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Role of tumour necrosis factor in the induction of nitric oxide synthase in a rat model of endotoxin shock
Author(s) -
Thiemermann Christoph,
Wu ChinChen,
Szabó Csaba,
Perretti Mauro,
Vane John R.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13789.x
Subject(s) - lipopolysaccharide , nitric oxide synthase , in vivo , nitric oxide , ex vivo , mean arterial pressure , tumor necrosis factor alpha , thoracic aorta , aorta , chemistry , shock (circulatory) , medicine , endocrinology , blood pressure , in vitro , pharmacology , biology , heart rate , biochemistry , microbiology and biotechnology
1 This study investigates the role of tumour necrosis factor (TNF) in the induction of nitric oxide synthase (NOS) by bacterial endotoxin (lipopolysaccharide; LPS) in a rat model of endotoxin shock. 2 In anaesthetized rats, pretreatment with a monoclonal antibody for TNF (TNF ab ; 20 mg kg −1 , s.c., at 16 h prior to LPS) ameliorated the fall in mean arterial blood pressure (MAP) in response to LPS (2 mg kg −1 , i.v.). For instance, endotoxaemia for 180 min resulted in a fall in MAP from 114 ± 6 (control) to 84 ± 5 mmHg ( P < 0.01; n = 7). In contrast, animals pretreated with TNF ab prior to LPS injection maintained significantly higher MAP when compared to LPS‐control (MAP at 180 min; 118 ± 3 mmHg; P < 0.01, n = 5). 3 Three hours of endotoxaemia was also associated with a significant reduction of the contractile effects of noradrenaline (NA) (10 −1 –10 −6 m ) on the thoracic aorta ex vivo . This hyporeactivity to NA was partially restored by in vitro treatment of the vessels with N G ‐nitro‐ l ‐arginine methyl ester ( l ‐NAME, 20 min, 3 × 10 −4 m ). Pretreatment of rats with TNF ab (20 mg kg −1 ; at 16 h prior to LPS) significantly ( P < 0.05) attenuated the LPS‐induced hyporeactivity of rat aortic rings ex vivo . l ‐NAME did not enhance the contractions of aortic rings obtained from TNF ab pretreated LPS‐rats. 4 At 180 min after LPS there was a significant elevation of the induced NOS activity in the lung (5.14 ± 0.57 pmol citrulline mg −1 min −1 , n = 8). TNF ab pretreatment significantly attenuated this induction of NOS in response to LPS by 37 ± 6% ( n = 5; P < 0.05). 5 We conclude that the formation of endogenous TNF contributes to the induction of the calcium‐independent isoform of NOS in response to LPS in vivo . Thus, the beneficial effects of agents which inhibit either the release or the action of TNF in circulatory shock may be, in part, due to inhibition of NOS induction.