HMR 1883, a novel cardioselective inhibitor of the ATP-Sensitive potassium channel.: Part I:: Effects on cardiomyocytes, coronary flow and pancreatic β-cells

The novel sulfonylthiourea HMR 1883 was investigated in in vitro systems. The rilmakalim-induced shortening of the APD(90) in guinea pig right papillary muscle at pH(o) = 6.0 was antagonized half-maximally by glibenclamide and HMR 1883 with 0.14 mu M and 0.6 mu M, respectively. Hypoxia-induced shortening of the APD(90) was significantly attenuated by the sulfonylureas when applied 60 min after induction of hypoxia. In isolated guinea pig ventricular myocytes the APD(90) as well as the whole-cell current was measured with the patch-clamp technique. The rilmakalim-induced shortening of the APD(90) was half-maximally antagonized by glibenclamide and HMR 1883 with 10 nM and 0.4 mu M, respectively (pH(o) = 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 mu M, respectively (pH(o) = 7.4). In isolated perfused guinea pig hearts, the coronary flow (CF) was increased by perfusion with hypoxic solution (20% O-2). Whereas 1 mu M glibenclamide completely inhibited the hypoxia-induced increase in CF, 10 mu M HMR 1883 reduced it by only 18%. Pancreatic effects were investigated in rat insulinoma cells (RINm5F), which were hyperpolarized with 100 mu M diazoxide. Addition of glibenclamide or HMR 1883 depolarized the cell potential half-maximally with concentrations of 9 nM and approximately 20 mu M, respectively. In conclusion, the sulfonyl-thiourea HMR 1883 blocks K(ATP)s in cardiac muscle cells with 10-50 fold higher potency than in pancreatic beta-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.