Influence of action potential duration and resting potential on effects of quinidine, lidocaine and ethmozin on [formula omitted] in guinea-pig papillary muscles

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The effects of class I antiarrhythmic drugs (quinidine, lidocaine, ethmozin) on the maximum upstroke velocity ( V ̇ max ) 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 μ m) decreased AP duration from 208 ± 13 ms to 148 ± 17 ms ( P < 0.05, n = 4), but did not influence resting potential and V ̇ max . Removal of K + from the perfusate increased the membrane potential from −86 ± 4 mV to −103 ± 7 mV ( P < 0.05, n = 4). Quinidine (20 μ m) lidocaine (40 μ m) and ethmozin (2 μ m) decreased V ̇ max . Nifedipine and K +-free solution elevated V ̇ max when depressed by lidocaine and ethmozin. At 2 Hz rate of stimulation, V ̇ max increased from 69.5 ± 12.0% to 76.0 ± 10.6% and 98.5 ± 3.2% ( P < 0.05, n = 7) for lidocaine and from 33.9 ± 13.9% to 41.3 ± 14.4% and 75.3 ± 10.3% ( P < 0.05, n = 6) for ethmozin, compared to the control, when nifedipine or K +-free solution was used, respectively. Nifedipine induced a slight decrease and potassium-free solution, a slight increase of V ̇ max in the case with quinidine from 49.9 ± 11.8% to 48.8 ± 7.2% and 52.7 ± 6.7 ( P > 0.05, n = 7), respectively. The time constant of recovery ( τ r) from use-dependent block of V ̇ max decreased in K +-free solution containing lidocaine and ethmozin, but not quinidine. The guarded receptor hypothesis was used to simulate the effects of these drugs. Our estimates of the drug affinities for activated, inactivated, and rested channels were: for quinidine 1.28 × 10 5, 1.15 × 10 4, 1.0 × 10 3; for lidocaine 1.7 × 10 4, 1.88 × 10 5, 2.5 × 10 1; and for ethmozin 1.5 × 10 6, 3.0 × 10 6, 1.5 × 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 V ̇ max despite a marked increase in AP duration and resting potential.