The hypothesis that nitric oxide antagonizes pressure-flow autoregulation in the superior mesenteric artery was tested with the use of a nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), and L-arginine. Autoregulation was assessed with the use of two indexes: 1) the autoregulatory index (ARI), expressed as the ratio of change in flow to change in pressure tested over the nonautoregulatory range, 40-70 mmHg, and over the autoregulatory range, 70-140 mmHg; and 2) the slope index, an index of linearity of the pressure-flow curve calculated by dividing the slope of the pressure-flow curve over the autoregulatory range by the slope of the curve over the nonautoregulatory range, expressed as percent. L-NAME significantly increased autoregulation from an ARI of 0.06 +/- 0.05 to 0.28 +/- 0.09 over the autoregulatory range (P < 0.003), and the nitric oxide synthase substrate L-arginine reversed ARI to 0.12 +/- 0.07 (mean +/- SE, n = 7). ARI in the nonautoregulatory range was not altered. The slope index revealed that L-NAME enhanced autoregulation (61 +/- 5.6 compared with control, 93.4 +/- 7.9; P < 0.003), which was reversed by the action of L-arginine (88.5 +/- 5.5, P < 0.007). The data were consistent with the hypothesis that increased flow leads to nitric oxide-induced dilation, which counteracts autoregulation.