Anti-inflammatory glucocorticoids inhibit the induction by endotoxin of nitric oxide synthase in the lung, liver and aorta of the rat

Knowles, Richard G.; Salter, Mark; Brooks, S.L.; Moncada, Salvador

doi:10.1016/0006-291x(90)91551-3

Cited by 386 publications

(182 citation statements)

References 19 publications

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“…This finding is consistent with studies in other tissues in vitro (Palmer et al, 1988b;Amezcua et al, 1989;Rees et al, 1989a;1990b;Moore et al, 1990) and in vivo (Aisaka et al, 1989;Rees et al, 1989b;1990b;Gardiner et al, 1990) and further strengthens the belief that basal release on NO modulates vascular tone (Rees et al, 1990b;Amrani et al, 1992;see Moncada et al, 1991). In the vasculature, constitutive NO synthase is localized entirely in the endothelial layer (Knowles et al, 1990). Our observation that the vasodilator action of LPS was endothelium-dependent and abolished following perfusion of air through the coronary circulation further supports the concept that LPS activates constitutive NO synthase in endothelium.…”

Section: Discussionsupporting

confidence: 78%

“…Synthesis of NO under these conditions involves induction of the Ca2+/calmodulinindependent NO synthase previously identified in macrophages (Stuehr & Marletta, 1987;Marletta et al, 1988). Expression of this enzyme is time-dependent and involves de novo protein synthesis which can be inhibited by the protein synthesis inhibitor, cyclohexamide and by the glucocorticoid, dexamethasone (Knowles et al, 1990;Radomski et al, 1990;Rees et al, 1990a). Once induced the activity of the enzyme can be blocked by inhibitors of NO synthase including NGmonomethyl-L-arginine (L-NMMA) (Kilbourn et al, 1990;Radomski et al, 1990;Rees et al, 1990a;Thiemermann & Vane, 1990, Wright et al, 1992.…”

Section: Introductionmentioning

confidence: 99%

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Bacterial endotoxin rapidly stimulates prolonged endothelium‐dependent vasodilatation in the rat isolated perfused heart

Baydoun

Foale

Mann

1993

British J Pharmacology

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1 The effects of bacterial lipopolysaccharide (Escherichia coli 011 1-B4; LPS) on coronary vascular tone were examined in the isolated perfused heart of the rat. The role of nitric oxide and/or prostaglandin products of the cyclo-oxygenase pathway in mediating the actions of LPS were also investigated. 2 Coronary vascular tone was raised and maintained by a continuous perfusion of the thromboxanemimetic U46619 (5nM). LPS perfusion (0.1-100itgml-') caused a concentration-dependent fall in coronary tone without any significant change in the force of cardiac contractility.3 At 5 lggml', LPS reduced perfusion pressure by 38±9mmHg. This effect was rapid in onset, maximal within the first 5 min and sustained for 90 + 10 min (n = 6). 4 The vasodilatation induced by LPS was dependent on the presence of an intact endothelium and abolished following endothelial damage caused by air embolism.5 NW-nitro-L-arginine methylester (L-NAME; 50 gM) or N0-nitro-L-arginine (L-NOARG; 50 tM) blocked the vasodilatation induced by LPS (5 jLg ml--). The inhibition caused by these arginine analogues was partially reversed by 1 mM L-but not D-arginine. 6 The vasodilator action of LPS was also completely blocked by the glucocorticoid, dexamethasone (10 jiM) but unaffected by indomethacin (10 jiM).7 These results suggest that LPS evokes rapid release of nitric oxide (NO) in the microvasculature of the rat isolated heart presumably via activation of the constitutive L-arginine-NO pathway in the endothelium. Furthermore, the lack of effect of indomethacin suggests that prostaglandins released via the cyclo-oxygenase pathway are not involved in mediating this action of LPS.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Bacterial endotoxin rapidly stimulates prolonged endothelium‐dependent vasodilatation in the rat isolated perfused heart

Baydoun

Foale

Mann

1993

British J Pharmacology

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“…Glucocorticosteroids such as dexamethasone inhibit the LPS-mediated induction of NOS in vitro and in vivo (Radomski et al, 1990;Knowles et al, 1990). Glucocorticosteroid pretreatment also ameliorates the delayed fall in MAP after LPS administration (Wright et al, 1992;Szabo et al, 1993a).…”

Section: Tnf Prevents the Lps-induced Vascular Hyporeactivity To Nomentioning

confidence: 99%

“…Similarly, inhibition of NOS induction with corticosteroids (Radomski et al, 1990;Knowles et al, 1990), prevents the cardiovascular failure caused by LPS, but does not exert beneficial cardiovascular effects once NOS induction has occurred (Wright et al, 1992;Szabo et al, 1993a;Paya et al, 1993). This is consistent with the hypothesis that NOS induction contributes importantly to the delayed cardiovascular failure in endotoxaemia (Wright et al, 1992;Szabo et al, 1993a) and haemorrhagic shock (Thiemermann et al, 1993).…”

Section: Tnf Prevents the Lps-induced Vascular Hyporeactivity To Nomentioning

confidence: 99%

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

Thiemermann

Szabó

et al. 1993

British J Pharmacology

188

110

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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 (TNFab; 20 mg kg-', s.c., at 16 h prior to LPS) ameliorated the fall in mean arterial blood pressure (MAP) in response to LPS (2 mg kg-', 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 TNFab prior to LPS injection maintained significantly higher MAP when compared to LPS-control (MAP at 180 min; 118± 3mmHg; 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-'-10-6 M) on the thoracic aorta ex vivo. This hyporeactivity to NA was partially restored by in vitro treatment of the vessels with N0-nitro-L-arginine methyl ester (L-NAME, 20 min, 3 x 10-4 M). Pretreatment of rats with TNFab (20 mg kg-'; 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 TNFab pretreated LPS-rats. 4 At 180min after LPS there was a significant elevation of the induced NOS activity in the lung (5.14 ± 0.57 pmol citrulline mg-' min-', n = 8). TNFab 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 calciumindependent 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.

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Secondary ischemic tolerance improved by administration of L-NAME in rat flaps

et al. 1996

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Nitric oxide (NO) under basal conditions is an important regulator of vascular tone. Under ischemic conditions, however, NO can combine with superoxide anion to produce the damaging hydroxyl free radical. The current project observes the effect of inhibiting NO production (L-Nitro-amino-methyl-arginine, L-NAME) on flaps rendered ischemic by secondary (2 degrees) venous obstruction. Eighty rats had 3 x 6 cm skin flaps based on the epigastric vessels. Primary (1 degree) ischemia was produced by arteriovenous occlusion for 2 hours; (2 degrees) venous ischemia was induced by clamping the vein, alone for either 3 or 5 hours. Thirty minutes prior to 2 degrees ischemia, rats received either L-NAME (30 mg/kg) or saline buffer. Flap survival was assessed 7 days later and Chi-square analysis was used. At 3 hours of ischemia, treatment improved survival from 55% to 85% (P < 0.05). Treatment also improved survival at 5 hours of ischemia from 5% to 35% (P < 0.04). Although under resting conditions, NO is a potent vasodilator, during 2 degrees venous obstruction it may contribute to flap necrosis.

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Anti-inflammatory glucocorticoids inhibit the induction by endotoxin of nitric oxide synthase in the lung, liver and aorta of the rat

Cited by 386 publications

References 19 publications

Bacterial endotoxin rapidly stimulates prolonged endothelium‐dependent vasodilatation in the rat isolated perfused heart

Bacterial endotoxin rapidly stimulates prolonged endothelium‐dependent vasodilatation in the rat isolated perfused heart

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

Secondary ischemic tolerance improved by administration of L-NAME in rat flaps

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