M. Guivernau et al., INVESTIGATIONS ON THE ETHANOL-INDUCED FLUSHING REACTION - EFFECTS OF PROPRANOLOL AND DIPYRIDAMOLE ON ACETALDEHYDE AND PROSTACYCLIN METABOLISM, Toxicology, 90(1-2), 1994, pp. 1-9
Disulfiram, an aldehyde dehydrogenase (ALDH) inhibitor, induces a flus
hing reaction upon the ingestion of ethanol, exerting aversion against
alcohol that has been used in the treatment of alcoholism. This unple
asant response has been associated with an accumulation of acetaldehyd
e, and more recently, with an increase in vascular prostacyclin (PGI(2
)) production. To evaluate the possibility of evoking the flushing rea
ction with drugs less toxic than disulfiram, we studied the effects of
propranolol and dipyridamole on ALDH and PGI(2). Acetaldehyde oxidati
on rate was assessed by gas chromatography in mitochondria from rats t
reated with these drugs for seven days. Prostacyclin generation was de
termined in rat aortic rings incubated in Krebs-Ringer with these drug
s separately and associated to acetaldehyde, and measured by radioimmu
noassay of 6-keto-PGF(1 alpha). Propranolol inhibited acetaldehyde oxi
dation rate whereas dipyridamole did not. Furthermore, propranolol inc
reased blood acetaldehyde levels without affecting ethanol elimination
rate. Both drugs stimulated prostacyclin synthesis but only dipyridam
ole enhanced the stimulatory effect of acetaldehyde on vascular prosta
cyclin production. These results strongly suggest the possibility of p
roducing a deterrent effect on the consumption of alcohol by using pro
pranolol 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.