Effects of a selective neutral endopeptidase and a nonselective neutral endopeptidase/endothelin-converting enzyme inhibitor on lipopolysaccharide-induced endotoxaemia in anaesthetized Sprague-Dawley rats

The gene expression and levels of endothelins (ETs) are increased in variou s animal models of lipopolysaccharide-(LPS) induced septic shock as well as in patients with endotoxaemia (ENDO). A positive correlation was reported between the expression and production of ETs, and the severity of haemodyna mic and haematological disturbances, organ injury and circulatory failure i n ENDO. Previous studies using ETA- and/or ETB-receptor antagonists exacerb ated the effects of LPS in anaesthetized and conscious rats. We investigate d the effect of a selective neutral endopeptidase (NEP) (CGS 24592) or a mi xed NEP/endothelin-converting enzyme (ECE) (CGS 26303) inhibitor in LPS-ind uced ENDO in anaesthetized Sprague-Dawley rats. Four hours post-LPS injecti on, blood pressure was 39% lower in the presence of CGS 26303, compared to control-saline or LPS-injected rats. In rats treated with CGS 26303, white blood cells and platelet counts decreased, whereas lymphocytes increased. I n addition, progressive liver dysfunction, characterized by increases in pl asma bilirubin and alanine transferase, became even more apparent (higher t han in those injected with LPS). Plasma creatinine and blood urea were simi lar to those of the LPS-injected group. Similar results were observed with CGS 24592. Thus, these inhibitors enhanced some, but not all, of the LPS-in duced deleterious effects.