THE MULTIPLE ORGAN DYSFUNCTION SYNDROME CAUSED BY ENDOTOXIN IN THE RAT - ATTENUATION OF LIVER DYSFUNCTION BY INHIBITORS OF NITRIC-OXIDE SYNTHASE

1 We have investigated whether (i) endotoxaemia caused by E. coli lipo polysaccharide in the anaesthetized rat causes a multiple organ dysfun ction syndrome (MODS; e.g. circulatory failure, renal failure, liver f ailure), and (ii) an enhanced formation of nitric oxide (NO) due to in duction of inducible NO synthase (iNOS) contributes to the MODS. In ad dition, this study elucidates the beneficial and adverse effects of am inoethyl-isothiourea (AE-ITU), a relatively selective inhibitor of iNO S activity, and N-G-methyl-L-arginine (L-NMMA), a non-selective inhibi tor of NOS activity on the MODS caused by endotoxaemia. 2 In the anaes thetized 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) an d 84 +/- 4 mmHg at 6 h (P<0.05, n=15). The presser effect of noradrena line (NA, 1 mu g 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 L PS) caused only a transient rise in MAP, but significantly attenuated the delayed vascular hyporeactivity seen in LPS-rats. Infusion of L-NM MA (3 mg kg(-1), i.v. plus 3 mg kg(-1) h(-1)) caused a rapid and susta ined 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 pr esser effect elicited by NA in rats infused with saline rather than LP S. 3 Endotoxaemia for 6 h was associated with a significant rise in th e serum levels of aspartate or alanine aminotransferase (i.e. GOT or G PT), gamma-glutamyl-transferase (gamma GT), and bilirubin, and hence, liver dysfunction. Treatment of LPS-rats with AE-ITU significantly att enuated this liver dysfunction (rise in GOT, GPT, gamma GT and bilirub in) (P<0.05, n=10). In contrast, L-NMMA reduced the increase in the se rum levels of gamma GT and bilirubin, but not in GOT and GPT (n= 5). I njection of LPS also caused a time-dependent, but rapid (almost maxima l at 2 h), increase in the serum levels of urea and creatinine, and he nce, renal dysfunction. This renal dysfunction was not affected by eit her 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 ef fect 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 ser um levels of nitrite (9.13 +/- 0.77 mu M, P<0.01, n=15), which was sig nificantly reduced by treatment with AE-ITU (6.32 +/- 0.48 mu M, P<0.0 5, n=10) or L-NMMA (5.10 +/- 0.40 mu M, P<0.05, n=5). In addition, end otoxaemia for 6 h was also associated with a significant increase in i NOS activity in lung and liver homogenates, which was significantly re duced 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 a ctivity in LPS-rats without causing a significant increase in MAP in r ats infused with saline and, hence inhibition of endothelial NOS activ ity, and (ii) attenuates the delayed circulatory failure as well as th e liver dysfunction caused by endotoxaemia in the rat. Thus, an enhanc ed formation of NO may contribute to the development of liver failure in endotoxic shock.