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To define dose-and time-response properties for in vivo inhibition of renal prostaglandin (PG) synthesis, aspirin, diclofenac sodium, indomethacin and d-naproxen were injected intravenously in different doses to unanaesthetized rabbits. After 30 min. the animals were killed and the post morrem accumulation of PGE, and PGF,, in the renal medulla was determined by mass fragmentography. In control animals, the accumulated levels of PGE, and PGF,, in the medulla were 9.2k2.2 (S.D.) and 1.5+0.6 pg/g. respectively. Dose-dependent inhibition was demonstrated with all the drugs. The ED95 was for aspirin 15 mg/kg, for diclofenac sodium 1.5 mg/kg, for indomethacin 1.5 rng/kg and for d-naproxen 5 mg/kg. The duration of inhibition was studied by radioimmunoassay in anaesthetized rabbits by following the urinary excretion of PGF,, and PGE, after an intravenous injection of solvent or test drug in doses twice the ED95. For three hours following aspirin, diclofenac sodium, indomethacin and d-naproxen, the decreases in urinary excretion of PGF,, ranged from 64 to 88, 87 to 95,64 to 90 and from 40 to 77 per cent of the control, respectively, and the decreases in PGE, excretion were of similar magnitude. Together these results indicate that diclofenac sodium might be used as a long-lasting and potent alternative to indomethacin and aspirin in experimental studies on the renal P G system in vivo.

The occurrence of 6‐keto‐prostaglandin Flα (6‐keto‐PGF1α) was demonstrated in rabbit kidney medulla and cortex by mass‐spectrometry. The post‐mortem accumulation of 6‐keto‐PGF1α was studied by mass‐fragmentography in regions of the rabbit kidney using (3,3,4,4,‐2H4) 6‐keto‐PGFlα as an internal standard. The cortex contained 1.4 + 0.3 μMg/g, the medulla 2.1 ± 0.6 μg/g and the papilla 3.7 ± 0.7 (S.E.) μg/g. The accumulation of 6‐keto‐PGF1α is thus about 5 fold higher in the cortex than reported for PGE2 and PGF2α, whereas accumulation of PGE2 and PGF2α dominates over 6‐keto‐PGFlα in the medulla and the papilla. The occurrence of 6‐keto‐PGFlα in rabbit urine was demonstrated by mass‐fragmentography. On a low salt diet unanesthetized, female rabbits (n = 6) excreted Na+ 0.09 ± 0.01 (S.E.) mmol/day, 6‐keto‐PGFlα 11.8 ± 2.2 μg/day and immunoreactive PGF2α (iPGF2α) 2.0 ± 0.6 μg/day. Two days treatment with acetylsalicylic acid (30 mg/kgx 2) reduced urinary excretion of 6‐keto‐PGFlα and iPGF2α by 71 and 85%, respectively (both p < 0.05), but sodium excretion was unchanged. On the same diet supplemented with NaCl, the rabbits excreted Na+ 27.5 ± 3.4 mmol/day (p < 0,05), 6‐keto‐PGFlα 13.3 ± 4.6 μg/day (p > 0.05) and iPGF2α 0.63 ± 0.10 μg/day (p < 0.05). 6‐keto‐PGFlα is a major metabolite of prostacyclin (PGI2). The occurrence of 6‐keto‐PGFlα in kidney and urine indicates a considerable synthesis of PGI2 in the kidney. The data on urinary PG excretion indicate that intrarenal synthesis of PGI2, in contrast to PGF2α, is not influenced by dietary variations in NaCl.

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