Effects of Trimebutine Maleate on Delayed Rectifier K+ Currents in Guinea-pig Ventricular Myocytes

Abstract

Abstract The effects of trimebutine maleate, a drug commonly used to regulate motility in the gastrointestinal tract, on the delayed rectifier K+ current (IK) were evaluated in guinea-pig ventricular myocytes to determine whether the drug has a proarrhythmic effect through blockade of IK. Trimebutine decreased IK in a concentration-dependent manner. To investigate the effects of trimebutine on two components of IK (IKr and IKs; rapidly activated and slowly activated components, respectively), we performed the envelope-of-tails test. Trimebutine-sensitive IK was determined by digital subtraction of IK during exposure to trimebutine from control IK for each duration of the test pulse over the range 50 ms-2 s. The ratio of ΔIK, tail/ΔIK plotted against pulse duration for trimebutine-sensitive IK gradually decreased to a steady-state value as the duration of the test pulse was lengthened. This finding suggested a weak inhibitory effect of trimebutine on both IKr and IKs. The effects of trimebutine on the inward rectifier K+ current (IKl) responsible for the resting potential and final repolarization phase of the action potential were investigated by applying voltage clamp ramps over a broad range of potentials. No significant effects were observed at 10 or 100 μm. We next investigated the effects of the drug on the L-type Ca2+ current (ICa). Significant inhibition of ICa was observed at trimebutine concentrations greater than 10 μm. These results suggested that trimebutine maleate has weak inhibitory effects on IKr, IKs and ICa at concentrations much higher than those in clinical use.