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, b osentan, were investigated together with those of relatively selective indu cible nitric oxide synthase inhibitors, aminoguanidine and L-canavanine, on mesenteric blood flow decrease, liver and spleen injury elicited by endoto xaemia. Swiss albino mice (20-40 g) were administered intraperitoneally bos entan (3, 10 or 30 mg kg(-1)), aminoguanidine (15 mg kg(-1)) or L-canavanin e (20 or 100 mg kg(-1)) 10 min before they received saline or Escherichia c oli endotoxin (10 mg kg(-1)). After 4 h, the mice were anaesthetized, mesen teric blood flow values were measured, spleen and Liver weight/body weight ratios were determined and the organs were examined histopathologically. En dotoxin decreased mesenteric blood flow (ml min(-1) saline: 3.0 +/- 0.2; en dotoxin: 2.2 +/- 0.2; n = 10, P < 0.05), increased the weight of liver (g p er 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 histopatholog ical 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 endo toxin without exception. Aminoguanidine blocked most of the effects of endo toxin except those on spleen. In contrast, L-canavanine blocked only the en dotoxin-induced increase in liver weight but itself increased spleen weight and failed to block any other effects of endotoxin. Thus, it can be specul ated 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 endot helin inhibition by using bosentan in endotoxaemia can be further exploited for the understanding and the therapy of sepsis-related syndromes. (C) 199 9 Elsevier Science B.V. All rights reserved.