In the present study, a novel sulfonylthiourea, 1-[[5-[2-(5-chloro-o-anisamido)ethyl]-beta-methoxyethoxyphenyl]sulfonyl]-3-methylthiourea,
sodium salt (
HMR 1402), was investigated using in vitro and in vivo systems.
HMR 1402 inhibited
rilmakalim-induced currents in rat and guinea pig myocytes (IC(50) = 60 and 509 nM, respectively).
Hypoxia-induced shortening of action potential duration at 90% repolarization was also significantly attenuated by
HMR 1402 (68.1 +/- 3.9% of control at 0.3 microM). In contrast,
HMR 1402 had a smaller effect on pancreatic beta-cells (rat
insuloma cells, RINm5F) hyperpolarized with 100 microM
diazoxide (IC(50) = 3.9 microM, compared with
glibenclamide IC(50) = 9 nM). In a similar manner,
hypoxia induced increases in coronary flow in isolated guinea pig hearts were only slightly reduced by
HMR 1402. These data strongly suggest that
HMR 1402 has pharmacological selectivity for cardiac myocytes and, therefore, may protect against ischemically induced
ventricular fibrillation (VF) without the untoward effects of nonselective compounds. To test this hypothesis, VF was induced in 8 dogs with healed
myocardial infarctions by a 2-min
coronary occlusion during the last minute of exercise. On a subsequent day, the exercise plus
ischemia test was repeated after
HMR 1402 (3.0 mg/kg i.v., n = 4, infusion 4 microg/kg/min for 1 h before exercise, n = 4). This
drug significantly reduced the incidence of VF protecting seven of eight animals (p = 0.0007) without altering plasma
insulin,
blood glucose, or the increases in mean coronary blood flow induced by either exercise or 15-s
coronary occlusions. Thus, the
ATP-sensitive potassium channel antagonist
HMR 1402 can prevent ischemically induced VF without altering coronary blood flow or
blood glucose.