Dissociation of tumor necrosis factor from endotoxin-induced nitric
oxide and acute-phase hypotension.
Xie, Jianming, Kevin O. Joseph, Greg J. Bagby, Thomas D. Giles, and
Stan S. Greenberg.
Departments of Medicine and Physiology, The Cardiovascular Research
Center of Excellence and The Alcohol Research Center, Louisiana State
Univ. Medical Center, New Orleans, LA, 70112
APStracts 4:0043H, 1997.
We tested the concept that tumor necrosis factor alpha (TNF[alpha]) or
activating factor (PAF) mediates Escherichia coli endotoxin
lipopolysaccharide (LPS)-induced up-regulation of nitric oxide (NO)
and acute phase hypotension (APH) in the rat. LPS (0.5 mg/kg, iv)
given to rats treated with saline or non-immune goat-derived gamma
globulin (IgG, 22 mg/kg, im) produced APH. Moreover, LPS increased
the concentrations of plasma TNFa, as well as nitrate and nitrite
anion (RNI) in plasma and in the ex vivo incubates of neutrophils
(PMN). Inducible NO synthase (iNOS) mRNA was also up-regulated in PMN
obtained from LPS-treated rats. Pretreatment of rats with a goat
-derived polyclonal TNF[alpha] antibody (TNF-Ab, 22 mg/kg, im)
abolished LPS-mediated increases of TNF[alpha] but failed to inhibit
APH or the NO system. TNF[alpha] (8.2 [mu]g/kg, iv) produced
transient hypertension and sustained tachycardia rather than APH,
increased plasma TNF[alpha] and iNOS mRNA in PMN but did not
significantly increase RNI. LPS and TNF[alpha]_ decreased the
spontaneous, calcimycin (a calcium ionophore, 1 [mu]M) and PAF
-mediated (1 [mu]M) increases of headspace NO production by rings of
mesenteric artery incubated ex vivo. TNF-Ab abolished all effects of
TNFa._ _Since neutralization of TNF[alpha] with TNF-Ab did not
attenuate LPS-mediated APH or increases of iNOS mRNA and RNI within
PMN, we conclude that 1) LPS induces parallel changes in TNF[alpha]
and RNI in rat plasma and PMN during the acute phase of endotoxemia
and 2) endogenous TNF[alpha] is not required for induction of iNOS
mRNA by LPS and subsequent generation of RNI during APH. PAF (25, 50
and 100 ng/kg) produced APH without increasing plasma TNF[alpha] or
RNI. BN-50730 (80 [mu]g/kg, i.v.), a PAF-receptor antagonist,
abolished PAF-induced APH, converted LPS-induced APH into a transient
increase in blood pressure and attenuated LPS-induced increases of
RNI with only a 20% reduction in circulating TNF[alpha]. Thus, we
conclude that PAF mediates LPS-induced APH.
Received 22 August 1996; accepted in final form 17 January 1997.
APS Manuscript Number H780-6.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 19 February 1997