Role of tumour necrosis factor in the induction of nitric oxide synthase in a rat model of endotoxin shock

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. 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). 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. 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). 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. 1993 British Pharmacological Society