A series of para-substituted triamterene derivatives (Table 1) were evaluated for their antiarrhythmic properties in vitro. Pharmacological evaluation of the compounds and some class-I- (quinidine, lidocaine, and propafenone) as well as class-III-antiarrhythmic drugs ((+/-)-sotalol and amiodarone) was carried out by measuring the functional refractory period (FRP), the maximal driving frequency (MDF) and the force of myocardial contractions (FC) of electrically stimulated guinea pig atria. The increase in FRP and the decrease in MDF was most pronounced with the class-I-antiarrhythmic drugs, but these compounds showed the typical negative inotropic effects, too. For the class-III-antiarrhythmics only a weak influence on FRP and MDF could be demonstrated, while FC was not altered in the presence of (+/-)-sotalol and amiodarone. Neutral substituted triamterenes like compounds 2-5 as well as most of the benzyltriamterene derivatives showed similar or stronger effects on FRP and MDF as (+/-)-sotalol and amiodarone. With the exception of 4 and 5, these effects were combined with an increase of FC. Compounds 6 and 7, well known-potent diuretics, showed no influence to FRP, MDF and FC. Therefore, we conclude different mechanisms for the antikaliuretic and cardiac activity.