TRADITIONAL INOTROPIC agents used in the treatment of congestive heart failure (CHF), such as catecholamines and phosphodiesterase inhibitors, enhance myocardial contractile force via adenosine 38,58-cyclic monophosphate (cAMP)-dependent pathways, which are downregulated in CHF (2, 7). Accordingly, inotropic responsiveness is frequently depressed in CHF patients, and tolerance may develop during longer term infusions. In addition, these agents increase heart rate and may enhance ventricular ectopy, both of which are undesirable side effects. The existence of a class of dihydropyridine compound derivatives that exert positive inotropic actions by enhancing systolic transsarcolemmal calcium flux through L-type calcium channels has been recognized for a long time; the most prominent of these is BAY K 8644 (21). However, lack of myocardial specificity of that compound greatly limited its potential clinical utility, mainly because of its vasoconstricting actions (10, 12).
More recently, BAY y 5959, a dihydropyridine derivative with cardioselective calcium-channel agonistic activity, has been discovered (1, 11). BAY y 5959 binds with high affinity to the cardiac dihydropyridine receptor component of the calcium channel and prolongs the single-channel open time (1). Preliminary studies of this compound in various models have shown its inotropic actions to be preserved in heart failure (20, 24), that it has bradycardic actions (with associated action potential prolongation) (6, 17), and that it may exert a relative oxygen-saving effect compared to inotropism with b-agonists (4, 5, 20). These features have renewed interest in this class of compounds as a potential new therapy for heart failure (16, 17). However, interpretation of results of studies in intact, awake dogs are complicated by direct or indirect effects of drug infusion on baroreflexes and potentially on vascular properties (preload and afterload), and the degree to which the identified characteristics reflect direct vs. indirect myocardial effects on the heart, while of primary importance, is not certain.