Effects of ketotifen on in vitro bronchoconstriction

We have studied the effects of Ketotifen [Ke] (10(-4)M and 10(-6)M) on two in vitro models of bronchoconstriction: actively sensitized guinea-pig trachea (GPT), and passively sensitized human bronchial muscle (HBM). Experiments were performed on matched pairs of tissues. Cumulative dose response curves [CDRC] for histamine and acetyl choline were constructed, and repeated after pre-incubation with Ke or saline control. The effect of Ke on maximal antigen induced contractions was also studied. Contraction of GPT by histamine and acetyl choline was inhibited by Ke 10(-4)M, though this effect was not apparent at high doses of acetyl choline. Ke 10(-6)M had a weaker inhibitory effect on histamine and acetyl choline induced responses. Contraction of GPT by antigen was unaffected by Ketotifen. In the HBM model, Ke 10(-4)M inhibited acetyl choline and antigen induced responses. Ketotifen, 10(-6)M had an inhibitory effect on acetyl choline induced contractions, though this was small, and not seen at higher agonist doses. Contraction of HBM by antigen was unaffected by Ke 10(-6)M. We were unable to obtain reproducible CD RC's to histamine with HBM. The weaker or absent effects of Ke 10(-6)M, a level close to that obtained in clinical practice, may explain some of the poor results of clinical trials, and suggest that efficacy may be improved by the use of higher doses.