Effects of a novel cardioselective ATP-sensitive potassium channel antagonist, 1-[[5-[2-(5-chloro-o-anisamido)ethyl]-beta-methoxyethoxyphenyl]sulfonyl]-3-methylthiourea, sodium salt (HMR 1402), on susceptibility to ventricular fibrillation induced by myocardial ischemia: in vitro and in vivo studies.

Abstract

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.