FREQUENCY-DEPENDENT EFFECTS OF AMITRIPTYLINE AND MAPROTILINE ON CONDUCTION IN THE GUINEA-PIG HIS-PURKINJE-SYSTEM IN-VIVO

In the Cardiac Arrhythmia Suppression Trial antiarrhythmic drug therap y with slow kinetic sodium channel blockers (class Ic antiarrhythmic d rugs) was associated with excess mortality, presumably due to drug ind uced proarrhythmia. It has been suggested that the degree of rate-depe ndent conduction slowing produced by agents that have sodium channel b locking properties may be related to the proarrhythmic propensity of t hese agents. In the present study, rate-dependent conduction slowing b y the antidepressants amitriptyline and maprotiline was investigated i n anesthetized guinea pigs. After electrical ablation of the sinus nod e the left atrium was stimulated at cycle lengths between 200 ms and 5 00 ms. His bundle electrograms were registered by means of an epicardi al electrode. Drugs were administered by i.v. infusion of 0.2 mg kg(-1 ) min(-1) for 30 min followed by 0.1 mg kg(-1) min(-1) for up to 30 mi n. Both drugs produced substantial rate-dependent conduction slowing w ithin the His-Purkinje-system. The relationship between pacing rate an d conduction slowing was well fitted by linear regression. The steepne ss of the regression line was significantly greater for amitriptyline than for maprotiline (slope factors: 9.10 x 10(-4) +/- 7.85 x 10(-5), n = 6, vs. 6.29 x 10(-4) +/- 2.97 x 10(-5), n=6, P<0.001), indicating that conduction slowing by amitriptyline exhibits a greater degree of rate-dependence than conduction slowing by maprotiline. On abruptly ch anging the driving cycle length from 500 ms to 300 ms, conduction slow ing reached a new steady state with-rate constants of 0.83 +/- 0.093 b eat(-1) (amitriptyline) and 0.14 +/- 0.05 beat(-1) (maprotiline, P< 0. 001). Following interruption of rapid pacing at a cycle length of 250 ms, conduction slowing recovered with time constants of 332.4 +/- 52.8 ms (amitriptyline) and 1088.1 +/- 143.5ms (maprotiline, P= 0.001). Th us, amitriptyline exhibited fast kinetic properties similar to class I b antiarrhythmic action while the slower kinetic properties of maproti line resembled those of class Ia agents.