title: Delayed resuscitation with physostigmine increases end organ damage in alcohol intoxicated rats.
abstract: Previous studies from our laboratory have identified a role for blunted central sympathetic activation in the acute alcohol intoxication (AAI)-induced impairment of the counterregulatory response to hemorrhagic shock (HS). Immediate fluid resuscitation (FR) with acetylcholinesterase inhibitors restores the neuroendocrine and pressor responses to FR in AAI + HS. We hypothesized this intervention would remain beneficial after delay and that restoration of mean arterial blood pressure (MABP) during FR would attenuate organ damage. Male Sprague-Dawley rats received a primed constant alcohol infusion (2.5 g · kg + 0.3 g · kg · h for 15 h) or isocaloric dextrose (DEX) before HS (40 mmHg for 60 min) and FR with lactated Ringer's (LR) solution ± physostigmine (PHYS; 100 µg · kg) immediately or after a 60-min delay after HS. Immediate LR solution elevated MABP in DEX + HS. Acute alcohol intoxication delayed the initial MABP recovery. Delayed LR solution did not further increase MABP in DEX- or AAI + HS. LR solution + PHYS increased MABP in DEX- and AAI + HS after immediate and delayed FR. No differences were noted in markers of organ dysfunction (alanine aminotransferase [ALT], aspartate aminotransferase, blood urea nitrogen, creatinine) after DEX + HS, and this was unaltered by immediate or delayed LR solution + PHYS. Acute alcohol intoxication + HS increased ALT, which was attenuated by immediate LR solution + PHYS. In contrast, delayed LR solution + PHYS exacerbated tissue injury in AAI + HS, as reflected by increased ALT, aspartate aminotransferase, blood urea nitrogen, creatinine, and liver protein carbonylation over time-matched LR solution. In conclusion, PHYS enhanced blood pressure recovery independent of time of FR and presence of AAI. However, in AAI + HS, delayed LR solution + PHYS accentuated organ damage and dysfunction. These findings suggest that although enhancing the sympathetic response can improve hemodynamic recovery during AAI, it may compromise tissue perfusion and enhance tissue injury.
authors.affiliation: Department of Physiology and Alcohol and Drug Abuse Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112-1393, USA.
authors.forename: Jesse K
authors.initials: JK
authors.lastname: Sulzer
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Molina
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000435:Alcoholic Intoxication / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010830:Physostigmine / Q000627:therapeutic use*; D050050:Protein Carbonylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000628:therapy
chemical_list: D010830:Physostigmine; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase