SYSTEMIC ADMINISTRATION OF A CENTRALLY ACTING ACETYLCHOLINESTERASE INHIBITOR IMPROVES OUTCOME FROM HEMORRHAGIC SHOCK DURING ACUTE ALCOHOL INTOXICATION

Abstract

Previously, we have demonstrated that acute alcohol intoxication impairs hemodynamic counter-regulation to hemorrhage in unanesthetized rats, and that this phenomenon is associated with an impaired neuroendocrine response to blood loss. Moreover, we demonstrated that central acetylcholinesterase inhibition restores the hemodynamic and neuroendocrine responses to hemorrhage in alcohol-intoxicated rats. We hypothesized that similar responses could be elicited by systemic administration of physostigmine, an acetylcholinesterase inhibitor that penetrates the blood brain barrier. The relevance of this approach was to establish effectiveness of a more clinically applicable route of drug administration than that used previously. Chronically catheterized adult male Sprague-Dawley rats (250-275 g) were administered a bolus of physostigmine (i.v., 100 microg/kg) at rest, and in a separate study, simultaneously with Ringer's lactate solution after an overnight intragastric infusion of 30% alcohol (approximately 7 g/kg for 15 h) or 52% isocaloric dextrose and fixed-pressure hemorrhage. I.v. physostigmine administration immediately increased sympathetic outflow via activation of central nicotinic receptors and improved the pressor response to fluid resuscitation in both dextrose controls and alcohol-intoxicated animals. The improved hemodynamic recovery achieved with physostigmine was also associated with attenuation of the rises in the markers of liver and renal damage alanine aminotransferase and blood urea nitrogen in alcohol-intoxicated animals. Additional studies are warranted to determine the effect of central acetylcholinesterase inhibition on tissue injury and survival after severe blood loss, as well as its effects on long-term metabolic and inflammatory responses.