Selective beta 1-receptor full agonists, T-0509 and T-1583, increase the force monophasically and cyclic AMP biphasically in canine ventricular muscle

In canine right ventricular muscle, we investigated the mechanism of action of the positive inotropic effects of T-0509 and T-1583, derivatives of denopamine, a new selective beta 1-partial agonist. T-1583 has already been characterized as a selective beta 1 full agonist (pD2 = 7.39). T-0509 also behaved as a full agonist (pD2 = 8.27) and its positive inotropic effect was antagonized competitively by atenolol (pA2 = 7.53) and noncompetitively by carbachol, and potentiated by 3-isobutyl-1-methylxanthine. With increasing concentrations of T-0509 (10(-9) to 10(-7) M) and T-1583 (10(-8) to 10(-6) M), cyclic AMP increased and increases reached plateaus approximately 40% above the baseline levels with approximately 10(-7) M T-0509 and approximately 10(-6) M T-1583, at which their positive inotropic effects reached maxima. However, with further increasing concentrations, cyclic AMP again started to increase and increases amounted to approximately 120% above the baseline levels with 10(-5) M T-0509 and with 10(-4) M T-1583. These results suggest the following: Like denopamine, the selective beta 1 full agonists, T-0509 and T-1583, at lower concentrations produce positive inotropic effects accompanied by only a small increase in cyclic AMP via stimulation of high-affinity beta 1-receptors. In higher concentrations, unlike denopamine, the two full agonists produce large increases in cyclic AMP loosely coupled to positive inotropy via stimulation of low-affinity beta 1-receptors.