Central acetylcholinesterase inhibition improves hemodynamic counterregulation to severe blood loss in alcohol-intoxicated rats

Abstract

Acute alcohol intoxication results in impaired hemodynamic counterregulation to blood loss and is associated with an attenuated hemorrhage-induced release of catecholamines and 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 demonstrated that intracerebroventricular (i.c.v.) 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 i.c.v. neostigmine, an acetylcholinesterase inhibitor, would enhance SNS outflow, restore the neuroendocrine response, and in turn improve hemodynamic responses to hemorrhage during acute alcohol intoxication. I.c.v. neostigmine (1 microg) increased MABP, catecholamines, and AVP within 5 min and reversed hypotension due to 40% hemorrhage and intragastric alcohol (30% wt/vol, 2.5 g/kg) administration in chronically catheterized male Sprague-Dawley rats (225-250 g body wt). Acute alcohol intoxication before 50% hemorrhage decreased basal MABP, accentuated hypotension midhemorrhage, suppressed the hemorrhage-induced release of norepinephrine and AVP, and prevented restoration of MABP to basal levels after fluid resuscitation with lactated Ringer solution. I.c.v. neostigmine (0.5 microg) produced a sustained increase in MABP beginning at 30 min of hemorrhage that persisted throughout fluid resuscitation in control and alcohol-treated animals. I.c.v. 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 counterregulation during acute alcohol intoxication. This study provides evidence for a central (and not peripheral) role of alcohol in impairing hemodynamic stability during hemorrhagic shock.

Dose-related effects of red wine and alcohol on heart rate variability

“…In a rat model of hemorrhagic shock, alcohol intoxication disturbed neurohumoral cardiovascular regulation, but this could be reversed by an intracerebroventricular administration of an acetylcholinesterase inhibitor, suggesting that alcohol altered the central nicotinic receptor-mediated modulation of automomic outflow (20). The present findings are therefore consistent with centrally mediated sympathoexcitatory and vagolytic effects of alcohol.…”

Hypertonic saline resuscitation enhances blood pressure recovery and decreases organ injury following hemorrhage in acute alcohol intoxicated rodents

“…To determine the contribution of AVP to MABP recovery, a subset of animals received the V1 a antagonist [b-mercapto-b, b-cyclpentamethylenepropionyl 1 , O-me-Tyr 2 , Arg 8 ]-vasopressin, (10ug/kg in ~0.25ml normal saline; Sigma Aldrich, St. Louis, MO) intravenously 5 min prior to FR. This dose was previously shown to inhibit the pressor effects of AVP following central neostigmine administration (9). …”

“…Impaired MABP recovery is associated with attenuated circulating levels of the counter-regulatory hormones arginine vasopressin (AVP), epinephrine, and norepinephrine (8, 9). Recently, we demonstrated that enhanced nitric oxide (NO) inhibitory tone in the hypothalamic paraventricular nucleus (PVN) contributes to the attenuated AVP levels following HS during AAI (10).…”

Delayed Resuscitation with Physostigmine Increases End Organ Damage in Alcohol Intoxicated Rats

“…Investigations into the mechanism of this impaired counterregulatory response have ruled out impaired vascular pressor response as a primary mechanism for the greater hypotension following blood loss observed in the intoxicated host (7). In contrast, studies examining the role of the blunted sympathetic response to hemorrhage have provided strong support for the hypothesis that the impaired response to blood loss during AAI is due to central alterations in sympathetic outflow (8, 9). Central administration of acetylcholinesterase inhibitors increases sympathetic outflow, significantly improves the blunted counterregulatory hormone response associated with AAI, and contributes to an enhanced blood pressure recovery following hemorrhage (8).…”

“…In contrast, studies examining the role of the blunted sympathetic response to hemorrhage have provided strong support for the hypothesis that the impaired response to blood loss during AAI is due to central alterations in sympathetic outflow (8, 9). Central administration of acetylcholinesterase inhibitors increases sympathetic outflow, significantly improves the blunted counterregulatory hormone response associated with AAI, and contributes to an enhanced blood pressure recovery following hemorrhage (8). Further studies investigating the therapeutic potential of this approach have confirmed the ability of peripherally administered acetylcholinesterase inhibitors, such as physostigmine, to restore the neuroendocrine response and improve the pressor response to fluid resuscitation following hemorrhagic shock during AAI (10).…”