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.
D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D006632:Histamine / Q000494:pharmacology; D006868:Hydrolysis; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D007700:Kinetics; D008297:Male; D010643:Phenoxybenzamine / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D011738:Pyrilamine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011968:Receptors, Histamine / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000378:metabolism*
D007295:Inositol Phosphates; D010716:Phosphatidylinositols; D011968:Receptors, Histamine; D011969:Receptors, Histamine H1; D010643:Phenoxybenzamine; C002647:inositol 1-phosphate; D006632:Histamine; D011738:Pyrilamine