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 (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.

Probing the Contribution of I Ks to Canine Ventricular Repolarization

“…Concentrationresponse studies on I Ks tails ( Figure 2B) confirmed that HMR 1556 is a more potent I Ks blocker than 293B. 10,11 During AP recordings with high-resistance microelectrodes under baseline conditions, AP configurations remained unaltered at 3 and 10 mol/L 293B, but a slight loss of the notch occurred at 30 mol/L, consistent with I to inhibition. 13 Complete loss of the notch, triangulation of the AP, and aspecific APD responses were observed at 100 mol/L.…”

“…For studies in conscious dogs (6 beagle dogs and 4 mongrel dogs), aliquots of the selective I Ks blocker HMR 1556 10,11 were suspended in 0.5% hydroxyethylcellulose or packed in gelatin capsules and fed to the animals in the morning after overnight fasting. ECG monitoring was done with 24-hour Holter recordings or with telemetry transmitters and a computerized acquisition system (Data Science Inc).…”

Antiarrhythmic Efficacy of Combined IKs and β-Adrenergic Receptor Blockade

“…The magnitude of APD prolongation with chromanol 293b was increased in guinea pig papillary muscle and dog Purkinje fiber in the presence of isoproterenol (Schreieck et al, 1997;Han et al, 2001). HMR1556 prolonged APD in vitro in guinea pig papillary muscle in a frequency-independent manner, again with APD prolongation increased in the presence of isoproterenol (Gogelein et al, 2000). In dog left ventricular epicardial, mid-myocardial, and endocardial tissues, exposure to chromanol 293b produced a homogeneous frequency-independent prolongation in APD (Burashnikov and Antzelevitch, 2000).…”

“…These are the chromanols exemplified by compound 293b and HMR1556 (Busch et al, 1996;Gogelein et al, 2000), and the benzodiazepines L-735821 and L-768673 ( Fig. 1) (Salata et al, 1996b;Selnick et al, 1997).…”

Evidence for KCNQ1 K+ channel expression in rat zymogen granule membranes and involvement in cholecystokinin-induced pancreatic acinar secretion

“…1A). Moreover, HMR-1556 (0.1-100 M), another specific inhibitor of KCNQ1-type K ϩ channels (15,17,32), also inhibited the ZG K ϩ conductive pathway with a similar potency (data not shown). When K ϩ is used as the major osmolyte, both K ϩ -selective and a nonselective monovalent cation permeability pathway contribute to overall ZG lysis (49).…”