Inhibition of immunological histamine release from guinea pig lungs and other organs by mepyramine, ketotifen, and picumast in vivo.

The effect of mepyramine, ketotifen and picumast (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin dihydrochloride) on anaphylactic histamine release from lungs, heart, stomach, and intestine of guinea pigs in response to antigen was examined in vivo. When sensitized animals were pretreated intraperitoneally with a single dose of these compounds 60 min before i.v. antigen challenge (native ovalbumin 20 mg/kg), a dose related inhibition of immunological histamine release from the lung was established. After pretreatment of the animals with 3 mg/kg of mepyramine, 10 mg/kg of ketotifen, and 6 mg/kg of picumast dihydrochloride, the inhibitory effect on histamine release from the lung was so marked that both the acute and the protracted anaphylactic shock were completely suppressed. The corresponding histamine levels in blood plasma, regularly measured 1.5 min after antigen stimulation, had dropped to about 40%, 50%, and 35%, respectively (p less than 0.05), whereas lung histamine content increased by about 60%, 150%, and 90% compared with unpretreated, shocked controls. According to these findings the number of lung mast cells in protected animals was significantly increased. In addition, ketotifen significantly reduced histamine release from heart and intestine. In contrast the compound injected intravenously 1 min before antigen challenge had no effect on mast cell degranulation and on histamine liberation, thus only decreasing the acute anaphylactic bronchospasm. These data suggest that all three drugs were acting as H1-antagonists when administered immediately prior to the antigen-provoked anaphylactic reaction. The property of these drugs to inhibit mast cell degranulation and the reduction of mediator release, however, appears to depend on their prolonged action on these cells. Together with their histamine antagonism anaphylactic death is thus prevented.