The straight portion (S3) of the proximal tubule lies in close proximity to the thick ascending limbs (TALs) at the cortico-medullary junction. Since a delicate balance exists between oxygen demand and the limited oxygen supply in this region, we hypothesized that reduction of thick limb metabolic activity might augment oxygen availability to S3 segments, which depend heavily upon aerobic metabolism, and prevent hypoxic damage. The degree of functional deterioration and morphological damage to S3 was assessed in isolated rat kidneys perfused with an erythrocyte-free medium. Bumetanide (10(-5) M) and furosemide (10(-4) M) reduced S3 fragmentation from 9.8 +/- 3.9% of tubules in controls to 0 and 1.4 +/- 0.9%, respectively (P < 0.0005). Tubular glucose reabsorption was better preserved in kidneys exposed to loop diuretics than in control kidneys (P < 0.01), and urinary alkaline phosphatase (P < 0.05) and the total amount of LDH released into the perfusate and urine (P < 0.01) were lower in the treatment groups. Morphological damage to S3 was closely correlated with medullary TAL necrosis (r = 0.66, P < 0.001), urinary alkaline phosphatase excretion (r = 0.89, P < 0.001) and glycosuria (r = 0.83, P < 0.001). We conclude that under hypoxic conditions TALs and S3 segments may compete with each other for a limited oxygen supply. Reduction of active transport in the mTAL might augment oxygen availability to S3 segments and improve their survival.