NEGATIVE DROMOTROPIC EFFECTS OF CLASS-I ANTIARRHYTHMIC DRUGS IN ANISOTROPIC VENTRICULAR MUSCLE

Objective: In a computer simulation study to mimic cardiac action pote ntial, the total open time of the sodium channel at each excitation ha s 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 t his hypothesis. Methods: Effects of flecainide (F), quinidine (Q), apr indine (A) and SD3212 (S) on conduction velocity (theta), amplitude of extracellular potentials (phi(e)), and maximum upstroke velocity (V o ver dot max) of action potentials were examined in isolated rabbit ven tricular muscles with microscopic anisotropy. Results: F (0.1-1 mu M) or Q (2-10 mu M), which blocks the sodium channel mainly during the ac tivated state, caused a concentration- and frequency-dependent decreas e in theta and phi(e). The reduction was more prominent during L than T propagation, giving rise to a decrease in their anisotropic ratio (t heta(L)/theta(T)). A (1-5 mu M) or S (3-10 mu M), which blocks the cha nnel during the inactivated state, also decreased theta and phi(e). Ho wever, the reduction was similar during L and T propagation, and the a nisotropic ratio of theta and phi(e) remained unaffected. The decrease of maximum upstroke velocity (V over dot max) of action potential by F or Q was greater during L than T propagation; V over dot max(L)/V ov er dot max(T) was decreased significantly. In contrast, the V over dot max reduction by A(3 mu M) or S (10 mu M) was similar during L and T propagation. Conclusion: Different state-dependence of sodium channel block may underlie different negative dromotropic effects of Class I d rugs in anisotropic cardiac muscle.