 +/- 0.2 muM for disopyramide and 40.4 +/- 3.1 muM for MIP. It wa
s therefore concluded that both agents exert insulinotrphic effect through
the inhibition of membrane K-ATP channels in MIN6 cells.