Dynamics of histamine H(3) receptor antagonists on brain histamine metabolism: do all histamine H(3) receptor antagonists act at a single site?

Thioperamide, the prototypical histamine H(3) receptor antagonist, acts at the brain histamine H(3) autoreceptor to promote the release and metabolism of neuronal histamine, resulting in higher brain levels of the metabolite tele-methylhistamine. However, unlike thioperamide, several new histamine H(3) receptor antagonists enter the central nervous system (CNS), block brain histamine H(3) receptors and increase histamine release without increasing brain tele-methylhistamine levels. Experiments were performed presently in an attempt to understand these results. Consistent with previous findings, thioperamide significantly increased the content and synthesis rate of tele-methylhistamine in mouse and rat brain. In contrast, the histamine H(3) receptor antagonists GT-2227 (4-(6-cyclohexylhex-cis-3-enyl)imidazole) and clobenpropit did not affect tele-methylhistamine synthesis rate in mouse whole brain. The histamine H(3) receptor ligand GT-2016 (5-cyclohexyl-1-(4-imidazol-4-ylpiperidyl)pentan-1-one) had no effect on tele-methylhistamine levels in any rat brain region and decreased tele-methylhistamine synthesis rates in the mouse whole brain. To examine the possibility that these histamine H(3) receptor antagonists might prevent the methylation of newly released histamine, they were co-administered with thioperamide to determine their effects on the thioperamide-induced stimulation of tele-methylhistamine synthesis. GT-2016 significantly reduced the thioperamide-induced activation of tele-methylhistamine synthesis in mouse whole brain and in several regions of rat brain. Although further clarification is needed, these results suggest that some histamine H(3) receptor antagonists may promote the release of neuronal histamine, but also act to reduce histamine methylation in vivo by an unknown mechanism.

Synthesis of N pi-methylhistamine and N alpha-methylhistamine by purified rabbit lung indolethylamine N-methyltransferase.

N tau-Methylhistamine is a major inactive metabolite of histamine and is formed by histamine N-methyltransferase (EC 2.1.1.8). However, a controversy exists concerning the presence of other N-methylated histamines, such as N pi- and N alpha-methylhistamine in mammalian tissues. Indolethylamine N-methyltransferase is present in mammalian tissues with the rabbit lung containing the highest concentration, but the physiologic function of this enzyme remains unclear. Using rabbit lung as a tissue source, we purified indolethylamine N-methyltransferase 260-fold and separated it completely from histamine N-methyltransferase. Histamine was a substrate for purified indolethylamine N-methyltransferase and unlike histamine N-methyltransferase which exclusively formed N tau-methylhistamine, indolethylamine N-methyltransferase catalyzed the in vitro formation of both N pi-methylhistamine and N alpha-methylhistamine. In contrast to histamine N-methyltransferase, indolethylamine N-methyltransferase activity was not inhibited by either high histamine concentrations or by quinacrine. Thus, mammalian tissues contain an enzyme capable of forming N pi-methylhistamine and N alpha-methylhistamine. This supports the concept of the existence of these compounds and suggests they may serve a physiologic function in mammals.

Histamine uptake and metabolism in intact isolated parietal cells.

3H-Histamine binding, uptake and metabolism were investigated in intact isolated and enriched parietal cells from the dog and guinea pig. Histamine uptake was sodium dependent and followed by intracellular metabolism. The only metabolite that was detected and extracted from cytosol has been identified by TLC to N tau-methylhistamine. The histamine N-methyltransferase activity appeared to be sodium dependent and was inhibited by mepyramine and chlorpromazine, and also by higher concentrations (10(-4)--10(-3) mol/l) of cimetidine. Two blockers of the sodium channel, amiloride an aminoguanidine, also reduced the enzyme activity by an as yet unknown mechanism.