TY - JOUR
T1 - An explanation of bell-shaped, dose-positive inotropic effect curves for denopamine in canine right ventricular muscle
AU - Yokoyama, Hitoshi
AU - Ishii, Kuniaki
AU - Yanagisawa, Teruyuki
AU - Taira, Norio
PY - 1989/10
Y1 - 1989/10
N2 - 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.
AB - 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.
KW - Cardiotonic agent
KW - Cyclic AMP
KW - Denopamine
KW - β Agonist
KW - β Receptors
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U2 - 10.1097/00005344-198910000-00008
DO - 10.1097/00005344-198910000-00008
M3 - Article
C2 - 2478770
AN - SCOPUS:0024432543
VL - 14
SP - 570
EP - 576
JO - Journal of Cardiovascular Pharmacology
JF - Journal of Cardiovascular Pharmacology
SN - 0160-2446
IS - 4
ER -