MEMBRANE PERTURBATIONAL EFFECTS OF ANTI-ARRHYTHMIC DRUGS

The structural and functional consequences of the interaction of various antiarrhythmic agents with human erythrocyte membranes were analyzed using drug concentrations influencing the stability of intact erythrocytes to hypotonic lysis, with the assumption that such stabilization may bear some molecular analogy to the stabilizing properties of these molecules in excitable tissues. Most of the agents tested, including quinidine, lidocaine, the verapamil analogue D-600 and the two quaternary analogues QX-572 and pranolium, produced concentration-dependent perturbations of membrane structural components as reflected by increases in the incorporation of 5,5′-dithio-bis-(2-nitrobenzoic acid) (DTNB) and trinitrobenzenesulfonic acid (TNBS) into membrane sulfhydryl and amino groups respectively. Practolol, a β-adrenergic antagonist which, unlike the foregoing agents, lacks significant cardiodepressant actions, did not appreciably modify the membrane incorporation of TNBS or DTNB, despite the fact that this molecule possessed marked antihemolytic properties. It, therefore, appears that the membrane perturbational actions of antiarrhythmics as analyzed here by means of group-specific chemical probes are a better index of the direct myocardial membrane actions than erythrocyte stabilization. The diverse perturbational characteristics of the various antiarrhythmics studied, as revealed by their different effects on the incorporation of TNBS into membrane protein and phospholipid components suggested the possibility that the molecular mechanisms by which these drugs alter cardiac automaticity may not be identical. This, in turn, might underlie the different spectra of clinical effectiveness exhibited by these agents. © 1979.