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 β1-partial agonist. T-1583 has already been characterized as a selective β1 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 non-competitively by carbachol, and potentiated by 3-isobutyl-l-methyl-xanthine. 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 40% above the baseline levels with 10-7 M T-0509 and 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 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 β1 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 β1-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 β1-receptors.
- Cyclic AMP
- Positive inotropic effect
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine