Blockade of I_Ks by HMR 1556 increases the reverse rate‐dependence of refractoriness prolongation by dofetilide in isolated rabbit ventricles

Abstract

1 The rate-dependent contributions of the rapid and slow components of the cardiac delayed rectifier K þ current (I Kr and I Ks , respectively) to repolarization are not fully understood. It is unclear whether the addition of I Ks block will attenuate reverse rate-dependence seen after I Kr block. 2 The individual and combined electrophysiological effects of selective I Kr and I Ks blockers, dofetilide and HMR 1556, respectively, were evaluated using Langendorff-perfused rabbit hearts. Monophasic action potential duration at 90% repolarization (MAPD 90 ) and ventricular effective refractory period (VERP) were determined at cycle lengths (CLs) of 200-500 ms (at 50 ms intervals). 3 Dofetilide (1-100 nM) prolonged MAPD 90 in a concentration-dependent manner (Po0.001, n ¼ 6) with reverse rate-dependence (Po0.0001). In contrast, HMR 1556 (10-240 nM) alone did not prolong MAPD 90 . However, in the presence of 7.5 nM dofetilide, HMR 1556 (100 nM) increased the extent of reverse rate-dependence by further prolonging MAPD 90 at CLs of 400, 450 and 500 ms (Po0.05, n ¼ 9) and, to a lesser extent, at shorter CLs (e.g. by 1774 ms at CL 500 vs 273 ms at CL 200 ms). 4 Effects of dofetilide and HMR 1556 on VERP were similar to those on MAPD 90 . The slope of the VERP vs CL relation was steeper after the combination (0.08170.013) than after dofetilide alone (0.02870.018, Po0.01, n ¼ 9). 5 Blockade of rabbit I Ks increased reverse rate-dependence of I Kr block.

Selective Targeting of Gain-of-Function KCNQ1 Mutations Predisposing to Atrial Fibrillation

“…31 In Langendorff-perfused rabbit hearts, HMR-1556 alone was not sufficient to prolong monophasic action potential duration (APD) but co-administration of either dofetilide alone or dofetilide with veratridine caused significant lengthening of APD. 32,33 These reports emphasize the potential proarrhythmic effects of high concentration HMR-1556 or of concurrent I Ks and I Kr inhibition. Fortunately, our data indicate that selective inhibition of S140G-I Ks can be achieved at HMR-1556 concentrations that do not suppress WT-I Ks .…”

The anaesthetized rabbit with acute atrioventricular block provides a new model for detecting drug‐induced Torsade de Pointes

“…Also, the QT interval of the acute AVB rabbit was longer than that of normal rabbits (139–192 ms), those receiving α 1 ‐adrenoceptor agonist (131–163 ms), transgenic LQT1 rabbits (241 ms), LQT2 rabbits (264 ms) or LQT5 rabbits (140 ms) during sinus rhythm (200–250 beats min −1 ) without AVB (Carlsson et al , ; Lu et al , ; Brunner et al , ; Hagiwara et al , ; Major et al , ). The sensitivity of the heart to QT‐interval prolonging drugs is modified by the contribution of I Ks in the repolarization phase (Jost et al , ; So et al , ), whereas the density of I Ks in the isolated ventricular myocytes from rabbits is lower than those from other species like guinea pigs (Lu et al , ). In addition, I Ks in the ventricle is accumulated in a frequency‐dependent manner in the presence of β 1 ‐adrenoceptor stimulation (Stengl et al , ; Nissen et al , ).…”

Voltage-gated potassium channels as therapeutic targets

“…Selective inhibitors of K V 7.1 like the chromanol HMR1556 ( 24 ) from Sanofi-Aventis133,134 and L-768,673 ( 25 ) from Merck have also been reported to prolong cardiac action potentials and reduce the incidence of arrhythmias in animal models. HMR1556 - which has greater than 1000-fold selectivity for IKs over IKr, restores sinus rhythm and prevents heart failure in pigs with persistent atrial fibrillation135,136. However, in a canine model of vagal AF, HMR1556 prolonged the atrial effective refractory period, but exerted only a modest effect on the duration of induced AF137.…”