Histamine deficiency induces tissue-specific down-regulation of histamine H2 receptor expression in histidine decarboxylase knockout mice.

Histidine decarboxylase (HDC) is the single enzyme responsible for histamine synthesis. HDC-deficient mice (HDC(-/-)) have no histamine in their tissues when kept on a histamine-free diet. Therefore, the HDC(-/-) mice provide a suitable model to investigate the involvement of histamine in the regulation of histamine receptor expression. Gene expression of H1 and H2 histamine receptors was studied in several organs of HDC(-/-) mice and compared to standard (HDC(+/+)) mice. In many tissues, prolonged absence of histamine induced down-regulation of the H2 receptor subtype. The expression of the H1 receptor was less sensitive to histamine deficiency. Exogenous histamine present in the diet abolished the differences observed in H2 receptor expression. These results suggest that the expression of mouse H2 receptor is under the control of histamine in a tissue-specific manner.

Vincamine and vincanol are potent blockers of voltage-gated Na+ channels.

The effects of three vinca derivatives on [3H]batrachotoxin binding in rat cortical synaptosomes, on the inhibition of whole-cell Na+ currents evoked in voltage-clamped cortical neurones of the rat, on the protection against veratridine-induced cell death in cortical cultures and on the maximal electroshock-induced seizures in mice were compared. Vinpocetine, vincamine and vincanol reduced [3H]batrachotoxin binding with IC50 values of 0.34, 1.9 and 10.7 microM, blocked Na+ currents with IC50 values of 44.72 and 40 microM, and protected cortical against veratridine-induced cell death with IC50 values of 0.49, 26 and 33 microM, respectively. Upon i.p. administration, vinpocetine, vincamine and vincanol attenuated maximal electric shock-induced convulsions in a dose-dependent manner with ED50 values of 27, 15.4 and 14.6 mg/kg, respectively. The present findings indicate that the three vinca derivatives are potent blockers of voltage-gated Na+ channels, a mechanism that may contribute at least in part to the pharmacological/therapeutic benefit of these drugs.

Differential sensitivity to Arg side chain modification of IL-1 beta binding to type I and type II receptors.

The central role of interleukin-1 (IL-1) in several disease processes, including fever and inflammation, makes the characterization of ligand-receptor interaction of prime importance. The role of arginine (Arg) side chains of hr-IL-1 beta in receptor recognition was studied by the modification of Arg residues with the specific reagent 1,2-cyclohexanedione. It was found that chemical modification of Arg residues decreased the binding potential of IL-1 beta to type I receptor dramatically (by 230-fold) while the affinity to type II receptor was reduced only moderately (by 10-fold), with an insignificant reduction of the dissociation rate. These studies suggest that intact Arg side chains of IL-1 beta may be necessary for high affinity binding to type I IL-1 receptor, but have less importance for the interaction of IL-1 beta with type II IL-1 receptor. This observation may be useful in the study of type II IL-1 receptor-mediated biological responses and design of receptor-subtype specific ligands as well.