We studied the onset and offset of use-dependent block (UDB) of maximum rate of rise of action potential (Vmax) with 3 x 10(-5)M mexilietine in guinea pig left atrium. A large decrease of Vmax was observed between the first and the second excitation when the preparations were stimulated at 4Hz after two minutes of rest period. UDB after the second excitation developed slowly to reach steady state within 30 sec. These two onset rates were 1.016 +/- 0.055 and 0.070 +/- 0.009/action potential. Recovery process was also fitted with two exponential equations. The time constant of the fast recovery was 528 +/- 23 msec. and the slow one was 3099 +/- 435 msec. The relative contribution of the slow component was 38.3 +/- 2.6% in the onset and 29.7 +/- 3.1% in the recovery. In spite of elevated maximum diastolic potential at 4 Hz stimulation, the relationship between resting membrane potential and Vmax disclosed voltage-dependent block of Vmax was no more than 5%. It is concluded that mexiletine has a slow kinetic component as well as a fast one. When atrial muscle is depolarized, Vmax decreases further. Therefore, mexiletine may be more effective against the atrial arrhythmias than predicted previously.