The saturability of a site of loss and the degree of supersensitivity to agonists which are substrates of this site of loss.

The present investigation was undertaken to test the hypothesis that the experimentally determined degree of supersensitivity to an agonist caused by inhibition of a site of loss depends on the ratio "Km of the site of loss/ED50 of the agonist". The influence of inhibition of neuronal uptake by cocaine on the alpha-adrenoceptor-mediated effect of noradrenaline was studied on the dog saphenous vein; the influence of inhibition of COMT by U-0521 on the beta-adrenoceptor-mediated effect of isoprenaline was studied on the dog saphenous vein and on the guinea-pig trachea; the influence of inhibition of acetylcholinesterase by physostigmine on the effect of acetylcholine was studied on the guinea-pig ileum. To further extend the range of values of the ratio "Km/ED50", several concentrations of phentolamine, propranolol or atropine were used to "increase the ED50" of the respective agonist. It was thus possible to determine the degree of supersensitivity caused by inhibition of a site of loss over a range of "Km/ED50" values of 0.02 to 2,307. In seven situations the ratio "Km/ED50" was higher than 10. In all of these cases the supersensitivity caused by inhibition of the site of loss was maximal. In eleven situations the ratio "Km/ED50" was less than 10 and higher than 0.1 and the supersensitivity obtained was sub-maximal but was closer to the maximum, the closer the ratio was to 10. In two situations the ratio was less than 0.1 and no supersensitivity was obtained. The results confirm the hypothesis.