Analysis of competitive antagonism when this property occurs as part of a pharmacological resultant

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Abstract
In this paper, pharmacological resultant is defined as the net effect of a single compound resulting from the simultaneous expression of two or more specific actions. The principles of concentration‐ratio analysis are extended to develop a method for detecting and quantifying competitive antagonism when this property is a component of a pharmacological resultant. The method is general to the extent that it allows analysis of competitive antagonism in combination with all types of post‐receptor intervention. Essentially it depends on the altered expression of competition by a reference antagonist. It incorporates tests for validating its application and it is independent of agonist concentration‐effect curve shape: in these respects the method is analogous to Schild plot‐analysis of simple competition. The methodology for the practical application of the analysis is exemplified by studying the net effect of a combination of a phosphodiesterase inhibitor (isobutylmethylxanthine) and histamine H2‐ receptor antagonist (metiamide) on histamine‐stimulated tachycardia in guinea‐pig, isolated, right atrium. Cimetidine was used as the reference antagonist. The equation used in this analysis is similar in form to one recently described by Hughes & Mackay (1985) to elucidate the situation when competitive antagonism occurs in combination with functional interactions. The relation between their method and the present analysis is discussed.

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