title: Inhibition of IKs 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 (IKs), 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 IKs channels. HMR 1556 inhibited this current half-maximally at a concentration of 120 nmol/l (IC50). Expression of the K+ channels Herg, Kv 1.5, Kv 1.3 and Kir2.1, and also the cationic current HCN2, were blocked little or not at all by 10 micromol/l HMR 1556. In isolated ventricular myocytes from the guinea pig the whole-cell patch-clamp method revealed inhibition of the IKs current with an IC50, of 34 nmol/l. Other current components, like IKr and IK1. were only slightly blocked at an HMR 1556 concentration of 10 micromol/l, whereas 10 micromol/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 micromol/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 micromol/l) caused a prolongation of the action potential duration at 90% repolarization (APD90) by 19%-27%. In the presence of isoproterenol (10 micromol/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 micromol/l and 1 micromol/l, prolonged the MAPD90 by 3% and 10%, respectively, with no further prolongation at 10 micromol/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 micromol/l HMR 1556, but it decreased by 15% at 10 micromol/l. Other parameters, like the heart rate and coronary flow, were only slightly decreased at 1 micromol/l HMR 1556. In conclusion, HMR 1556 is a potent and selective inhibitor of the IKs current in guinea pig ventricular myocytes. The prolongation of the action potential duration is maintained at fast pacing rates.
authors.affiliation: Aventis Pharma Deutschland GmbH, DG Cardiovascular Diseases, Frankfurt am Main, Germany. heinz.goegelein@aventis.com
authors.forename: H
authors.initials: H
authors.lastname: Gögelein
authors.forename: A
authors.initials: A
authors.lastname: Brüggemann
authors.forename: U
authors.initials: U
authors.lastname: Gerlach
authors.forename: J
authors.initials: J
authors.lastname: Brendel
authors.forename: A E
authors.initials: AE
authors.lastname: Busch
mesh_terms: D000818:Animals; D016275:Atrial Function; D002839:Chromans / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006325:Heart Atria / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D009206:Myocardium / Q000166:cytology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010477:Perfusion; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D002839:Chromans; C420023:HMR 1556; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D013449:Sulfonamides; C059983:potassium channel protein I(sk)