Pharmacological characterization of effects of UK-1745, a novel cardiotonic agent with beta-adrenoceptor-blocking action, in aequorin-loaded canine right ventricular muscle.
UK-1745, a derivative of furoindolinone, is a novel cardiotonic agent that was designed to have both beta-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 3x10(-5)m and amounted to approximately 15% of the maximum response to isoproterenol. The EC50 for the positive inotropic effect of UK-1745 was 3.3x10(-6)m. Carbachol, a muscarinic receptor agonist, at 3x10(-6)m completely inhibited the positive inotropic effect of UK-1745. UK-1745 shifted the concentration-response curve for isoproterenol to the right with pA2 value of 5.70. By contrast, UK-1745 at 3x10(-7)to 3x10(-5)m 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 3x10(-5)m 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 has beta-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.
Sawada
H
H
Department of Pharmacology, Yamagata University School of Medicine, Yamagata, Japan.
Endoh
M
M
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000331:Aequorin; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D006352:Heart Ventricles / Q000187:drug effects*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D011817:Rabbits
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D007211:Indoles; C112026:UK 1745; D005576:Colforsin; D000331:Aequorin; D002217:Carbachol; D000242:Cyclic AMP; D007545:Isoproterenol