HMR 1556, A Potent and Selective Blocker of Slowly Activating Delayed Rectifier Potassium Current

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Abstract
The slowly activating delayed rectifier potassium current (IKs) contributes prominently to ventricular repolarization of the cardiac action potential. Development of a selective IKs blocker is important for the elucidation of the physiologic and pathophysiologic relevance of IKs and the development of antiarrhythmic strategies. HMR 1556 [(3R,4S)-(+)-N-[3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy) chroman-4-yl]-N-methylmethanesulfonamide] is a new chromanol derivative developed as a selective IKs blocker. Chromanol 293B, the most specific IKs blocker currently available, also inhibits the transient outward current (Ito). HMR 1556 was examined for its effects on IKs compared with rapidly activating delayed rectifier (IKr), inward rectifier (IK1), Ito, and L-type calcium (ICa,L) currents in canine left ventricular myocytes. HMR 1556 (0.5-500 n M) inhibited IKs in a concentration-dependent manner (IC50 of 10.5 n M, compared with chromanol 293B's IC50 of 1.8 μM). Inhibition of Ito was observed only at relatively high concentrations (IC50 of 33.9 μM, comparable to chromanol 293B's IC50 of 38 μM). High concentrations of HMR 1556 also inhibited ICa,L (IC50 of 27.5 μM) and IKr (IC50 of 12.6 μM) while IK1 was unaffected. Our results indicate that HMR 1556 is superior to chromanol 293B in its potency and specificity for inhibition of IKs, making it a valuable experimental tool and a potential therapeutic agent.