Stereoselective inhibition of ethanol-induced gastric lesions in the rat by the H-3-receptor agonist (R)-alpha-methylhistamine and its (S)-configuredisomer

The histamine H-3 receptor shows high degree of stereoselectivity for hista mine analogues branched in the side chain. The hypothesis that gastroprotec tion by (R)-alpha-methylhistamine could be H-3 receptor-mediated was tested by comparing the effect: of (R)-alpha-methylhistamine and of (S)-alpha-met hylhistamine on ethanol-induced histologic lesions in the mt gastric mucosa . Extensive damage was caused by 60 min exposure to absolute ethanol, 91% o f the mucosa examined being damaged. Conversely only 23% of the mucose was damaged after pretreatment with (R)-alpha-methylhistamine (100 mg/kg i.g.). In the groups pretreated with (S)-alpha-methylhistamine (55.44 and 166.3 m g/kg i.g.) total damage ranged from 77 to 79%, though it was confined to th e upper portion of the mucose. Morphometric analysis of stained intraepithe lial mucosubstances revealed that (R)-alpha-methylhistamine pretreatment re sulted in an increase in number and volume of surface mucous cells, not evi dent after (S)-alpha-methylhistamine pretreatment. Scanning electron micros copy confirmed light microscopy evaluations. The two isomers of alpha-methy lhistamine differently affect the response of rat gastric mucose to absolut e ethanol and they appear to differ in their influence on surface mucous ce lls. A basis for interpreting the effects of the two isomers of a-methylhis tamine rests on the high degree of stereoselectivity of H-3 receptors and o n the different affinities of the two isomers for these receptors.