Histamine‐induced inositol phospholipid breakdown in the longitudinal smooth muscle of guinea‐pig ileum

Abstract

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 H₁-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 H₁-mediated contractile responses obtained with mepyramine in this tissue. 4 The H₁-receptor antagonists (+)-chlorpheniramine and promethazine similarly had no effect on the EC₅₀ 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 × 10⁷ 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 × 10⁴ M⁻¹). This inhibition, however, was not consistent with antagonism of an H₂-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 EC₅₀, slope and maximal response attainable relative to histamine. 7 The H₁-agonists, N^α, N^α-dimethylhistamine, N^α-methylhistamine, 2-pyridylethylamine and 2-thiazolylethylamine produced the largest accumulations of [³H]-inositol-1-phosphate. A very weak response was produced by the H₂-selective agonist impromidine, while dimaprit (also H₂-selective) was without significant effect. 8 Mepyramine appeared to antagonize competitively the response to the H₁-selective agonist 2-pyridylethylamine. This was in contrast to the data obtained with other H₁-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 H₁-receptor component in guinea-pig ileum, may coexist with a larger inositol phospholipid response to histamine which is independent of the activation of H₁- or H₂-receptors.