Abstract
BACKGROUND: Our previous work showed a survival advantage with L-arginine (L-Arg) pretreatment in a swine model of severe hemorrhagic shock. This study was designed to evaluating whether the benefit is sustained when L-Arg is given during resuscitation and whether the mechanism is mediated by enzymatic activation of nitric oxide (NO) synthesis. METHODS: Adult rats (n = 30) underwent 40% blood volume loss and were resuscitated with saline (3 shed blood volume). Animals were divided into five treatment groups of six animals each: (1) Sham, (2) Control (resuscitation alone), (3) L-Arg (300 mg/kg)with resuscitation, (4) L-Arg + L-nitroarginine methyl ester pretreatment, and (5) D-arginine (300 mg/kg) with resuscitation.Animals were observed for 240 minutes postresuscitation or until death. Hemodynamic, metabolic, histologic, and survival outcomes were measured. RESULTS: Administration of L-Arg after hemorrhage and before resuscitation significantly improved outcomes, relative to the control group.The L-Arg infusion improved terminal arterial pressures, lowered lactate, improved small bowel histologic signs of reperfusion injury, and increased survival (p < 0.05). Endpoints of the L-Arg group were similar to the Sham group. The benefits of L-Arg infusion were abolished or attenuated when animals were pretreated with L-nitro arginine methyl ester and potentiated with D-arginine, suggesting a NO-specific mechanism of L-Arg. Finally, severe shock and resuscitation injury significantly elevated circulating asymmetric dimethylarginine levels, which are potent competitive inhibitors of NO synthetase. CONCLUSION: L-Arg infusion during resuscitation offers a significant functional, metabolic, and survival benefit after severe hemorrhagic shock.The mechanism seems to be by activation of NO synthesis with its attendant benefits to local perfusion and inflammation after global reperfusion.