Triamterene Inhibits the Delayed Rectifier Potassium Current (IK) in Guinea Pig Ventricular Myocytes

In humans, proarrhythmia during therapy with action potential-prolonging drugs can be associated with hy-pokalemia often provoked by concomitant administration of diuretic agents. Consequently, therapy with class III antiar-rhythmics and K-sparing diuretics, such as triamterene, may be indicated. Triamterene, along with its K-sparing properties, exhibits other pharmacological effects. In the heart, it can increase action potential duration (guinea pig atria and papillary muscles), protect against reperfusion-induced arrhythmias (rat), and increase the QT interval (humans). Therefore, studies were undertaken to assess effects of triamterene on cardiac K repolarizing currents. Guinea pig ventricular myocytes were superfused at 30°C with Cd-containing solution to block Isi and held at −40 mV to inactivate INa. Currents were measured in the whole-cell configuration of the patch-clamp technique. The delayed rectifier outward current (IK) was elicited by short (250-millisecond) and long (5000-millisecond) depolarizing pulses, and time-independent currents were assessed by a rapid ramp test protocol. After high-voltage long pulses (+50 mV; 5000 milliseconds), tail current amplitude of the slow component of IK (IKs) was decreased 36±6% (n=6) and 51±8% (n=6) by triamterene 10 and 10 mol/L, respectively. After low-voltage short pulses (−20 mV; 250 milliseconds), tail current amplitude corresponding essentially to the rapid component of IK (IKr) was decreased only 14±11% (n=9) and 19±10% (n=10) by triamterene 10 and 10 mol/L, respectively. These results were confirmed under conditions of pure Iks (block of IKr by E-4031) and pure IKr (block of Isi with nisoldipine, extracellular Ca decreased to virtually 0 mmol/L, and 250-millisecond depolarizing pulse to −20 mV). In contrast, triamterene had no effects on time-independent currents. Thus, data obtained indicate that triamterene, at clinically relevant concentrations, inhibits IKs in a selective manner, although both components of IK (IKr and IKs) were decreased. This block of IK may explain triamterene-related prolongation of cardiac repolarization and warn about potential drug interaction with action potential-prolonging agents.