Phosphoinositide hydrolysis mediated by histamine H1-receptors in rat brain cortex

Histamine stimulated the accumulation of [3H]inositol 1-phosphate in the presence of lithium in [3H]inositol-prelabelled slices from rat brain cortex in a concentration-dependent manner, with an EC50 value of 94.7 microM. High concentrations of antagonists of histamine H2 receptors, muscarinic receptors, alpha 1-adrenoceptors and serotonin receptors did not inhibit the effect. The histamine H1-receptor antagonists mepyramine, triprolidine, promethazine, d-chlorpheniramine and the tricyclic antidepressant doxepin inhibited the response with Ki values corresponding to an interaction with histamine H1-receptors. The EC50 for the response was about three times lower than the Ki value (approximately 300 microM) for the inhibition by histamine of [3H]mepyramine binding to membranes from rat brain cortex. Partial inactivation of H1-receptors with the alkylating antagonist phenoxybenzamine resulted in similar reductions in [3H]mepyramine binding sites and in the maximal histamine-induced [3H]inositol 1-phosphate accumulation, without affecting the KD for the radioligand or the EC50 for the response. The apparent dissociation constant for histamine calculated from these experiments (KA = 92.2 microM) was not different from the EC50 value. The present results indicate that histamine-stimulated phosphoinositide hydrolysis in rat brain cortex is mediated by H1-receptors and that no receptor reserve is present.