Though membrane depolarization is an imoportant step in signal transduction in living cells, it is immpossible to use microelectrode for analyses of the phenomenon in platelets due to the size limitation. Cetiedil, oc-cyclohexyl�3�thiophenacetic acid 2-(hexahydro-1H-azep in-1-yl) ester, is the drug which inhibits erythrocyte sickling by promoting net salt and water gain. It increases flux of both Na and K, and net Na gain exceeds net K loss. We used cetiedil as a tool to modify intracellular Na and K contents which are closely related to membrane potential.Normal human platelets contained 23.5±3.7 nEq of Na and 82.7±5.6 nEq of K per 108 platelets measured by atomic absorption spectrophotometer (n=6, meantSE). When 0.5 µ/ml of thrombin was added, Na content increased to 200 % and K content decreased to 80% of the resting value after 15 sec. 22 Na spaces of platelets (0.3L±0.07 µl/l0° platelets in the resting stage, n=4) increased to 0.53±0.12 at 2 min after thrombin. After 5 min incubation with 50 µM cetiedil, Na contents increased and K contents decreased slightly. Under the cetiedil treatment, the increase in Na and decrease in K contents induced by thrombin were inhibited significantly. The increase in 22 Na spaces induced by thrombin was also inhibited. Thrombin-induced membrane depolarization measured by membrane potential probe dye, diS, also was inhibited by cetiedil. In the presence of 50 yM cetiedil, magnitude of depolarization was 27.6±1.0 mV (n=30). The depolarization was not affected by Na transport inhibitors, such as procaine and tetrodotoxine, but inhibited by low Na content in the suspension medium. Cetiedil also inhibited platelet aggregation and TXA2 synthesis by thrombin. However, the treatment did not induce any changes in platelet volume, their morphology under elecrton microscope, Ca content and LDH leakage. There is a concept that a small degree of depolarization can inhibit the stimulus-response coupling of various kinds of cells. A similar mechanism might be present in platelet membrane. A role of membrane depolarization in platelet activation is suggested