The present study aimed to elucidate the reciprocal interactions between oxygen (O(2)), nitric oxide (NO), and superoxide (O(2)(-)) and their effects on vascular and tubular function in the outer medulla. We expanded our region-based model of transport in the rat outer medulla (Edwards A, Layton AT. Am J Physiol Renal Physiol 301: F979-F996, 2011) to incorporate the effects of NO on descending vasa recta (DVR) diameter and blood flow. Our model predicts that the segregation of long DVR in the center of vascular bundles, away from tubular segments, gives rise to large radial NO concentration gradients that in turn result in differential regulation of vasoactivity in short and long DVR. The relative isolation of long DVR shields them from changes in the rate of NaCl reabsorption, and hence from changes in O(2) requirements, by medullary thick ascending limbs (mTALs), thereby preserving O(2) delivery to the inner medulla. The model also predicts that O(2)(-) can sufficiently decrease the bioavailability of NO in the interbundle region to affect the diameter of short DVR, suggesting that the experimentally observed effects of O(2)(-) on medullary blood flow may be at least partly mediated by NO. In addition, our results indicate that the tubulovascular cross talk of NO, that is, the diffusion of NO produced by mTAL epithelia toward adjacent DVR, helps to maintain blood flow and O(2) supply to the interbundle region even under basal conditions. NO also acts to preserve local O(2) availability by inhibiting the rate of active Na(+) transport, thereby reducing the O(2) requirements of mTALs. The dual regulation by NO of oxygen supply and demand is predicted to significantly attenuate the hypoxic effects of angiotensin II.