Inhibition of I_Ks channels by HMR 1556

Abstract.

Chromanol HMR 1556 [(3R,4S)-(+)-N-[3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methylmethanesulfonamide], a novel inhibitor of the slow component of the delayed outward current in heart muscle cells (I _Ks), has been characterized in several in-vitro systems. mRNA encoding for the human protein minK was injected into Xenopus oocytes, leading to the expression of I _Ks channels. HMR 1556 inhibited this current half-maximally at a concentration of 120 nmol/l (IC₅₀). Expression of the K⁺ channels Herg, Kv1.5, Kv1.3 and Kir2.1, and also the cationic current HCN2, were blocked little or not at all by 10 µmol/l HMR 1556. In isolated ventricular myocytes from the guinea pig the whole-cell patch-clamp method revealed inhibition of the I _Ks current with an IC₅₀ of 34 nmol/l. Other current components, like I _Kr and I _K1, were only slightly blocked at an HMR 1556 concentration of 10 µmol/l, whereas 10 µmol/l HMR 1556 inhibited the transient outward current I _to and the sustained outward current I _sus in rat ventricular myocytes by 25% and 36%, respectively. The L-type Ca²⁺ channel in guinea pig cardiomyocytes was blocked by 10 µmol/l HMR 1556 by 31%. Guinea pig right papillary muscles were investigated by the micropuncture technique at various pacing rates. In the frequency range of 0.5–7 Hz HMR 1556 (1 µmol/l) caused a prolongation of the action potential duration at 90% repolarization (APD₉₀) by 19%–27%. In the presence of isoproterenol (10 µmol/l) the prolongation of the APD₉₀ was more pronounced at low pacing rates (47% at 0.5 Hz and 35% at 1 Hz, compared with 25% at 7 Hz). The monophasic action potential was recorded in Langendorff-perfused guinea pig hearts. In spontaneously beating preparations, HMR 1556, at 0.1 µmol/l and 1 µmol/l, prolonged the MAPD₉₀ by 3% and 10%, respectively, with no further prolongation at 10 µmol/l. The prolongation was much greater at low pacing rates [25% at 100 beats per min (bpm) and 13% at 150 bpm] than at fast pacing rates (9% at 350 bpm). The left ventricular pressure LVP_max was not affected at 1 µmol/l HMR 1556, but it decreased by 15% at 10 µmol/l. Other parameters, like the heart rate and coronary flow, were only slightly decreased at 1 µmol/l HMR 1556. In conclusion, HMR 1556 is a potent and selective inhibitor of the I _Ks current in guinea pig ventricular myocytes. The prolongation of the action potential duration is maintained at fast pacing rates.