EFFECT OF CALPAIN INHIBITOR-I, AN INHIBITOR OF THE PROTEOLYSIS OF I-KAPPA-B, ON THE CIRCULATORY FAILURE AND MULTIPLE ORGAN DYSFUNCTION CAUSED BY ENDOTOXIN IN THE RAT

1 We compared the effects of calpain inhibitor I (inhibitor of the pro teolysis of I kappa B and, hence, of the activation of nuclear factor kappa B (NF kappa B)) and dexamethasone on (i) the circulatory failure , (ii) multiple organ dysfunction and (iii) induction of the inducible isoforms of nitric oxide (NO) synthase (iNOS) and cyclo-oxygenase (CO X-2) in anaesthetized rats with endotoxic shock. 2 Injection of lipopo lysaccharide (LPS, E. coli, 10 mg kg(-1), i.v.) resulted in hypotensio n and a reduction of the presser responses elicited by noradrenaline. This circulatory dysfunction was attenuated by pretreatment of LPS-rat s with calpain inhibitor I (10 mg kg(-1), i.v., 2 h before LPS) or dex amethasone (1 mg kg(-1), i.v.). 3 Endotoxaemia also caused rises in th e serum levels of (i) urea and creatinine (renal dysfunction), (ii) al anine aminotransferase (ALT), aspartate aminotransferase (AST) (hepato cellular injury), bilirubin and gamma-glutamyl transferase (gamma GT) (liver dysfunction), (iii) lipase (pancreatic injury) and (iv) lactate . Calpain inhibitor I and dexamethasone attenuated the liver injury, t he pancreatic injury, the lactic acidosis as well as the hypoglycaemia caused by LPS. Dexamethasone, but not calpain inhibitor I, reduced th e renal dysfunction caused by LPS. 4 Endotoxaemia for 6 h resulted in a substantial increase in iNOS and COX-2 protein and activity in lung and liver, which was attenuated in LPS-rats pretreated with calpain in hibitor I or dexamethasone. 5 Thus, calpain inhibitor I and dexamethas one attenuate (i) the circulatory failure, (ii) the multiple organ dys function (liver and pancreatic dysfunction/injury, lactic acidosis, hy poglycaemia), as well as (iii) the induction of iNOS and COX-2 protein and activity in rats with endotoxic shock. We propose that prevention of the activation of NF-kappa B in vivo may be useful in the therapy of circulatory shock or of disorders associated with local or systemic inflammation.