ROLE OF NITRIC-OXIDE IN THE HEMODYNAMIC-CHANGES OF SEPSIS

Objective: To study the role of nitric oxide in the hemodynamic changes of sepsis. Design: Prospective, randomized, controlled, intervention study. Subjects: Twenty-five sheep randomized to four groups: Group A (n = 8, nonseptic sheep) received N(G)-nitro L-arginine (20 mg/kg iv) followed 15 mins later by L-arginine (200 mg/kg iv); group B (n = 4, nonseptic sheep) received L-arginine followed 15 mins later by N(G)-nitro L-arginine; group C (n = 7, septic sheep) received N(G)-nitro L-arginine (20 mg/kg iv) alone; group D (n = 6, septic sheep) received L-arginine (200 mg/kg iv) followed by N(G)-nitro L-arginine (20 mg/kg iv). Interventions: Sheep were anesthetized with pentobarbital, mechanically ventilated and monitored with a pulmonary artery catheter, a peripheral artery catheter, and a Millar catheter in the left ventricle. Sepsis was induced by the intravenous administration of live Escherichia coli (1.5 x 10(9) microorganisms/kg over 30 mins), which resulted in systemic hypotension, pulmonary hypertension, high cardiac output, and hyperlactatemia. Acetylcholine was administered before and after each intervention. Measurements and Main Results: In nonseptic sheep (groups A and B) N(G)-nitro L-arginine induced an increase in mean blood pressure (BP), pulmonary arterial pressure, and systemic and pulmonary vascular resistances, accompanied by a decrease in cardiac index and the first derivative of left ventricular pressure. L-arginine administered to normal sheep induced systemic vasodilation. In the sepsis groups (groups C and D), the increases in BP and systemic vascular resistances induced by N(G)-nitro L-arginine were significant but less marked than in nonseptic sheep. Pretreatment of septic sheep with L-arginine totally abolished the N(G)-nitro L-arginine induced increases in systemic and pulmonary vascular resistances in this group. The administration of L-arginine in these animals induced both systemic and pulmonary vasodilation. Acetylcholine-mediated vasodilation was severely impaired in sepsis. In this condition, pretreatment with L-arginine improved the response to acetylcholine. Conclusions. These data support the view that nitric oxide plays a significant role in modulating systemic and pulmonary vasomotor tone in normal and septic sheep. L-arginine produced systemic vasodilation in normal sheep, whereas both systemic and pulmonary vasodilation were observed in septic animals. The impaired response to an endothelium-dependent vasodilator in sepsis was improved by the previous administration of L-arginine.