TRANSIENT CENTRAL CHOLINERGIC ACTIVATION ENHANCES SYMPATHETIC NERVOUS SYSTEM ACTIVITY BUT DOES NOT IMPROVE HEMORRHAGE-INDUCED HYPOTENSION IN ALCOHOL-INTOXICATED RODENTS

Morbidity and mortality after traumatic injury and hemorrhagic shock (HS) are exacerbated in the alcohol-intoxicated individual. The level of hypotension at the time of admittance into the emergency department is a critical indicator of outcome from injury. Previously, we have demonstrated that acute alcohol intoxication (AAI) decreases basal mean arterial blood pressure (MABP), exaggerates hypotension throughout HS, and attenuates the pressor response to fluid resuscitation in male rodents. This AAI-induced impaired hemodynamic counter-regulation to blood loss is associated with dampened neuroendocrine activation (i.e., epinephrine, norepinephrine, and arginine vasopressin [AVP] release). We hypothesize that the blunted neuroendocrine response is the principal mechanism involved in hemodynamic instability during and after HS in AAI. The present study investigates whether enhancing central cholinergic activity via intracerebroventricular (ICV) choline, a precursor of acetylcholine, would restore the neuroendocrine response and, as a result, improve hemodynamic compensation after HS. Chronically catheterized, conscious, male Sprague-Dawley rats (225-250 g) received a primed 15-h alcohol infusion (30% wt/vol; total approximately 8 g x kg(-1)) before ICV choline (150 microg) injection and were subsequently subjected to fixed-volume HS (50%) and fluid resuscitation with lactated Ringer's solution (2x volume removed). There were a total of eight experimental groups (n = 5-12 rats per group): alcohol-treated not hemorrhaged (alcohol/sham), dextrose-treated not hemorrhaged (dextrose/sham), alcohol-treated hemorrhaged (alcohol/hemorrhage), and dextrose-treated hemorrhaged (dextrose/hemorrhage), with ICV choline or water injection. Intracerebroventricular choline immediately increased basal MABP in both control (16%) and AAI animals (12%), but did not alter MABP after HS in either group. Intracerebroventricular choline increased basal plasma epinephrine (196%), norepinephrine (96%), and AVP (145%) and enhanced the HS-induced increase in epinephrine and AVP, without altering norepinephrine responses to HS, in control animals. Acute alcohol intoxication blunted choline-induced neuroendocrine activation and prevented the HS-induced increase in norepinephrine, without affecting post-HS epinephrine and AVP levels. Intracerebroventricular choline administration to AAI animals enhanced the HS-induced increase in epinephrine without affecting post-HS norepinephrine or AVP. These results indicate that ICV choline produced immediate neuroendocrine activation and elevation in MABP that was not sustained sufficiently to improve hemodynamic counter-regulation in alcohol-treated animals.