EFFECTS OF L-CANAVANINE, AN INHIBITOR OF INDUCIBLE NITRIC-OXIDE SYNTHASE, ON ENDOTOXIN MEDIATED SHOCK IN RATS

The effects of L-canavanine, an inhibitor of nitric oxide synthase, on endotoxin-induced shock was investigated in the pentobarbitone anesth etized rat. Endotoxin infusion (2.5 mg kg(-1) h(-1) over 6 h) produced progressive and marked hypotension and hypoglycemia. Electron microsc opy showed marked changes in the kidney, comprising severe endothelial cell disruption and the accumulation of platelets in the blood vessel s. In the lung, there was marked accumulation of polymorphonuclear leu kocytes in small blood vessels and endothelial disruption. Treatment w ith L-canavanine (10 mg kg(-1) by bolus injection each hour starting 7 0 min after endotoxin or saline infusion) significantly reduced endoto xin-induced hypotension, without any effect on the hypoglycemia. This treatment markedly reduced the endotoxin-induced electron microscopica l changes in the kidneys and lungs. Although L-canavanine, like L-NAME , inhibited both cerebellar constitutive and splenic inducible nitric oxide synthase in vitro, in contrast to L-NAME it did not modify eithe r arterial blood pressure or carotid artery blood Row in control rats. The data are consistent with L-canavanine being a selective inhibitor of inducible nitric oxide synthase, at least in vivo, and suggest tha t inhibitors of this enzyme may be beneficial in endotoxin-induced sho ck.