Comparison between the activities of cationic amphiphilic drugs to affect phospholipid-membranes and to depress cardiac function.

The activity of cationic amphiphilic compounds to affect artificial phospholipid-membranes was compared with the membrane-stabilizing cardiodepressant potency of the drugs. The twenty-one investigated catamphiphilic compounds belonged to various pharmacological groups including antiarrhythmic, local anaesthetic, beta-blocking, antimalarial, and psychoactive drugs. The perturbing action of the drugs on phospholipid-membranes was evaluated by determining the drug-effect on the temperature of the phase-transition from the gel to the liquid crystalline state in liposomes of dipalmitoylphosphatidic acid by means of differential scanning calorimetry. The ability to interact with the polar headgroups of phospholipid-membranes was measured by recording the effects of the cationic compounds on the binding of 45Ca2+ to monomolecular layers of phosphatidylserine. The cardiodepressant action was observed in Langendorff-preparations of guinea-pig hearts. The drug-effect on excitability was indicated by the elevation of the threshold-intensity of 50 Hz alternating current to induce ventricular arrhythmia. For the sake of comparison, the negative chronotropic and inotropic effects were evaluated. There was only a moderate correlation found between the activities of the drugs to reduce the transition temperature and to inhibit 45Ca2+ -binding (r = 0.69). This result probably reflects that both methods look upon different consequences of the drug-phospholipid interaction. The membrane-stabilizing, anti-excitatory potency corresponded favourably with the ability of the drugs to affect the phospholipids. Almost 80% of the variance between the anti-excitatory potencies could be accounted for by the drug-phospholipid interactions. The negative chronotropic and inotropic effects accompanying the anti-excitatory actions were similar for most of the drugs. The results of the study are compatible with the hypothesis that the interaction with phospholipid-membranes is a major determinant of the membrane-stabilizing cardiodepressant potency of cationic amphiphilic drugs.