Effects of trimebutine maleate on delayed rectifier K+ currents in guinea-pig ventricular myocytes

The effects of trimebutine maleate, a drug commonly used to regulate motili ty in the gastrointestinal tract, on the delayed rectifier K+ current (I-K) were evaluated in guinea-pig ventricular myocytes to determine whether the drug has a proarrhythmic effect through blockade of I-K. Trimebutine decreased I-K in a concentration-dependent manner. To investiga te the effects of trimebutine on two components of I-K (I-Kr and I-Ks; rapi dly activated and slowly activated components, respectively), we performed the envelope-of-tails test. Trimebutine-sensitive I-K was determined by dig ital subtraction of I-K during exposure to trimebutine from control I-K for each duration of the test pulse over the range 50 ms-2 s. The ratio of Del ta I-K,I-tail/Delta I-K plotted against pulse duration for trimebutine-sens itive I-K gradually decreased to a steady-state value as the duration of th e test pulse was lengthened. This finding suggested a weak inhibitory effec t of trimebutine on both I-Kr and I-Ks The effects of trimebutine on the in ward rectifier K+ current (I-K1) responsible for the resting potential and final repolarization phase of the action potential were investigated by app lying voltage clamp ramps over a broad range of potentials. No significant effects were observed at 10 or 100 mu M. We next investigated the effects o f the drug on the L-type C2+ current (I-Ca). Significant inhibition of I-Ca was observed at trimebutine concentrations greater than 10 mu M. These results suggested that trimebutine maleate has weak inhibitory effect s on I-Kr, I-Ks and I-Ca at concentrations much higher than those in clinic al use.