Using microelectrode techniques we compared the effects of tetrodotoxin (TTX, 2-3 microM), DL-propranolol (1-3 micrograms/ml), and flecainide acetate (10-15 microM) on isolated canine ventricular epicardial (epicardium) and endocardial (endocardium) tissues. Propranolol, TTX, and flecainide decreased Vmax and phase 0 amplitude in a use-dependent manner in both tissues. The effects of propranolol were slow to develop and wash out. TTX and propranolol always abbreviated action potential duration in endocardium. Action potential duration was abbreviated by 23.8 +/- 5.6 msec after propranolol (1 microgram/ml, basic cycle length [BCL] = 1,000 msec) and 10.8 +/- 12.9 msec after TTX (2 microM, BCL = 1,000 msec). In epicardium, the reduction of phase 0 and 1 amplitudes led to a slowing of the second action potential upstroke and an increase in the amplitude of phase 2. This accentuation of the notch resulted in a paradoxical prolongation of the epicardial action potential. Action potential duration was prolonged 34.4 +/- 11.3 msec after 4 hours of exposure to propranolol (1 microgram/ml, BCL = 1,000 msec), 11.1 +/- 6.3 msec after 15 minutes of exposure to TTX (2 microM, BCL = 1,000 msec), and 19.9 +/- 8.2 msec after 25-45 minutes of exposure to flecainide (15 microM, BCL = 500 msec). With stronger sodium block, phase 1 terminated at more negative potentials, the second upstroke often failed to appear, and an all-or-none repolarization ensued causing a marked abbreviation of the epicardial action potential. In some epicardial preparations, we observed marked abbreviation at some sites but prolongation at other sites after sodium blockade with flecainide. The dispersion of repolarization was often attended by reentrant activity. The differential response of epicardium and endocardium to sodium blockade was not observed when the preparations were pretreated with 4-aminopyridine or ryanodine, agents known to diminish the transient outward current and epicardial notch. Acceleration-induced prolongation of refractoriness was observed after sodium blockade in epicardium but not in endocardium. Postrepolarization refractoriness also occurred in epicardium but not in endocardium after TTX, propranolol, or flecainide exposure. The data indicate that propranolol, TTX, and flecainide, via their action to block sodium current, may exert opposite effects on action potential duration and refractoriness in cells spanning the ventricular wall. The presence of the transient outward current in epicardium but not in endocardium appears to contribute importantly to these differences.(ABSTRACT TRUNCATED AT 400 WORDS)