Inhibition of prostaglandin synthesis in rat kidney perfused with and without erythrocytes: implication for analgesic nephropathy.
A marked defect in renal concentration ability associated with hypoxic lesions in the medullary thick ascending limb (mTAL) characterizes the isolated rat kidney perfused with cell-free solutions. Addition of erythrocytes to the perfusion medium, a maneuver known to eliminate signs of hypoxic cellular injury to mTALs, greatly improved renal concentrating ability. When indomethacin was given to kidneys perfused with erythrocyte-enriched medium, concentrating ability was further improved by the drug to an average U/Posm of 2.45 +/- 0.81, and medullary cellular structure remained normal in appearance. Since renal hypoperfusion predisposes to acute renal failure from non-steroidal antiinflammatory drugs (NSAIDs) and medullary ischemia might play a role in chronic analgesic nephropathy, a synergism between NSAIDs and medullary hypoxia was evaluated in the isolated perfused rat kidney. Indomethacin and naproxen added to the perfusion medium (at 10(-4) and 5 X 10(-4) M, respectively) effectively depressed prostaglandin E2 (PGE2) production by the isolated kidney but did not improve its concentrating ability when perfused with cell-free medium. Quantitation of hypoxic injury to mTALs, regularly observed in this model, indicated that both indomethacin and naproxen increased the extent and severity of damage in the deeper, most hypoxic portions of the inner stripe. Addition of PGE2 to cell-free perfusate reduced the extent of hypoxic damage to the mTAL. These results suggest that in medullary hypoxia, prostaglandins protect mTAL cells by either vasodilatation or reduction in active transtubular transport. NASAIDs, by suppressing prostaglandin production, could predispose the renal medulla to hypoxic injury.
Brezis
M
M
Rosen
S
S
Stoff
J S
JS
Spokes
K
K
Silva
P
P
Epstein
F H
FH
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D015232:Dinoprostone; D004912:Erythrocytes; D007213:Indomethacin / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism*; D007671:Kidney Concentrating Ability; D008297:Male; D010477:Perfusion; D011453:Prostaglandins / Q000096:biosynthesis*; D011458:Prostaglandins E / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D000596:Amino Acids; D011453:Prostaglandins; D011458:Prostaglandins E; D015232:Dinoprostone; D007213:Indomethacin