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 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.