Endogenous agonists may change the concentration-response curves of exogenous agonists: source of quantitative information about the endogenous tone.

The "pharmacological dogma" that competitive antagonists cause parallel shifts to the right with sustained maximum effect of semi-logarithmic concentration-response curves of exogenous agonists may not be true if an endogenous agonist is present in the preparation. In this case, the antagonist and the exogenous agonist interfere in a complex way with an existing circuit of regulation between the response and the endogenous agonist. In consequence, it is difficult to determine the true shift in the concentration-response curves as induced by the antagonist, since a deviation of the curves in a non-parallel manner can be observed. The extent of this deviation may be used to learn more about the variables involved. The present paper discusses this phenomenon: The regulatory circuit of the (auto)receptor modulated release of neutrotransmitters is used as an example. Paired samples of data are analysed in this example. Since the extent of the non-parallel deviation also depends on the manner in which the paired samples are mathematically linked, two different ways of data evaluation have been used. A theoretical model of the relation between receptor activation and response is proposed which allows to evaluate experimental concentration-response curves by means of non-linear regression analysis. This evaluation yields quantitative information on the parameters of the regulatory circuit: the concentration of the endogenous agonist, its KD value and the true shift of the concentration-response curve caused by the applied antagonist.