We recently demonstrated that the short-acting analog of amiodarone, ATI-2001, caused favorable effects in guinea pig ventricular myocardium on electrophysiological substrates underlying tachyarrhythmia initiation, perpetuation, and termination. Here, the acute effects of 1.0 microM ATI-2001 and 1.0 microM amiodarone (90-min infusion followed by 90-min washout period) on atrial and atrioventricular (AV) nodal electrophysiological properties were studied in guinea pig isolated hearts. Neither ATI-2001 nor amiodarone significantly prolonged atrial conduction time. Compared with amiodarone, ATI-2001 caused significantly more rapid and greater prolongation of atrial monophasic action potential duration at 90% repolarization (maximal change 21.4 +/- 3.7 versus 19.0 +/- 4.0 ms) and atrial effective refractory period (ERP, 27.8 +/- 6.1 versus 9.2 +/- 2.3 ms). Shortening of the atrial cycle length from 250 to 200 ms did not significantly alter drug-induced changes in atrial repolarization and refractoriness. ATI-2001 prolonged the atrium-to-His bundle interval (22.1 +/- 2.6 versus 8.8 +/- 2.3 ms), His bundle-to-ventricle interval (2.8 +/- 0.4 versus 0.9 +/- 0.3 ms), AV nodal ERP (72.5 +/- 7.3 versus 31.4 +/- 4.1 ms), and Wenckebach cycle length (69.6 +/- 5.2 versus 35.8 +/- 4.1 ms) significantly more than did amiodarone. Unlike amiodarone, the effects of ATI-2001 were markedly reversed upon discontinuation of drug infusion. Given these data, ATI-2001 should not only be useful for terminating ongoing and preventing reoccurrence of atrial tachyarrhythmias but also to treat supraventricular tachycardias involving the AV node and to control ventricular rate during atrial tachyarrhythmias. Whether the observed differences in the pharmacokinetic properties render ATI-2001 superior to amiodarone in acute tachyarrhythmia management and less likely to accumulate into tissues during chronic therapy remains to be established.