Stereoselective inhibition of ethanol-induced gastric lesions in the rat by the H(3)-receptor agonist (R)-alpha-methylhistamine and its (S)-configured isomer.
The histamine H(3) receptor shows high degree of stereoselectivity for histamine analogues branched in the side chain. The hypothesis that gastroprotection by (R)-alpha-methylhistamine could be H(3) receptor-mediated was tested by comparing the effect of (R)-alpha-methylhistamine and of (S)-alpha-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)-alpha-methylhistamine (100 mg/kg i.g.). In the groups pretreated with (S)-alpha-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)-alpha-methylhistamine pretreatment resulted in an increase in number and volume of surface mucous cells, not evident after (S)-alpha-methylhistamine pretreatment. Scanning electron microscopy confirmed light microscopy evaluations. The two isomers of alpha-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 alpha-methylhistamine rests on the high degree of stereoselectivity of H(3) receptors and on the different affinities of the two isomers for these receptors.
Morini
G
G
Institute of Pharmacology, University of Parma, Italy.
Grandi
D
D
Bertaccini
G
G
Leschke
C
C
Schunack
W
W
D000818:Animals; D002492:Central Nervous System Depressants / Q000633:toxicity*; D004848:Epithelium / Q000473:pathology; D000431:Ethanol / Q000633:toxicity*; D005753:Gastric Mucosa / Q000473:pathology; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced / Q000473:pathology; D017442:Histamine Agonists / Q000494:pharmacology*; D008297:Male; D008761:Methylhistamines / Q000494:pharmacology*; D008855:Microscopy, Electron, Scanning; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*
D002492:Central Nervous System Depressants; D017442:Histamine Agonists; D008761:Methylhistamines; D000431:Ethanol; C069357:alpha-methylhistamine