Potent and reversible effects of ATI-2001 on atrial and atrioventricular nodal electrophysiological properties in guinea pig isolated perfused heart

We recently demonstrated that the short-acting analog of amiodarone, ATI-20 01, caused favorable effects in guinea pig ventricular myocardium on electr ophysiological substrates underlying tachyarrhythmia initiation, perpetuati on, and termination. Here, the acute effects of 1.0 muM ATI-2001 and 1.0 mu M amiodarone (90- min infusion followed by 90- min washout period) on atria l and atrioventricular (AV) nodal electrophysiological properties were stud ied in guinea pig isolated hearts. Neither ATI-2001 nor amiodarone signific antly prolonged atrial conduction time. Compared with amiodarone, ATI-2001 caused significantly more rapid and greater prolongation of atrial monophas ic action potential duration at 90% repolarization (maximal change 21.4 +/- 3.7 versus 19.0 +/- 4.0 ms) and atrial effective refractory period (ERP, 2 7.8 +/- 6.1 versus 9.2 +/- 2.3 ms). Shortening of the atrial cycle length f rom 250 to 200 ms did not significantly alter drug-induced changes in atria l repolarization and refractoriness. ATI-2001 prolonged the atrium-to-His b undle interval (22.1 +/- 2.6 versus 8.8 +/- 2.3 ms), His bundle-to-ventricl e 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 3 5.8 +/- 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 termina ting ongoing and preventing reoccurrence of atrial tachyarrhythmias but als o to treat supraventricular tachycardias involving the AV node and to contr ol ventricular rate during atrial tachyarrhythmias. Whether the observed di fferences in the pharmacokinetic properties render ATI-2001 superior to ami odarone in acute tachyarrhythmia management and less likely to accumulate i nto tissues during chronic therapy remains to be established.