Chronic cyclooxygenase-2 inhibition blunts low sodium-stimulated renin without changing renal haemodynamics

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Abstract
Cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, is found in the macula densa of the renal cortex and is upregulated by dietary sodium restriction. Because of this discrete cortical localization, we hypothesized that COX-2 plays a role in the chronic stimulation of renin via the macula densa pathway. We examined the effect of the selective COX-2 inhibitor NS 398 in male Sprague–Dawley rats. A low sodium diet (0.02% NaCl) for 14 days elevated plasma–renin activity (PRA) nine-fold, from 6.1 ± 2.0 to 54.9 ± 6.5 ng angiotensin I (Ang I)/ml per h (P < 0.0001). Selective COX-2 inhibition with NS 398 had no effect on PRA in animals on normal sodium (5.1 ± 1.3 ng Ang I/ml per h), but decreased PRA by 41% in sodium-restricted rats, to 33.3 ± 3.6 ng Ang I/ml per h (P < 0.05). Chronic treatment with NS 398 did not decrease renal renin content (31.8 ± 1.8 versus 33.5 ± 2.6 ng Ang I/mg per h, with NS 398 versus controls), nor did it influence systemic blood pressure or renal haemodynamics. Neither urinary sodium excretion nor prostaglandin (PG)E2 excretion was altered in rats given NS 398. Chronic treatment with the non-selective COX inhibitor indomethacin during sodium restriction over 5 days reduced PRA by 35%, from 29.36 ± 4.81, to 19.13 ± 2.88 ng Ang I/ml per h (P < 0.05). Indomethacin had no effect on blood pressure or renal blood flow but reduced urinary PGE2 excretion by 70%. One component of the chronic stimulation of PRA by dietary sodium restriction via the macula densa pathway appears to involve the induction of COX–2.