pyrimidinones and lupitidine

The gastric parietal cell is responsible for the secretion of HCl into the lumen of the stomach mainly due to stimulation by histamine via the cAMP pathway. However, the participation of several other receptors and pathways have been discovered to influence both stimulation and inhibition of acid secretion (e.g., cholinergic). Here we examine the role of phosphoinositide 3-kinase (PI3K) in the modulation of acid secretion. Treatment of isolated gastric glands and parietal cells with the PI3K inhibitor, LY294002 (LY), potentiated acid secretion in response to histamine to nearly the maximal secretion obtained with histamine plus phosphodiesterase inhibitors. As cAMP levels were elevated in response to histamine plus LY, but other means of elevating cAMP (e.g., forskolin, dbcAMP) were not influenced by LY, we posited that the effect might require activation of G-protein-coupled histamine H(2) receptors, possibly through the protein kinase B pathway (also known as Akt). Study of downstream effectors of PI3K showed that histaminergic stimulation increased Akt phosphorylation, which in turn was blocked by inhibition of PI3K. Expression studies showed that high expression of active Akt decreased acid secretion, whereas dominant-negative Akt increased acid secretion. Taken together, these data suggest stimulation with histamine increases the activity of PI3K leading to increased activity of Akt and decreased levels of cAMP in the parietal cell.

Topics: 1-Methyl-3-isobutylxanthine; Aminopyrine; Androstadienes; Animals; Carbachol; Cell Shape; Cells, Cultured; Cholinergic Agonists; Chromones; Cyclic AMP; Dose-Response Relationship, Drug; Epidermal Growth Factor; Gastric Acid; Gastric Mucosa; Histamine; Histamine H2 Antagonists; Morpholines; Mutation; Organ Culture Techniques; Parietal Cells, Gastric; Phosphatidylinositol 3-Kinases; Phosphodiesterase Inhibitors; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrimidinones; Rabbits; Receptors, Histamine H2; Signal Transduction; Time Factors; Transduction, Genetic; Wortmannin

A multiwavelength spectrophotometric (WApH) titration method was applied to study several multi-protic histamine H2-receptor antagonists which involved four acid dissociation constants (pKa values) over the pH range of 2-10. Specifically, UV absorption spectra of the drug solution were acquired in the course of a pH-metric titration using an optical device based on a fibre optics dip probe, a light source and a diode array detector. Target factor analysis was utilized to deduce the pKa values from the spectral data recorded at different pH. It was noted that some of the pKa values were within mid pH range which were difficult to obtain because of insufficient absorption spectra acquired in the un-buffered region of the titration curve. With the aid of the WApH technique coupled with an optically transparent buffer, all pKa values have been successfully determined and were in excellent agreement with those measured using a conventional pH-metric method.

Topics: Algorithms; Histamine H1 Antagonists; Hydrogen-Ion Concentration; Pyridines; Pyrimidinones; Solubility; Spectrophotometry, Ultraviolet

Murine hematopoietic progenitor cells synthesize substantial amounts of histamine in response to IL-3 or calcium ionophore. They also take up extracellular histamine by an active transport system. In the present study we demonstrate that this system mediates both influx and efflux of histamine. Indeed, MR16155 and thioperamide, the two H3 antagonists which are most effective in inhibiting histamine uptake, likewise diminish the release of preloaded histamine from bone marrow cells. These compounds also inhibit the release of histamine which has been newly synthesized by hematopoietic progenitors in response to IL-3 or calcium ionophore, as assessed by the accumulation of the mediator inside the cells in the presence of the antagonists. The potency of different histamine receptor antagonists as inhibitors of histamine release increases with their capacity to block histamine uptake.

Topics: Animals; Biological Transport; Calcium; Cell Line; Cetirizine; Cimetidine; Female; Hematopoietic Stem Cells; Histamine; Histamine Antagonists; Interleukin-3; Male; Mice; Mice, Inbred C57BL; Piperidines; Pyrimidinones; Sodium