Stereoselective Inhibition of Ethanol- Induced Gastric Lesions in the Rat by the H3-Receptor Agonist (R)-α-Methylhistamine and Its (S)-Configured Isomer

Abstract

The histamine H₃ receptor shows high degree of stereoselectivity for histamine analogues branched in the side chain. The hypothesis that gastroprotection by (R)-α-methylhistamine could be H₃ receptor-mediated was tested by comparing the effect of (R)-α-methylhistamine and of (S)-α-methylhistamine on ethanol-induced histologic lesions in the rat gastric mucosa. Extensive damage was caused by 60 min exposure to absolute ethanol, 91% of the mucosa examined being damaged. Conversely only 23% of the mucosa was damaged after pretreatment with (R)-α-methylhistamine (100 mg/kg i.g.). In the groups pretreated with (S)-α-methylhistamine (55.44 and 166.3 mg/kg i.g.) total damage ranged from 77 to 79%, though it was confined to the upper portion of the mucosa. Morphometric analysis of stained intraepithelial mucosubstances revealed that (R)-α-methylhistamine pretreatment resulted in an increase in number and volume of surface mucous cells, not evident after (S)-α-methylhistamine pretreatment. Scanning electron microscopy confirmed light microscopy evaluations. The two isomers of α-methylhistamine differently affect the response of rat gastric mucosa to absolute ethanol and they appear to differ in their influence on surface mucous cells. A basis for interpreting the effects of the two isomers of α-methylhistamine rests on the high degree of stereoselectivity of H₃ receptors and on the different affinities of the two isomers for these receptors.