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

1 The rate‐dependent contributions of the rapid and slow components of the cardiac delayed rectifier K + 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 n M ) prolonged MAPD 90 in a concentration‐dependent manner ( P <0.001, n =6) with reverse rate‐dependence ( P <0.0001). In contrast, HMR 1556 (10–240 n M ) alone did not prolong MAPD 90 . However, in the presence of 7.5 n M dofetilide, HMR 1556 (100 n M ) increased the extent of reverse rate‐dependence by further prolonging MAPD 90 at CLs of 400, 450 and 500 ms ( P <0.05, n =9) and, to a lesser extent, at shorter CLs (e.g. by 17±4 ms at CL 500 vs 2±3 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 (0.081±0.013) than after dofetilide alone (0.028±0.018, P <0.01, n =9). 5 Blockade of rabbit I Ks increased reverse rate‐dependence of I Kr block.British Journal of Pharmacology (2006) 148 , 255–263. doi: 10.1038/sj.bjp.0706721