1. We have investigated whether (i) endotoxaemia caused by E. coli
lipopolysaccharide in the anaesthetized rat causes a
multiple organ dysfunction syndrome (
MODS; e.g.
circulatory failure,
renal failure,
liver failure), and (ii) an enhanced formation of
nitric oxide (NO) due to induction of inducible
NO synthase (iNOS) contributes to the
MODS. In addition, this study elucidates the beneficial and adverse effects of
aminoethyl-isothiourea (
AE-ITU), a relatively selective inhibitor of iNOS activity, and NG-methyl-
L-arginine (
L-NMMA), a non-selective inhibitor of NOS activity on the
MODS caused by endotoxaemia. 2. In the anaesthetized rat, LPS caused a fall in mean arterial blood pressure (MAP) from 117 +/- 3 mmHg (time 0) to 97 +/- 4 mmHg at 2 h (P < 0.05, n = 15) and 84 +/- 4 mmHg at 6 h (P < 0.05, n = 15). The pressor effect of
noradrenaline (NA, 1 micrograms kg-1, i.v.) was also significantly reduced at 1 to 6 h after LPS (vascular hyporeactivity). Treatment of LPS-rats with
AE-ITU (1 mg kg-1, i.v. plus 1 mg kg-1 h-1 starting at 2 h after LPS) caused only a transient rise in MAP, but significantly attenuated the delayed vascular hyporeactivity seen in LPS-rats. Infusion of
L-NMMA (3 mg kg-1, i.v. plus 3 mg kg-1 h-1) caused a rapid and sustained rise in MAP and attenuated the delayed vascular hyporeactivity to NA. Neither
AE-ITU nor
L-NMMA had any effect on either MAP or the pressor effect elicited by NA in rats infused with saline rather than LPS. 3. Endotoxaemia for 6 h was associated with a significant rise in the serum levels of
aspartate or
alanine aminotransferase (i.e. GOT or GPT), gamma-glutamyl-
transferase (gamma GT), and
bilirubin, and hence,
liver dysfunction. Treatment of LPS-rats with
AE-ITU significantly attenuated this
liver dysfunction (rise in GOT, GPT, gamma GT and
bilirubin) (P < 0.05, n = 10). In contrast,
L-NMMA reduced the increase in the serum levels of gamma GT and
bilirubin, but not in GOT and GPT (n = 5). Injection of LPS also caused a time-dependent, but rapid (almost maximal at 2 h), increase in the serum levels of
urea and
creatinine, and hence, renal dysfunction. This renal dysfunction was not affected by either
AE-ITU (n = 10) or
L-NMMA (n = 5). In rats infused with saline rather than LPS, neither
AE-ITU (n = 4) nor
L-NMMA (n = 4) had any significant effect on the serum levels of GOT, GPT, gamma GT,
bilirubin,
creatinine or
urea. 4. Endotoxaemia for 6 h resulted in a 4.5 fold rise in the serum levels of
nitrite (9.13 +/- 0.77 microM, P < 0.01, n = 15), which was significantly reduced by treatment with
AE-ITU (6.32 +/- 0.48 microM, P < 0.05, n = 10) or
L-NMMA (5.10 +/- 0.40 microM, P < 0.05, n = 5). In addition, endotoxaemia for 6 h was also associated with a significant increase in iNOS activity in lung and liver homogenates, which was significantly reduced in lung or liver homogenates obtained from LPS-rats treated with either
AE-ITU or
L-NMMA. 5. Thus,
AE-ITU or
L-NMMA (i) inhibits iNOS activity in LPS-rats without causing a significant increase in MAP in rats infused with saline and, hence inhibition of endothelial NOS activity, and (ii) attenuates the delayed
circulatory failure as well as the
liver dysfunction caused by endotoxaemia in the rat. Thus, an enhanced formation of NO may contribute to the development of
liver failure in endotoxic
shock.