beta-Adrenergic tachyphylaxis in the rat and its reversal and prevention by ketotifen

Abstract

A strong, long-lasting and reproducible tachyphylaxis was produced in rats by implantation of osmotic minipumps delivering isoprenaline continuously. The degree of tachyphylaxis was determined by measuring the inhibitory effect of isoprenaline on the passive cutaneous anaphylaxis (PCA). One dose of ketotifen given 1 h before the PCA test reversed this in vivo tachyphylaxis, as did dexamethasone given 24 h earlier. Implantation of a second minipump containing ketotifen prevented the development of tachyphylaxis. Weak tachyphylaxis was induced in guinea-pig trachea in vitro by incubation with a high concentration of isoprenaline, the effect being estimated by measuring the relaxation of carbachol-contracted trachea. Ketotifen partially restored the sensitivity of the trachea but this was considered to be a direct potentiation of isoprenaline effects rather than a reversal of tachyphylaxis since the same effect was seen in non-pretreated trachea. It is thought that the reversal of experimental beta-adrenergic tachyphylaxis by ketotifen could have implications for its use in the prophylactic treatment of asthma.