Studies were conducted to determine whether the diffusion of NO from the renal medullary thick ascending limb (mTAL) to the contractile pericytes of surrounding vasa recta was reduced and, conversely, whether diffusion of oxygen free radicals was enhanced in the salt-sensitive Dahl S rat (SS/Mcwi). Angiotensin II ([Ang II] 1 mu mol/L)-stimulated NO and superoxide (O(2)(.-)) production were imaged by fluorescence microscopy in thin tissue strips from the inner stripe of the outer medulla. In prehypertensive SS/Mcwi rats and a genetically designed salt-resistant control strain (consomic SS-13(BN)), Ang II failed to increase either NO or O(2)(.-) in pericytes of isolated vasa recta. Ang II stimulation resulted in production of NO in epithelial cells of the mTAL that diffused to vasa recta pericytes of SS-13(BN) rats but not in SS/Mcwi rats except when tissues were preincubated with the superoxide scavenger TIRON (1 mmol/L). Ang II resulted in a greater increase of O(2)(.-) in the mTAL of SS/Mcwi compared with SS.13(BN) mTAL. The O(2)(.-) diffused to adjoining pericytes in tissue strips only in SS/Mcwi rats but not in control SS-13(BN) rats. Diffusion of Ang II-stimulated O(2)(.-) from mTAL to vasa recta pericytes was absent when tissue strips from SS/Mcwi rats were treated with the NO donor DETA-NONOate (20 mu mol/L). We conclude that the SS/Mcwi rat exhibits increased production of O(2)(.-) in mTAL that diffuses to surrounding vasa recta and attenuates NO cross-talk. Diffusion of O(2)(.-) from mTAL to surrounding tissue could contribute to reduced bioavailability of NO, reductions of medullary blood flow, and interstitial fibrosis in the outer medulla of SS/Mcwi rats.