Negative inotropic effects of tetrodotoxin and seven class 1 antiarrhythmic drugs in relation to sodium channel blockade

Summary

• 1. The negative inotropic effect and the effect on action potential configuration were investigated for TTX and 7 class 1 antiarrhythmic drugs (aprindine, AR-LH 31, CCI 22277, disopyramide, mexiletine, quinidine and sparteine) in the isolated guinea-pig papillary muscle contracting at 1 Hz.

• 2. The ratio of the molar concentration producing 50% reduction of $\dot V_{\max }$ to that reducing force of contraction by 50% ranged from 0.23 (sparteine) to 2.2 (disopyramide) showing that some of the drugs were more potent Na channel blockers than negative inotropic agents, while the reverse was true for others.

• 3. With the exceptions of sparteine and AR-LH 31, all the drugs produced a larger negative inotropic effect than TTX at concentrations equieffective in reducing $\dot V_{\max }$. Thus, blockade of Na channels can account for only part of the negative inotropic effect of aprindine, CCI 22277, disopyramide, mexiletine and quinidine. Even sparteine and AR-LH 31 showed a negative inotropic property independent of Na channel blockade because, unlike TTX and like all other agents, they retained their negative inotropic activity after inactivation of Na channels by elevated extracellular K concentration (24 mmol/l).

• 4. Relative negative inotropic effects of lorcainide, Org 6001 and propafenone were similar at 5.9 and 24 mmol/l (K)_o. In contrast, the-log molar IC50(F _c) of flecainide, prajmalium bitartrate and tocainide was significantly decreased (by 0.35 to 0.81 log units) if Na channels were inactivated by K depolarization.

• 5. Ouabain-sensitive Na,K-ATPase was not inhibited by sparteine, while mexiletine and AR-LH 31 produced partial inhibition (each at 1 mmol/l).

• 6. We conclude that the negative inotropic effect of class 1 antiarrhythmic drugs represents the sum of their Na channel blocking and additional drug-dependent inotropic properties. Quinidine, aprindine and mexiletine appear to be combined Na channel and Ca channel inhibiting agents thus causing a larger negative inotropic effect than TTX. However, a superimposed positive inotropic mechanism may also be operative in some antiarrhythmic drugs (sparteine, AR-LH 31, high concentrations of mexiletine).