Desensitization of the isolated guinea pig ileum to antihistaminic agents

Guinea pig ileum developed in vitro a progressive desensitization to the antihistaminic agents mepyramine and benadryl. This desensitization had uncommon characteristics: (1) at the 6.5-9 h period of the experiments, it consisted only of a decreased rate of action of the drugs (1.66 fold and 2 fold increases in the 2 min Kb value of mepyramine and benadryl respectively), without variation in the equilibrium Kb values; (2) it was not a drug effect since control strips (strips exposed to the first dose of antihistaminic agent after 5.5 h in vitro) also showed a decreased rate of action of the drugs (1.58 fold and 1.6 fold increases in the 2 min Kb value of mepyramine and benadryl respectively), without variation in the Kbe values. The desensitization also did not depend on the bathing medium or on the amount of available histamine receptors. The only explanation of the desensitization is a slowing in the antihistaminic agent-receptor reaction either in its access stage or less probably in its interaction stage.