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Inhibitors of mast cell‐mediated shock in the rat: Relationship to histamine and serotonin antagonism
Author(s) -
Awouters Frans,
Niemegeers Carlos J. E.,
Janssen Paul A. J.
Publication year - 1981
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.430010203
Subject(s) - histamine , antagonism , serotonin , cyproheptadine , pharmacology , tryptamine , serotonin antagonists , chemistry , in vivo , biology , 5 ht receptor , biochemistry , receptor , microbiology and biotechnology
Thirteen compounds of heterogenous chemical structure and pharmacologic profile were studied in vivo in tests that measure antagonism of histamine and/or serotonin in the rat. These tests were the compound 48/80‐lethality test, skin reactions to histamine and serotonin, the PCA test, and tryptamine‐induced bilateral convulsions and tremors. The compounds were always administered orally with a time interval of 2 hr between dose and challenge, to allow quantitative comparisons between activities in different tests. Compounds that preferentially antagonize histamine in the skin test have the same potency rank in the histamine skin test and in the compound 48/80‐lethality test. This indicates not only that H 1 ‐antagonism is sufficient to prevent compound 48/80‐induced lethal shock, but also that the basis of the protection is the maintenance of a sufficiently large intravascular fluid volume compatible with normal cardiovascular function. Inhibition of a serotonin‐induced increase of capillary permeability may also be sufficient to prevent lethal shock, although the ergoline derivatives were much weaker than expected. For full inhibition of PCA‐reactions, doses are required that exhibit effective antagonism of both serotonin and histamine. Antagonism of tryptamine‐induced bilateral convulsions and tremors, which is a centrally mediated effect, showed no clear relation to any of the peripheral actions that were investigated.