The clinical use of positive inotropic agents has been associated with increased mortality, with proarrhythmia speculated to be a contributing factor. This study compares the arrhythmogenic potentials of six positive inotropic agents representing different mechanistic classes: the
beta-adrenergic agonist dobutamine, the
adenylyl cyclase activator
forskolin, the
phosphodiesterase-III inhibitor
milrinone, the
cardiac glycoside ouabain, and the
sodium channel agonists DPI 201-106 and
BDF 9148. These agents were studied in dogs with anterior
myocardial infarction using lower and higher dose i.v. regimens targeted to elicit 20-40% and 70-90% increases in LV+dP/dt, respectively. Precipitation of new ventricular
arrhythmia by programmed ventricular stimulation was observed in all treatment groups. Incidences of new
arrhythmia were comparable in the lower dose regimens, ranging from 16.7% (3/18 animals with
BDF 9148) to 31.6% (6/19 animals with
DPI 201-106), and in the higher dose regimens, ranging from 10.0% (1/10 animals with
milrinone) to 27.7% (5/18 animals with
DPI 201-106). The overall incidence of new ventricular
arrhythmia ranged from 27.3% (3/11 animals with
ouabain) to 47.4% (9/19 animals with
DPI 201-106). No differences were observed in underlying
infarct size or time from
infarction to electrophysiologic study between subgroups of animals in which new arrhythmias were precipitated vs. those remaining non-responsive in any treatment group. The positive inotropic agents tested displayed diverse total group effects on heart rate, electrocardiographic intervals including QTc and ventricular refractoriness. Within individual treatment comparisons revealed a general but not universal pattern of greater ventricular refractory period values in newly inducible vs. non-inducible subgroups in the
DPI 201-106,
BDF 9148 and
ouabain (low and high dose);
milrinone and
dobutamine (high dose) treatment groups. These findings indicate that regardless of underlying cellular mechanism of action, the six positive inotropic agents tested all displayed comparable proarrhythmic potentials unrelated to underlying
infarct size and time from
infarction. This observation suggests the general shared property of increased myocardial contractility, potentially adversely affecting myocardial
oxygen balance, myocardial perfusion and electrical stability in the setting of previous
myocardial infarction, to be a common underlying cause for arrhythmogenesis. Additionally, alterations in ventricular refractoriness and repolarization may contribute significantly to proarrhythmia with some positive inotropic interventions.