DYNAMICS OF RECOVERY AND MEASURE OF DRUG ANTAGONISM. INHIBITION OF SMOOTH MUSCLE BY LYSOCITHIN AND ANTIHISTAMINICS

¹ Instituto Biologico, São Paulo, Brazil
² Department of Physiology, Faculty of Medicine, Univ. of São Paulo

A method of preparation of lysocithin is described and its inhibitory effect upon the action of histamine, acetylcholine and KCl on the guinea pig gut studied. A simple method for quantitative estimation of lysocithin is described on the basis of the speed of recovery of the gut from inhibition produced by 1 minute contact with lysocithin.

The index R₅₀ is defined as the time in seconds for a 50 per cent recovery after washing out of the inhibitor. This index is proposed as a measure of antagonism and it can be correlated to the dose of the inhibitor. A "spectrum" of inhibition can be obtained by testing alternately, upon the same gut, equipotent doses of several spasmogenic agents (histamine, acetylcholine, KCl, etc.).

Application of the method was extended to the antagonism produced by anti-histaminics, as neo-antergan, pyribenzamine, benadryl and antistine and also to antispasmodics of the trasentine type.

The kinetics of the process of recovery from inhibition was studied and a new constant k' was defined as the ratio k/P multiplied by 100, where k represents the "constant" of a first order reaction and P, the percentage contraction at any time, the initial response taken as 100 per cent.

R₅₀ was found to be theoretically and experimentally correlated to the average of k' for each concentration of inhibitor, according to the equation of a hyperbola. The reciprocal of k' () is numerically equivalent to the time in minutes for 85 per cent recovery. Since recovery from inhibition followed the same law, no matter which antagonist has been used, the suggestion is made that it depends upon the same intimate process developing in the muscle and that it probably depends upon the auto-catalytic regeneration of a metabolite or of some ionic arrangement in the surface of an operative enzyme, the activity of which is essential for muscle response.