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Vol. 286, Issue 3, 1453-1464, September 1998
-Cells
Hoechst Marion Roussel, DG Cardiovascular, H 821, D-65926
Frankfurt/Main, Germany
The novel sulfonylthiourea HMR 1883 was investigated in in
vitro systems. The rilmakalim-induced shortening of the
APD90 in guinea pig right papillary muscle at
pHo = 6.0 was antagonized half-maximally by glibenclamide
and HMR 1883 with 0.14 µM and 0.6 µM, respectively. Hypoxia-induced
shortening of the APD90 was significantly attenuated by the
sulfonylureas when applied 60 min after induction of hypoxia. In
isolated guinea pig ventricular myocytes the APD90 as well
as the whole-cell current was measured with the patch-clamp technique.
The rilmakalim-induced shortening of the APD90 was
half-maximally antagonized by glibenclamide and HMR 1883 with 10 nM and
0.4 µM, respectively (pHo = 6.5). The rilmakalim-induced
whole-cell current (at 0 mV clamp-potential) was inhibited by
glibenclamide and HMR 1883 half-maximally with 20 nM and 0.8 µM,
respectively (pHo = 7.4). In isolated perfused guinea pig
hearts, the coronary flow (CF) was increased by perfusion with hypoxic
solution (20% O2). Whereas 1 µM glibenclamide completely inhibited the hypoxia-induced increase in CF, 10 µM HMR 1883 reduced it by only 18%. Pancreatic effects were investigated in rat insulinoma cells (RINm5F), which were hyperpolarized with 100 µM diazoxide. Addition of glibenclamide or HMR 1883 depolarized the cell potential half-maximally with concentrations of 9 nM and approximately 20 µM,
respectively. In conclusion, the sulfonylthiourea HMR 1883 blocks
KATPs in cardiac muscle cells with 10-50 fold higher
potency than in pancreatic 
-cells and has little effect on the
coronary vascular system. Therefore, HMR 1883 has pharmacological
selectivity for cardiac myocytes and thereby may be a promising
substance for the prevention of ischemia-induced ventricular
fibrillation.
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