PMID- 7530365
OWN - NLM
STAT- MEDLINE
DCOM- 19950223
LR  - 20200930
IS  - 0037-9727 (Print)
IS  - 0037-9727 (Linking)
VI  - 208
IP  - 2
DP  - 1995 Feb
TI  - In vivo administration of endotoxin and tumor necrosis factor-alpha produce 
      different effects on constitutive and inducible nitric oxide synthase activity in 
      rat neutrophils and aorta ex vivo.
PG  - 199-208
AB  - Tumor necrosis factor-alpha (TNF-alpha) inhibits release of nitric oxide (NO) in 
      vitro by stimulating the degradation of constitutive NO synthase (cNOS III) mRNA. 
      However, TNF-alpha is believed to be the cytokine mediator of the hypotension and 
      upregulation of inducible NO synthase (iNOS II) produced by gram-negative 
      bacterial endotoxin (LPS). Some in vivo effects of TNF-alpha are opposite to 
      those which occur in vitro. This study tested the hypothesis that in vivo 
      administration of exogenous TNF-alpha and endogenously released TNF-alpha induce 
      iNOS II activity and inhibit cNOS III activity, and thereby mediate the acute 
      phase effects of LPS on blood pressure and the NO system in the rat. We show that 
      LPS produces acute phase hypotension in ketamine anesthetized rats. The 
      hypotension was associated with elevation of biologically active TNF-alpha in 
      plasma, increased production of RNI (NO2- and NO3- anion) in rat neutrophils 
      (PMN) and suppression of RNI production by A23187 (1 microM) stimulated thoracic 
      aorta (RTA) ex vivo. TNA-alpha (10(6) U/ml, iv) did not produce acute phase 
      hypotension but initially raised arterial blood pressure and heart rate (HR), did 
      not increase RNI production by PMN, and inhibited RNI production by A23187 
      stimulated RTA ex vivo. Pretreatment of rats with the immunex monomeric soluble 
      P75 receptor binding protein for TNF-alpha (TNFsr, 0.5 mg/kg, iv) 15 min prior to 
      LPS administration decreased circulating TNF-alpha from 92,137 +/- 12,456 U/ml to 
      undetectable levels as determined by the L929 bioassay. However, LPS-induced 
      increases in RNI in PMN was enhanced and LPS-induced decreases in RNI production 
      by RTA was inhibited by TNFsr. Thus, in vivo administration of TNF-alpha does not 
      mimic the hemodynamic and NO-inducing effects of LPS. However, TNF-alpha mediates 
      in part LPS-induced inhibition of RNI production by RTA. Thus, endogenous 
      TNF-alpha is not required for LPS-induced acute phase hypotension or iNOS II 
      activity. The importance of TNF-alpha in sepsis resides in systems other than 
      iNOSII and blood pressure.
FAU - Greenberg, S S
AU  - Greenberg SS
AD  - Department of Medicine, Louisiana State University Medical Center, New Orleans 
      70112.
FAU - Xie, J
AU  - Xie J
FAU - Joseph, K O
AU  - Joseph KO
FAU - Kolls, J
AU  - Kolls J
FAU - Summer, W
AU  - Summer W
LA  - eng
GR  - IP50AA09803-01/AA/NIAAA NIH HHS/United States
GR  - NIAAA 09816-01/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Soc Exp Biol Med
JT  - Proceedings of the Society for Experimental Biology and Medicine. Society for 
      Experimental Biology and Medicine (New York, N.Y.)
JID - 7505892
RN  - 0 (Endotoxins)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Nitrates)
RN  - 0 (Nitrites)
RN  - 0 (Receptors, Tumor Necrosis Factor)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 37H9VM9WZL (Calcimycin)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - EC 1.4.- (Amino Acid Oxidoreductases)
RN  - S8TIM42R2W (Bradykinin)
SB  - IM
MH  - Amino Acid Oxidoreductases/biosynthesis/*metabolism
MH  - Animals
MH  - Aorta/drug effects/*metabolism
MH  - Blood Pressure/drug effects
MH  - Bradykinin/pharmacology
MH  - Calcimycin/pharmacology
MH  - Endotoxins/*pharmacology
MH  - Enzyme Induction
MH  - Heart Rate/drug effects
MH  - In Vitro Techniques
MH  - Lipopolysaccharides/pharmacology
MH  - Male
MH  - Neutrophils/drug effects/*enzymology
MH  - Nitrates/metabolism
MH  - Nitric Oxide Synthase
MH  - Nitrites/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Tumor Necrosis Factor
MH  - Recombinant Proteins/pharmacology
MH  - Tumor Necrosis Factor-alpha/analysis/*pharmacology
EDAT- 1995/02/01 00:00
MHDA- 1995/02/01 00:01
CRDT- 1995/02/01 00:00
PHST- 1995/02/01 00:00 [pubmed]
PHST- 1995/02/01 00:01 [medline]
PHST- 1995/02/01 00:00 [entrez]
AID - 10.3181/00379727-208-43852 [doi]
PST - ppublish
SO  - Proc Soc Exp Biol Med. 1995 Feb;208(2):199-208. doi: 10.3181/00379727-208-43852.