Inhibition of cardiac inward-rectifier K+ current by terodiline

The antispasmodic agent terodiline has cardiotoxic effects that include QT lengthening. To determine whether inhibition of inwardly-rectifying K+ current (I-K1) might be a factor in the cardiotoxicity, we measured I-K1 in guinea pig ventricular myocytes. Terodiline reduced outward I-K1 with an IC50 of 7 mu M; maximal reduction was 60% with 100-300 mu M concentration. Inhibition was independent of current direction, and persisted after removal of the drug. Terodiline (3-5 mu M) lengthened action potentials in guinea pig papillary muscles by ca. 10%, primarily by slowing phase 3 repolarization; higher concentrations abbreviated the plateau and markedly slowed late repolarization. Terodiline washout provoked an extra lengthening, consistent with persistent inhibition of I-K1 and rapid recovery of net inward plateau current. The results suggest that inhibition of I-K1 is a likely factor in the cardiotoxicity of the drug. (C) 1999 Elsevier Science B.V. All rights reserved.