BACKGROUND The changes of the resting potential (RP) and of the current-voltage (I-V) relationship induced by l-palmitoylcarnitine (l-PC) in the presence of the IKI blocker, cesium, or in the presence of the INa/K blocker, ouabain, were tested in guinea pig ventricular myocytes to ascertain the relative contributions of IKI and INa/K suppression to the membrane depolarization caused by this amphiphile. RESULTS Ramp voltages were applied to myocytes with the whole cell, patch clamp technique. l-PC (10 microM) produced additional membrane depolarization in the presence of either 10 mM Cs+ or 30 microM ouabain. In the presence of Cs+, l-PC, like 3 microM ouabain, shifted current inward at potentials negative to -20 mV as a result of INa/K blockade. In the presence of 30 microM ouabain, l-PC, like Cs+, shifted current inward at potentials between -27 and -88 mV and outward at potentials negative to -88 mV. This is attributed to IKI block because the current was inwardly rectifying, with a reversal potential near EK. When l-PC or ouabain inhibited INa/K, the presence of an Ni(2+)-sensitive component attributed to INa/Ca distorted the membrane I-V relationship, particularly in the presence of Cs+. The relative contributions of IKI and INa/K block by l-PC were voltage dependent. At the RP, l-PC produced a greater block of INa/K than of IKI. CONCLUSIONS l-PC depolarizes the resting membrane by inhibiting both IKI and INa/K. It is concluded that suppression of INa/K by l-PC predominates over block of IKI to depolarize the membrane at the RP.