The effects of class I antiarrhythmic drugs (quinidine, lidocaine, ethmozin) on the maximum upstroke velocity (Vmax) of the action potential (AP) of guinea-pig papillary muscles were investigated in the presence and absence of nifedipine and a potassium-free solution. Nifedipine (10 microM) decreased AP duration from 208 +/- 13 ms to 148 +/- 17 ms (P less than 0.05, n = 4), but did not influence resting potential and Vmax. Removal of K+ from the perfusate increase the membrane potential from -86 +/- 4 mV to -103 +/- 7 mV (P less than 0.05, n = 4). Quinidine (20 microM) lidocaine (40 microM) and ethmozin (2 microM) decreased Vmax. Nifedipine and K(+)-free solution elevated Vmax when depressed by lidocaine and ethmozin. At 2 Hz rate of stimulation, Vmax increased from 69.5 +/- 12.0% to 76.0 +/- 10.6% and 98.5 +/- 3.2% (P less than 0.05, n = 7) for lidocaine and from 33.9 +/- 13.9% to 41.3 +/- 14.4% and 75.3 +/- 10.3% (P less than 0.05, n = 6) for ethmozin, compared to the control, when nifedipine or K(+)-solution was used, respectively. Nifedipine induced a slight decrease and potassium-free solution, a slight increase of Vmax in the case with quinidine from 49.9 +/- 11.8% to 48.8 +/- 7.2% and 52.7 +/- 6.7 (P greater than 0.05, n = 7), respectively. The time constant of recovery (tau r) from use-dependent block of Vmax decreased in K(+)-free solution containing lidocaine and ethmozin, but not quinidine. The guarded receptor hypothesis was used to stimulate the effects of these drugs. Our estimates of the drug affinities for activated, inactivated, and rested channels were: for quinidine 1.28 x 10(5), 1.15 x 10(4), 1.0 x 10(3); for lidocaine 1.7 x 10(4), 1.88 x 10(5) 2.5 x 10(1); and for ethmozin 1.5 x 10(6), 3.0 x 10(6), 1.5 x 10(4), respectively. The results suggest that the role of AP duration on lidocaine and ethmozin effectiveness is reduced when resting potential decreases and that removal of K+ from a perfusate containing. quinidine had a small effect on Vmax, despite a marked increase in AP duration and resting potential.