Modulation of systemic hemodynamics by exogenous L-arginine in normal and bacteremic sheep

Objective: To investigate whether exogenous L-arginine, the substrate for n itric oxide synthase, modulates systemic hemodynamics in sepsis. Design: Prospective, controlled study in a sheep model of sepsis. Setting: Animal research facility in a university hospital. Subjects: Adult sheep weighing between 35 and 55 kg. Interventions: Adult sheep sedated and mechanically ventilated, were monito red with a pulmonary arterial catheter and an ileal tonometer. Four groups of sheep were studied: nonseptic, septic, nonseptic treated with L-arginine , and septic treated with L-arginine. Sepsis was induced by the intravenous administration of Escherichia coli (1.5 x 10(8) colony-forming units/kg fo r 30 mins). L-arginine was administered as an intravenous bolus (200 mg/kg for 10 mins) before the septic challenge followed by 200 mg/kg/hr for 300 m ins. Measurements and Main Results: Sepsis induced a state of acidosis, hyperlac tatemia, hypoxemia, and gastric intramucosal acidosis. During the first 30 mins after the septic challenge, there was a decrease in cardiac index and blood pressure, and an increase in systemic vascular resistance. Thereafter , blood pressure returned to baseline values, and systemic vascular resista nce fell. Treatment with L-arginine in nonseptic sheep did not induce any b iochemical or hemodynamic effect. In septic sheep, treatment with L-arginin e was associated with a greater increase in systemic vascular resistance du ring the first 30 mins, and a more marked decrease in blood pressure and sy stemic vascular resistance after 180 mins. Conclusions: Exogenous administration of L-arginine does not induce hemodyn amic effects in normal animals, exacerbates the acute vasoconstriction asso ciated with the intravenous infusion of E. coli and potentiates the sepsis- induced vasodilation. Our results suggest that a) nitric oxide production i s not constitutively modulated by exogenous L-arginine, b) L-arginine proba bly enhances the sepsis-induced sympathetic discharge, and c) L-arginine be comes rate-limiting for the formation of nitric oxide at approximately 3 hr s after the initiation of the septic challenge.