A pharmacological method to estimate the pKi of competitive inhibitors of agonist uptake processes in isolated tissues.

An equation is derived from a mathematical model (proposed by Furchgott) which, under certain circumstances, estimates the pKI (-log dissociation constant) of a competitive inhibitor of agonist uptake by utilizing the sensitization of isolated tissues, to the substrate-agonist, by uptake inhibition. The method is theoretically more sound and appears to be improved by the use of potency-ratios of the substrate-agonist and an agonist which is not a substrate for the uptake process since this allows for the detection and correction of receptor and toxic effects of uptake inhibitors. The pKI values of cocaine, desmethylimipramine and imipramine for the neuronal uptake of norepinephrine were estimated by this method in guinea-pig tracheae and left atria. Also, the pKI values for 17 beta-oestradiol, corticosterone, clonidine and metanephrine for the extraneuronal uptake of isoproterenol were estimated in guinea-pig tracheae (and cat left atria for 17 beta-oestradiol). All estimates were consistent with literature pKI values obtained biochemically with radiolabelled substrates.