The effects of bosentan, aminoguanidine and L-canavanine on mesenteric blood flow, spleen and liver in endotoxaemic mice.

The modulatory effects of a non-selective endothelin receptor antagonist, bosentan, were investigated together with those of relatively selective inducible nitric oxide synthase inhibitors, aminoguanidine and L-canavanine, on mesenteric blood flow decrease, liver and spleen injury elicited by endotoxaemia. Swiss albino mice (20-40 g) were administered intraperitoneally bosentan (3, 10 or 30 mg kg(-1)), aminoguanidine (15 mg kg(-1)) or L-canavanine (20 or 100 mg kg(-1)) 10 min before they received saline or Escherichia coli endotoxin (10 mg kg(-1)). After 4 h, the mice were anaesthetized, mesenteric blood flow values were measured, spleen and liver weight/body weight ratios were determined and the organs were examined histopathologically. Endotoxin decreased mesenteric blood flow (ml min(-1), saline: 3.0 +/- 0.2; endotoxin: 2.2 +/- 0.2: n = 10, P < 0.05), increased the weight of liver (g per kg body weight, saline: 47.5 +/- 2.0; endotoxin: 60.8 +/- 1.9: n = 10, P < 0.05) and spleen (g per kg body weight, saline: 3.9 +/- 0.5; endotoxin: 8.6 +/- 0.9; n = 10, P < 0.01) while it inflicted significant histopathological injury to both organs. Bosentan was ineffective at 3 mg kg(-1) but at 10 and 30 mg kg(-1) doses, it abolished all the deleterious effects of endotoxin without exception. Aminoguanidine blocked most of the effects of endotoxin except those on spleen. In contrast, L-canavanine blocked only the endotoxin-induced increase in liver weight but itself increased spleen weight and failed to block any other effects of endotoxin. Thus, it can be speculated that the beneficial effects of aminoguanidine are produced largely by mechanisms other than selective inducible nitric oxide synthase inhibition since L-canavanine was not fully effective. The beneficial effects of endothelin inhibition by using bosentan in endotoxaemia can be further exploited for the understanding and the therapy of sepsis-related syndromes.