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 X 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 X 10(-5) to 3 X 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 beta 1 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 beta 1 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.
Yokoyama
H
H
Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan.
Ishii
K
K
Yanagisawa
T
T
Taira
N
N
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D013268:Stimulation, Chemical
D002316:Cardiotonic Agents; D004983:Ethanolamines; D000242:Cyclic AMP; D007545:Isoproterenol; C037293:denopamine