Inhibition of I-Ks channels by HMR 1556

Chromanol HMR 1556 [(3R,4S)-(+)-N-[3-hydroxy-2,2-dimethyl-6-(4,4,4-trifluor obutoxy)chroman-4-yl]-N-metrhylmethanesulfonamide], a novel inhibitor of th e slow component of the delayed outward current in heart muscle cells (I-Ks ), has been characterized in several in-vitro systems. mRNA encoding for th e human protein minK was injected into Xenopus oocytes, leading to the expr ession 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, K v1.5, Kv1.3 and Kir2.1, and also the cationic current HCN2, were blocked li ttle or not at all by 10 mu mol/l HMR 1556. In isolated ventricular myocyte s 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, l ike I-Kr and I-K1, were on slightly blocked at an HMR 1556 concentration of 10 mu mol/l, whereas 10 mu mol/l HMR 1556 inhibited the transient outward current I-to and the sustained outward current I-sus in rat ventricular myo cytes by 25% and 36%, respectively. The L-type Ca2+ channel in guinea pig c ardiomyocytes was blocked by 10 mu mol/l HMR 1556 by 31%. Guinea pig right papillary muscles were investigated by the micropuncture technique at vario us pacing rates. In the frequency range of 0.5-7 Hz HMR 1556 (1 mu mol/l) c aused a prolongation of the action potential duration at 90% repolarization (ADP(90)) by 19%-27%. In the presence of isoproterenol (10 mu mol/l) he pr olongation of the APD(90) was more pronounced at low pacing rates (47% and 0.5 Hz and 35% at 1 Hz, compared with 25% at 7 Hz). The monphasic action po tential was recorded in Langendorff-perfused guinea pig hearts. In spontane ously beating preparations, HMR 1556, at 0.1 mu mol/l and 1 mu mol/l, prolo nged the MAPD(90) by 3% and 10%, respectively, with no further prolongation at 10 mu mol/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 LVPmax was not affected at 1 mu mol/l HMR 1556, but it decreased by 15% at 10 mu mol/l. Other parameters , like the heart rate and coronary flow, were only slightly decreased at 1 mu mol/l HMR 1556. In conclusion, HMR 1556 is a potent and selective inhibi tor of the I-Ks current in guinea pig ventricular myocytes. The prolongatio n of the action potential duration is maintained at fast pacing rates.