Investigations on the ethanol-induced flushing reaction: effects of propranolol and dipyridamole on acetaldehyde and prostacyclin metabolism.
Disulfiram, an aldehyde dehydrogenase (ALDH) inhibitor, induces a flushing reaction upon the ingestion of ethanol, exerting aversion against alcohol that has been used in the treatment of alcoholism. This unpleasant response has been associated with an accumulation of acetaldehyde, and more recently, with an increase in vascular prostacyclin (PGI2) production. To evaluate the possibility of evoking the flushing reaction with drugs less toxic than disulfiram, we studied the effects of propranolol and dipyridamole on ALDH and PGI2. Acetaldehyde oxidation rate was assessed by gas chromatography in mitochondria from rats treated with these drugs for seven days. Prostacyclin generation was determined in rat aortic rings incubated in Krebs-Ringer with these drugs separately and associated to acetaldehyde, and measured by radioimmunoassay of 6-keto-PGF1 alpha. Propranolol inhibited acetaldehyde oxidation rate whereas dipyridamole did not. Furthermore, propranolol increased blood acetaldehyde levels without affecting ethanol elimination rate. Both drugs stimulated prostacyclin synthesis but only dipyridamole enhanced the stimulatory effect of acetaldehyde on vascular prostacyclin production. These results strongly suggest the possibility of producing a deterrent effect on the consumption of alcohol by using propranolol or dipyridamole. In contrast to disulfiram, these drugs could potentially induce the flushing reaction in humans in the presence of low acetaldehyde concentrations; this new therapeutic approach might have an important clinical and toxicological relevance.
Department of Pharmacology, School of Medicine, University of Chile, Santiago.
M
M
Guivernau
M E
ME
Quintanilla
L
L
Tampier
D000079:Acetaldehyde / Q000097:blood / Q000378:metabolism*; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D004176:Dipyridamole / Q000494:pharmacology*; D011464:Epoprostenol / Q000096:biosynthesis* / Q000378:metabolism; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D005483:Flushing / Q000139:chemically induced*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D011433:Propranolol / Q000494:pharmacology*; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar
D000431:Ethanol; D004176:Dipyridamole; D011433:Propranolol; D011464:Epoprostenol; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde