Effects of specific COX-2-inhibition on renin release and renal and systemic prostanoid synthesis in healthy volunteers

• Published in: Kidney international Vol. 68; no. 5; pp. 2197 - 2207
• Main Authors: Stichtenoth, Dirk O., Marhauer, Verena, Tsikas, Dimitrios, Gutzki, Frank-Mathias, Frolich, Jurgen C.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.11.2005; Nature Publishing; Elsevier Limited
• Subjects: 6-Ketoprostaglandin F1 alpha - analogs & derivatives; 6-Ketoprostaglandin F1 alpha - urine; Adult; aldosterone; Aldosterone - blood; Biological and medical sciences; Body Weight; Celecoxib; Creatinine - blood; Creatinine - urine; Cross-Over Studies; Cyclooxygenase 2 Inhibitors - administration & dosage; Cyclooxygenase Inhibitors - administration & dosage; cyclooxygenase isoenzymes; Dinoprostone - biosynthesis; Dinoprostone - urine; Diuretics - administration & dosage; Female; Furosemide - administration & dosage; Humans; indomethacin; Indomethacin - administration & dosage; Kidney - drug effects; Kidney - metabolism; Medical sciences; Nephrology. Urinary tract diseases; PGE-M; PGE2; Potassium - blood; Potassium - urine; prostacyclin; Prostaglandins - biosynthesis; Prostaglandins - urine; Pyrazoles - administration & dosage; renin; Renin - metabolism; Sodium - blood; Sodium - urine; Sulfonamides - administration & dosage; thromboxane; Thromboxane B2 - biosynthesis; Thromboxane B2 - urine; cyclooxygenase isoenzymes; thromboxane; PGE2; celecoxib; prostacyclin; renin; aldosterone; PGE-M; indomethacin; Prostaglandin-endoperoxide synthase; Nephrology; Prostaglandin I2; Mineralocorticoid; Isozyme; Cyclooxygenase 2; Prostaglandin E2; Cyclooxygenase 2 inhibitor; Systemic; Aldosterone; Kidney; Urology; Renin; Synthesis; Eicosanoid; Aspartic endopeptidases; Disseminated; Inhibition; indornethacin; Release; Healthy subject; thromboxane. prostacyclin; Enzyme; Steroid hormone; Arachidonic acid derivatives; Enzyme inhibitor; Celecoxib; Non steroidal antiinflammatory agent; Peptidases; Urinary system; Adrenal hormone; Prostanoid; Hydrolases; Oxidoreductases; Thromboxane
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1111/j.1523-1755.2005.00676.x

Effects of specific COX-2-inhibition on renin release and renal and systemic prostanoid synthesis in healthy volunteers. The renin-angiotensin system plays a critical role in cardiovascular function, but little is known about the effects of specific cyclooxygenase 2 (COX-2) inhibition on this system in healthy humans under physiologic conditions. Twenty-one healthy female volunteers received, in a randomized, double-blind, crossover study, celecoxib 200mg twice a day, indomethacin 50mg three times a day, or placebo for 4 days and a single dose, each, on day 5. On day 5 of each treatment, the following parameters were assessed with subjects in an upright position before and after administration of 20mg furosemide intravenously: plasma renin activity (PRA), plasma aldosterone, serum and urine electrolytes, and creatinine. Index metabolites of prostanoids were analyzed by gas chromatography-tandem mass spectrometry in 24-hour urine on day 4 and in 2-hour urines before and after furosemide administration. Baseline and furosemide-stimulated PRA were reduced to a similar degree by celecoxib and indomethacin. Plasma aldosterone and urinary excretion of potassium showed changes consistent with the alteration of PRA. Urinary excretion rates of prostaglandin E2, (PGE2), 7α-hydroxy-5, 11-diketotetranor-prosta-1,16-dioic acid (PGE-M), and 2,3-dinor-thromboxane B2 (TxB2) were not reduced by celecoxib, whereas indomethacin led to a decrease of 40%, 45%, and 80%, respectively. Both active treatments inhibited urinary excretion of 2,3-dinor-6-keto-PGF1α and 6-keto-PGF1α by 60% and 40%, respectively. Renin-release in healthy humans with normal salt intake is COX-2 dependent. While COX-1 is critical for renal and systemic PGE2 production, renal prostacyclin synthesis is apparently COX-2 dependent. Finally, the previously demonstrated shift of the thromboxane-prostacyclin balance toward prothrombotic thromboxane by specific COX-2 inhibition is confirmed.