On the use of a dynamic approach to the estimation of dissociation constants for reversible competitive antagonists.
A dynamic approach to evaluating reversible competitive antagonists has been used in estimating the dissociation constant (apparent KB) for (+/-)-sotalol at beta adrenergic receptors which mediate a positive chronotropic response in rat atria. Cumulative dose-response curves to the beta agonists (-)-isoproterenol and (-)-soterenol were obtained after mixing each agonist with (+/-)-sotalol at fixed ratios (Q = [antagonist]/[agonist]). Experimental and theoretical dose-response curves obtained with the dynamic approach were in good agreement and the lowered maximum responses to the agonist-antagonist mixtures were dependent on Q. Also, apparent KB values for (+/-)-sotalol determined by three methods were independent of Q and agonist employed in the experiment. Apparent KB values for (+/-)-sotalol obtained by the dynamic method (6 x 10(-7)-2 x 10(-6) M) were similar to those obtained by the traditional equilibrium or static approach. As judged by the similarity of the apparent KB values derived by the two independent theoretical models, the dynamic approach may be considered an effective and alternative means to evaluate reversible competitive antagonists.
D000818:Animals; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000494:pharmacology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008954:Models, Biological; D051381:Rats; D011941:Receptors, Adrenergic / Q000187:drug effects*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D013015:Sotalol / Q000494:pharmacology
D004983:Ethanolamines; D011941:Receptors, Adrenergic; D011943:Receptors, Adrenergic, beta; C100252:soterenol; D013015:Sotalol; D007545:Isoproterenol