EFFECTS OF IBUTILIDE FUMARATE, A NOVEL ANTIARRHYTHMIC AGENT, AND ITS ENANTIOMERS ON ISOLATED RABBIT MYOCARDIUM

Ibutilide fumarate is currently in Phase II clinical trials for the treatment of life-threatening cardiac arrhythmias. The cardiovascular effects of ibutilide and its d- and l-stereoisomers, U82208E and U82209E were tested in an isolated rabbit myocardium system. In a series of repeated measures experiments, threshold, effective refractory period, force of contraction, conduction time and rate were measured at various pacing frequencies in isolated papillary muscles, ventricular muscle strips and right atria exposed to 10(-7), 10(-6) and 10(-5) M drug. Although there were occasional instances where one form had a greater or lesser effect on a given parameter, overall there was little pharmacological difference between the racemic mixture and its constituent forms. At the highest dose, effective refractory periods at 1 and 3 Hz increased by 18-32 ms, conduction times measured at 3 Hz increased by 27-30% and atrial rate decreased by 19-32%, while threshold and force of contraction were generally unaffected. In this study there were no clear cut pharmacologic differences between the three forms of this class III antiarrhythmic agent. Parallel studies to determine pA2 values of ibutilide and sotalol demonstrated that ibutilide possesses weak beta-adrenoceptor blocking properties.