An explanation of bell-shaped, dose-positive inotropic effect curves for denopamine in canine right ventricular muscle

We investigated mechanisms by which denopamine produces bell-shaped, cumulative concentration-response curves for positive inotropic effect in canine right ventricular muscle. As in our previous study, the curves ascended at 10^-8 to 10^-6 M, reached a maximum at 3 × 10^-6 to 10^-5 M, and descended at higher concentrations. The ascending limb gave 6.58 ± 0.21 for the pD₂ value. Denopamine, when administered cumulatively up to 3 × 10^-5 to 3 × 10^-4 M, caused rightward shifts of concentration-response curves for the positive inotropic effect of isoproterenol. Application of a two-component fitting model to the concentration-response curves for isoproterenol in the presence of denopamine yielded two pA₂ values of denopamine; 6.59 ± 0.19 for the high- and 5.05 ± 0.21 for the low-affinity state of 13, receptors. The bell-shaped curves for denopamine were successfully computer-simulated with the following assumptions. (a) Denopamine produces a positive inotropic effect by binding to the high-affinity state of 13, receptors with an apparent dissociation constant of 10^-6.59 M. (b) The fraction of the high-affinity state decreases as denopamine binds to the low-affinity state with an apparent dissociation constant of 10^-5.05 M. Cyclic AMP levels were changed by denopamine, isoproterenol, and a combination of both, roughly in a parallel way to changes in positive inotropic effect.