A new method for determining affinity constants on isolated organs when a threshold value and spare receptors are present.
It was shown in previous studies that fixed ratio combinations of agonists with competitive antagonists emulate partial agonists and, therefore, mediate submaximal concentration-effect (E/[A]) curves. A linear plot was obtained by plotting the relative height (H) of these submaximal curves against phiH, where phi=[antagonist]/[agonist]. In this study, it was shown that in an agonist-effector system comprising a possible threshold value, the use of fixed ratio agonist-competitive antagonist concentrations (artificial partial agonists) induces E/[A] curves of different heights which allows one to quantify the threshold value. A nonlinear parabolic-like plot may be obtained when a threshold value is present in an agonist-effector system. By quantifying the threshold value, the nonlinear plot was converted to a linear plot from which the apparent affinity (KA) and an efficacy related parameter (eES) of an agonist could be estimated. The practical applicability of the method was shown by applying the method to E/[A] curves obtained for agonists (noradrenaline and acetylcholine) obtained in the presence and absence of increasing concentrations of their respective competitive antagonists on different effectors.
Venter
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DP
Department of Pharmacology, Potchefstroom University for Christian Higher Education, South Africa. fkldpv@puknet.puk.ac.za
Brink
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CB
D001667:Binding, Competitive; D008452:Maximum Allowable Concentration; D008962:Models, Theoretical; D010599:Pharmacokinetics; D011955:Receptors, Drug / Q000378:metabolism*; D013678:Technology, Pharmaceutical / Q000379:methods*
D011955:Receptors, Drug