Pharmacological Characterization of Effects of UK-1745, a Novel Cardiotonic Agent withβ-Adrenoceptor-blocking Action, in Aequorin-loaded Canine Right Ventricular Muscle

Abstract

UK-1745, a derivative of furoindolinone, is a novel cardiotonic agent that was designed to have bothβ-adrenoceptor-blocking and cardiotonic activity. The aim of this study was to clarify the mode of action of UK-1745 in the canine and rabbit myocardium. UK-1745 elicited a weak but definite concentration-dependent positive inotropic effect in association with a decrease in the total duration of contraction: in particular, a decrease in the relaxation time in isolated canine right ventricular trabeculae. The maximum positive inotropic effect of UK-1745 was achieved at 3×10−5m and amounted to approximately 15% of the maximum response to isoproterenol. The EC50for the positive inotropic effect of UK-1745 was 3.3×10−6m . Carbachol, a muscarinic receptor agonist, at 3×10−6m completely inhibited the positive inotropic effect of UK-1745. UK-1745 shifted the concentration-response curve for isoproterenol to the right with pA2value of 5.70. By contrast, UK-1745 at 3×10−7to 3×10−5m shifted the concentration-response curve for forskolin to the left. In aequorin-loaded ventricular trabeculae, UK-1745 induced a positive inotropic effect that was accompanied by an increase in Ca2+transients. It did not affect the relationship between the amplitude of Ca2+transients and peak force as compared with that associated with elevation of the extracellular concentration of Ca2+ions ([Ca2+]o). The level of cyclic AMP in tissue was not significantly increased at 3×10−5m UK-1745. The present results indicate that UK-1745 exerts a positive inotropic effect mainly via a cyclic AMP-dependent mechanism but, in addition, it hasβ-adrenoceptor-blocking activity over the same range of concentrations. A drug with such a pharmacological profile might have the potential advantage of avoiding Ca2+overload and superfluous oxygen consumption, which may contribute to the unfavorable effects of novel cardiotonic agents that act purely by inhibition of phosphodiesterase III.