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Histamine‐induced inositol phospholipid breakdown in the longitudinal smooth muscle of guinea‐pig ileum
Author(s) -
Donaldson J.,
Hill S.J.
Publication year - 1985
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1985.tb08887.x
Subject(s) - mepyramine , histamine , inositol , cimetidine , endocrinology , medicine , ileum , chemistry , histamine receptor , guinea pig , biology , receptor , biochemistry , antagonist
1 The characteristics of histamine‐stimulated inositol phospholipid breakdown in slices of guinea‐pig ileal smooth muscle and cerebellum have been investigated. 2 In cerebellar slices the inhibition of the inositol phospholipid response to histamine by mepyramine was consistent with competitive antagonism of histamine H 1 ‐receptors. 3 In slices of the longitudinal smooth muscle of guinea‐pig ileum, mepyramine produced only a weak inhibition of the response to histamine, at concentrations up to 1 μM. This was in striking contrast to the potent competitive antagonism of the H 1 ‐mediated contractile responses obtained with mepyramine in this tissue. 4 The H 1 ‐receptor antagonists (+)‐chlorpheniramine and promethazine similarly had no effect on the EC 50 value for histamine in guinea‐pig ileum, while promethazine competitively antagonized the muscarinic receptor‐mediated inositol phospholipid response in this tissue ( K a 3.6 × 10 7 M −1 ). 5 Cimetidine, on its own, did not significantly inhibit the inositol phosphate accumulation elicited by histamine in ileum. In the presence of 0.2 μM mepyramine, cimetidine (0.1 mM) produced a small parallel shift of the histamine concentration‐response curve ( K a 3 × 10 4 M −1 ). This inhibition, however, was not consistent with antagonism of an H 2 ‐receptor‐mediated response. 6 The effect of a range of histamine analogues on inositol phospholipid breakdown was determined. Dose‐response curves were constructed and characterized in terms of the EC 50 , slope and maximal response attainable relative to histamine. 7 The H 1 ‐agonists, N α , N α ‐dimethylhistamine, N α ‐methylhistamine, 2‐pyridylethylamine and 2‐thiazolylethylamine produced the largest accumulations of [ 3 H]‐inositol‐1‐phosphate. A very weak response was produced by the H 2 ‐selective agonist impromidine, while dimaprit (also H 2 ‐selective) was without significant effect. 8 Mepyramine appeared to antagonize competitively the response to the H 1 ‐selective agonist 2‐pyridylethylamine. This was in contrast to the data obtained with other H 1 ‐agonists, where mepyramine produced only a small dextral shift of the agonist curves at low agonist concentrations and an increase in the Hill coefficient. This was particularly striking in the case of 2‐methylhistamine. 9 The results suggest that an H 1 ‐receptor component in guinea‐pig ileum, may coexist with a larger inositol phospholipid response to histamine which is independent of the activation of H 1 ‐ or H 2 ‐receptors.