Inhibition of nitric oxide synthesis during severe shock but not after resuscitation increases hepatic injury and neutrophil accumulation in hemorrhaged rats.

Hemorrhagic shock results in hepatocellular dysfunction and hepatic injury that may contribute to the development of liver failure and multiple organ dysfunction in trauma patients. The specific mediators involved in this process remain incompletely defined. We have previously demonstrated that inhibition of nitric oxide (NO) synthesis in a rat model of moderately severe hemorrhagic shock increases hepatic injury, suggesting that NO synthesis is beneficial after hemorrhage. To further define the role of NO in hepatic function during hemorrhagic shock, rats were subjected to a severe hemorrhagic shock insult in which they were bled to a mean arterial pressure of 40 mmHg until 40% of their shed blood had been returned and then were resuscitated. Rats were treated with the NO synthase inhibitor L-nitroarginine methyl ester (L-NAME) or the NO donor S-nitroso-N-acetylpenicillamine beginning either during the hypotensive period or after resuscitation. When instituted during the hypotensive period, low dose L-NAME infusion significantly increased hepatic injury. When L-NAME was infused after resuscitation, no increase in hepatic injury was detected even when the L-NAME dose was increased by a factor of four. The increased hepatic injury produced by L-NAME was associated with increased myeloperoxidase content in the lung, suggesting that L-NAME led to a greater accumulation of neutrophils during shock. Administration of the NO donor S-nitroso-N-acetylpenicillamine reduced hepatocellular enzyme release. Our results suggest that ongoing NO synthesis during the hypotensive phase of hemorrhagic shock is essential in preventing shock-induced hepatic injury and this may be due, in part, to the interaction between NO and circulating neutrophils.