Ethanol suppresses endotoxin but not platelet activating factor-induced hypotension and nitric oxide.
Ethanol (ETOH) inhibits the immune response to endotoxemia. The early stage of endotoxin (LPS)-induced shock is associated with an acute phase cardiovascular depression (APCD). Release of platelet activating factor (PAF) and tumor necrosis factor alpha (TNF alpha) with upregulation of nitric oxide (NO) production may initiate the APCD. Since ETOH inhibits induction of NO synthase (iNOS) mNRA by LPS, we postulate that ETOH may mask the APCD associated with endotoxemia. To test this, Sprague-Dawley rats (280-320 g, n = 5-6/group) were given LPS [0.75 mg/kg, intravenously (i.v.)] or PAF (10 to 150 micrograms/kg, i.v.) 30 min after administration of sterile saline (PBS), BN-5073 a mixed PAF antagonist (0.50 microgram/kg, i.v.), or ETOH [2.2-5.5 g/kg, intraperitoneally (i.p.)]. Cardiovascular parameters and plasma concentrations of nitrate and nitrite (RNI), ETOH, TNF alpha, and neutrophil (PMN) generation of RNI were measured. LPS and PAF both produced APCD. LPS-induced APCD was associated with tachycardia, elevated plasma TNF alpha and RNI, and ex vivo generation of RNI by PMNs. ETOH and BN-50730 prevented LPS-induced APCD and increases in RNI and TNF alpha. ETOH, however, increased the mortality associated with APCD. PAF produced only hypotension, bradycardia and elevated plasma levels of TNF alpha. ETOH and LNMMA did not affect PAF-induced APCD. BN-50730 inhibited PAF-induced APCD and plasma TNF alpha. We conclude that 1) ETOH inhibits the APCD and induction of NO characteristic of endotoxemia and 2) ETOH-induced suppression of LPS-mediated APCD may be mediated in part by suppression of release of intracellular PAF. Ethanol may increase the morbidity and mortality of endotoxemia by masking the hypotension and humoral changes characteristic of early endotoxemia thereby delaying appropriate therapy and by diminution of the protective effects of endogenous NO.
Department of Medicine, Louisiana State University Medical Center, New Orleans 70112, USA.
S S
SS
Greenberg
J
J
Xie
D R
DR
Powers
T D
TD
Giles
D000428:Alcohol Drinking / Q000009:adverse effects / Q000276:immunology*; D000435:Alcoholic Intoxication / Q000276:immunology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D019446:Endotoxemia / Q000276:immunology; D000431:Ethanol / Q000494:pharmacology*; D007108:Immune Tolerance / Q000276:immunology; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D009569:Nitric Oxide / Q000502:physiology*; D010972:Platelet Activating Factor / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D000431:Ethanol