The impact of intrarenal nitric oxide synthase inhibition on renal blood flow and function in mild and severe hyperdynamic sepsis

Objective: In experimental hyperdynamic sepsis, renal function deteriorates despite renal vasodilatation and increased renal blood flow. Because nitric oxide is increased in sepsis and participates in renal blood flow control, we investigated the effects of intrarenal N omega-nitro-L-arginine methyl ester, a nonspecific nitric oxide synthase inhibitor, in mild and severe sepsis. Design: Prospective crossover and randomized control interventional studies. Setting: University-affiliated research institute. Subjects: Thirty-two merino ewes. Intervention: Examination of responses to intrarenal infusion of N omega-nitro-L-arginine methyl ester for 8 hrs in unilaterally nephrectomized normal sheep and in sheep administered Escherichia coli. Measurements and Main Results: In normal sheep, N omega-nitro-L-arginine methyl ester decreased renal blood flow (301 +/- 30 to 228 +/- 26 mL/min) and creatinine clearance (40.0 +/- 5.8 to 31.1 +/- 2.8 mL/min), whereas plasma creatinine increased, but fractional excretion of sodium was unchanged. In sheep with nonhypotensive hyperdynamic sepsis, plasma creatinine increased and there were decreases in creatinine clearance (34.5 +/- 4.6 to 20.1 +/- 3.7 mL/min) and fractional excretion of sodium despite increased renal blood flow. Infusion of N omega-nitro-L-arginine methyl ester normalized renal blood flow and increased urine output, but creatinine clearance did not improve and plasma creatinine and fractional excretion of sodium increased. In sheep with severe hypotensive sepsis, creatinine clearance decreased further (31.1 +/- 5.4 to 16.0 +/- 1.7 mL/min) despite increased renal blood flow. Infusion of N omega-nitro-L-arginine methyl ester restored mean arterial pressure and reduced renal blood flow but did not improve plasma creatinine or creatinine clearance. Conclusions: In hyperdynamic sepsis, with or without hypotension, creatinine clearance decreased despite increasing renal blood flow. Intrarenal N omega-nitro-L-arginine methyl ester infusion reduced renal blood flow but did not improve creatinine clearance. These data indicate that septic acute kidney injury is not the result of decreased renal blood flow nor is it improved by nonspecific nitric oxide synthase inhibition. (Crit Care Med 2011; 39: 770-776)