Nitric oxide synthase inhibition during experimental sepsis improves renal excretory function in the presence of chronically increased atrial natriuretic peptide

Objective: To test whether renal excretory function decreases after nitric oxide synthase inhibition during experimental hyperdynamic sepsis. Design: Prospective, randomized, controlled animal trial. Setting: Research laboratory at a large university medical center. Subjects: Chronically instrumented Merino breed ewes (n = 18). Interventions: Continuous infusion of Escherichia coli endotoxin (10 ng/kg/min) for the experimental period of 32 hrs. One group received a bolus of the nitric oxide synthase inhibitor, N-omega-nitro-L-arginine methyl ester (25 mg/kg), after 24 hrs, and the remaining sheep were given the carrier, sodium chloride 0.9%. Measurements and Main Results: The sheep developed a hyperdynamic cardiovascular response characterized by a decrease in systemic vascular resistance index (p < .05), and an increased cardiac index (p < .05) by 24 hrs. The sheep retained fluid, with creatinine clearance decreasing in the presence of chronically increased atrial natriuretic peptide. After the administration of N-omega-nitro-L-arginine methyl ester, systemic vascular resistance index and cardiac index returned to baseline values, fluid balance normalized, and glomerular filtration rate increased (p < .05), while the control animals continued to retain fluid and their creatinine clearance continued to decrease. The concentrations of atrial natriuretic peptide did not differ significantly between groups after N-omega-nitro-L-arginine methyl ester administration. Conclusions: In this ovine model of experimental hyperdynamic sepsis, renal excretory function decreases in the presence of chronically increased concentrations of atrial natriuretic peptide. Administration of the nitric oxide synthase inhibitor, N-omega-nitro-L-arginine methyl ester, reverses the vasodilatory state, thereby improving fluid balance and glomerular filtration.