Hepatocellular damage in porcine endotoxemia: beneficial effects of selective versus non-selective nitric oxide synthase inhibition?

While nitric oxide (NO) is implicated as an important mediator of hypotensi on in sepsis and endotoxemia, its role as a mediator of tissue injury in sh ock is controversial, During porcine endotoxemia (lipopolysaccharide (LPS) 1.7 mug(.)kg(-1 .)h(-1) i.v. for 6 h), we compared circulatory and morpholo gical changes in the liver induced by two different NO synthase inhibitors (N-G-nitro-L-arginine methyl ester, L-NAME, 25 mg(.)kg(-1) i.v., and aminoe thyl-isothiourea, AE-ITU, 10 mg(.)kg(-1) i.v.), both given after 3 h. LPS i nduced time-dependent tissue reactions with edema. sinusoidal dilation. pac king of red cells and leukocyte infiltration, progressing to endothelial ce ll and hepatocyte damage. formation of thrombi, and at 6h widespread necros is. These changes were similar in all pigs receiving LPS. regardless of tre atment with NOS inhibitors. LPS caused significant increases in aspartate a minotransferase (AST), alkaline phosphatase (ALP) and alpha glutathione S-t ransferase (alpha -GST). L-NAME caused further increases in AST, ALP and al pha -GST. while AE-ITU prevented the late increase in ALP and alpha -GST ob served in the other LPS groups. LPS reduced liver blood flow by similar to 40% L-NAME further reduced flow by similar to 50%, while AE- ITU restored l iver blood flow to baseline values. Conclusion: L-NAME in endotoxemia had d etrimental effects on liver circulation, while AE-ITU improved liver blood flow and attenuated the late increase in liver enzymes. Liver morphology wa s unaffected within the 3-h observation time after NOS inhibition.