The induction of nitric oxide synthase and intestinal vascular permeability by endotoxin in the rat

Abstract

1 The effect of endotoxin (E. coli lipopolysaccharide) on the induction of nitric oxide synthase (NOS) and the changes in vascular permeability in the colon and jejunum over a 5 h period have been investigated in the rat. 2 Under resting conditions, a calcium-dependent constitutive NOS, determined by the conversion of radiolabelled L-arginine to citrulline, was detected in homogenates of both colonic and jejunal tissue. 3 Administration of endotoxin (3 mg kg-', i.v.) led, after a 2 h lag period, to the appearance of calcium-independent NOS activity in the colon and jejunum ex vivo, characteristic of the inducible NOS enzyme. 4 Administration of endotoxin led to an increase in colonic and jejunal vascular permeability after a lag period of 3 h, determined by the leakage of radiolabelled albumin. 5 Pretreatment with dexamethasone (1 mg kg-' s.c., 2 h prior to challenge) inhibited both the induction of NOS and the vascular leakage induced by endotoxin. 6 Administration of the NO synthase inhibitor NG-monomethyl-L-arginine (12.5-50mg kg-', s.c.) 3 h after endotoxin injection, dose-dependently reduced the subsequent increase in vascular permeability in jejunum and colon, an effect reversed by L-arginine (300 mg kg-', s.c.). 7 These findings suggest that induction of NOS is associated with the vascular injury induced by endotoxin in the rat colon and jejunum.

Time‐dependent enhancement or inhibition of endotoxin‐induced vascular injury in rat intestine by nitric oxide synthase inhibitors

“…Delay of the administration of L-NMMA or L-NAME following challenge with endotoxin, until the time of significant expression of the inducible NO synthase in the intestine (Salter et al, 1991;Boughton-Smith et al, 1993), produced a dose-dependent reduction in the subsequent appearance of vascular damage in the ileum and colon. These findings thus extend and confirm previous preliminary studies in this model, that administration of L-NMMA 3 h after endotoxin challenge could reduce vascular injury in the jejunum and colon .…”

“…Changes in albumin extravasation were then determined over a 5 h period. To evaluate the role of the inducible NO synthase in the later phase of vascular injury following endotoxin challenge, these inhibitors were administered 3 h after LPS, at a time of known expression of this isoenzyme (Salter et al, 1991;Boughton-Smith et al, 1993), and the extent of albumin extravasation was subsequently determined.…”

Efeito do lipopolissacarídio bacteriano sobre o esvaziamento gástrico de ratos: avaliação do pré-tratamento com Nw-nitro-L-arginine methyl ester (L-NAME)

“…Tornando mais complexa a interpretação dos resultados deste estudo, tem sido proposto que administração de um inibidor de ONS na primeira fase da exposição ao LPS, como no presente caso, inibe o ON produzido pela ativação das ecONS, agravando o efeito deletério da toxina sobre o sistema vascular intestinal (4) . Este fenômeno seria conseqüência da liberação concomitante, induzida pela toxina, de fatores no endotélio (endotelinas) que, pelo bloqueio do ON, predominariam com conseqüente vasoconstrição (19,20,21) .…”

“…O LPS, em ratos, determina diminuição da pressão arterial e do fl uxo sangüíneo mesentérico, fenômenos atenuados pelo pré-tratamento com L-NAME (2,14) . Contudo, foi constatado que há também, com a administração do L-NAME, diminuição do fl uxo sangüíneo capilar na mucosa do sistema digestório, aumentado pela administração de LPS (4,15,17) . Assim, é possível admitir que, nas condições experimentais a que os animais foram submetidos no presente estudo, haja comprometimento da microcirculação das camadas musculares do sistema digestório.…”

Abnormal regulation of aortic NOS2 and NOS3 activity and expression from portal vein-stenosed rats after lipopolysaccharide administration

“…The dose of LPS and the 5-hour delay between the injection and the investigation of vessels has been shown to be sufficient to induce NOS2-related vascular hyporeactivity with low mortality. 37,38 The thoracic aorta was placed in a Petri dish containing prewarmed (37°C) modified Krebs-Henseleit salt solution (in mmol/L: 118.3 NaCl, 4.7 KCl, 2.5 CaCl 2 , 1.17 MgSO 4 , 1.18 KH 2 PO 2 , 25.0 NaHCO 3 , 0.026 ethylenediaminetetraacetic acid [EDTA], 11.1 glucose), cleaned of loose connective tissue and then cut into 3-mm rings. Three rings of each aorta were simultaneously investigated in 3 individual organ chambers.…”