HISTAMINE ACTIVATES PHOSPHORYLASE AND INOSITOL PHOSPHATE PRODUCTION IN GUINEA-PIG HEPATOCYTES

In guinea pig hepatocytes, histamine increased phosphorylase activity and inositol phosphate production. Similar effects were obtained with 2-(2-aminoethyl)-thiazole, a histamine H-1 receptor agonist, but not with dimaprit or impromidine, H-2 receptor agonists. These effects of histamine were dose-dependently inhibited by the H-1 antihistamines, (+)-chlorpheniramine and mepyramine (pyrilamine) but not by cimetidine or ranitidine, H-2 antagonists. (+)-Chlorpheniramine and mepyramine had similar potencies (apparent K(i) values almost-equal-to 3 nM) when incubated with the cells for 1 min (phosphorylase a assays) but the former was 15-20-fold more potent than the latter at longer incubation times (apparent K(i) values almost-equal-to 3-4 nM and 45-90 nM, respectively) indicating that mepyramine is actively metabolized by guinea pig hepatocytes. Histamine increased cytosol calcium approximately 2-fold, an effect also mediated through H-1 receptors. The actions of histamine were not affected by in vivo ADP-ribosylation by pertussis toxin. Our data clearly indicate that histamine modulates the metabolism of guinea pig hepatocytes via activation of H-1 receptors. These receptors are coupled to the phosphoinositide turnover-calcium mobilization signalling pathway through a pertussis toxin-insensitive process.