Submitted on March 24, 2009
Revised on May 20, 2009
Accepted on June 3, 2009
Central acetylcholinesterase inhibition improves hemodynamic counter-regulation to severe blood loss in alcohol-intoxicated rats
Keisa W Mathis1 and Patricia E. Molina2*
1 LSU Health Sciences Center
2 LSUHSC
* To whom correspondence should be addressed. E-mail: pmolin{at}lsuhsc.edu.
Acute alcohol intoxication results in impaired hemodynamic counter-regulation to blood loss and is associated with an attenuated hemorrhage-induced release of catecholamines and arginine vasopressin (AVP). We speculated that restoration of the neuroendocrine response to hemorrhage would improve mean arterial blood pressure (MABP) recovery during acute alcohol intoxication. Previously we have demonstrated that intracerebroventricular (ICV) choline, a precursor of acetylcholine, transiently increases sympathetic nervous system (SNS) outflow, but is not capable of improving neuroendocrine and hemodynamic compensation to hemorrhage in alcohol-treated rats. We hypothesized that prolongation of the observed effect via ICV administration of neostigmine, an acetylcholinesterase inhibitor, would enhance SNS outflow, restore the neuroendocrine response, and in turn improve hemodynamic responses to hemorrhage during acute alcohol intoxication. ICV neostigmine (1 µg) increased MABP, catecholamines, and AVP within 5 min, and reversed hypotension due to both 40% hemorrhage and intragastric alcohol (30% w/v; 2.5 g/kg) administration in chronically-catheterized male Sprague-Dawley rats (225-250g). Acute alcohol intoxication prior to 50% hemorrhage decreased basal MABP, accentuated hypotension mid-hemorrhage, suppressed the hemorrhage-induced release of norepinephrine and AVP, and prevented restoration of MABP to basal levels post-fluid resuscitation with lactated Ringers. ICV neostigmine (0.5 µg) produced a sustained increase in MABP beginning at 30 min of hemorrhage, which persisted throughout fluid resuscitation in both control and alcohol-treated animals. ICV neostigmine enhanced epinephrine responses and restored the hemorrhage-induced release of norepinephrine and AVP in alcohol-treated rats. These results demonstrate that inhibition of acetylcholinesterase in the central nervous system enhances SNS outflow, restores the neuroendocrine response to severe blood loss, and thereby improves hemodynamic counter-regulation during acute alcohol intoxication. Taken together, this study provides evidence for a central (and not peripheral) role of alcohol in impairing hemodynamic stability during hemorrhagic shock.
