Negative dromotropic effects of Class I antiarrhythmic drugs in anisotropic ventricular muscle

OBJECTIVE: In a computer simulation study to mimic cardiac action potential, the total open time of the sodium channel at each excitation has been shown by other authors to be longer during propagation parallel (longitudinal, L) to fiber orientation than perpendicular (transverse, T) to that. If this is the case in actual cardiac tissue, the Class I antiarrhythmic drug action on conduction would be affected by their mode of sodium channel block. The present study was designed to test this hypothesis. METHODS: Effects of flecainide (F), quinidine (Q), aprindine (A) and SD3212 (S) on conduction velocity (theta), amplitude of extracellular potentials (phi e), and maximum upstroke velocity (Vmax) of action potentials were examined in isolated rabbit ventricular muscles with microscopic anisotropy. RESULTS: F (0.1-1 microM) or Q (2-10 microM), which blocks the sodium channel mainly during the activated state, caused a concentration- and frequency-dependent decrease in theta and phi e. The reduction was more prominent during L than T propagation, giving rise to a decrease in their anisotropic ratio (theta L/theta T). A (1-5 microM) or S (3-10 microM), which blocks the channel during the inactivated state, also decreased theta and phi e. However, the reduction was similar during L and T propagation, and the anisotropic ratio of theta and phi e remained unaffected. The decrease of maximum upstroke velocity (Vmax) of action potential by F or Q was greater during L than T propagation; VmaxL/VmaxT was decreased significantly. In contrast, the Vmax reduction by A(3 microM) or S (10 microM) was similar during L and T propagation. CONCLUSION: Different state-dependence of sodium channel block may underlie different negative dromotropic effects of Class I drugs in anisotropic cardiac muscle.