title: Effects of specific COX-2-inhibition on renin release and renal and systemic prostanoid synthesis in healthy volunteers.
abstract: BACKGROUND
  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.
  
  
  METHODS
  Twenty-one healthy female volunteers received, in a randomized, double-blind, crossover study, celecoxib 200 mg twice a day, indomethacin 50 mg 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 20 mg 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.
  
  
  RESULTS
  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 E(2), (PGE(2)), 7alpha-hydroxy-5, 11-diketotetranor-prosta-1,16-dioic acid (PGE-M), and 2,3-dinor-thromboxane B(2) (TxB(2)) 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-PGF(1alpha) and 6-keto-PGF(1alpha) by 60% and 40%, respectively.
  
  
  CONCLUSIONS
  Renin-release in healthy humans with normal salt intake is COX-2 dependent. While COX-1 is critical for renal and systemic PGE(2) 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.
authors.affiliation: Institute of Clinical Pharmacology, Medizinische Hochschule Hannover, Germany. Stichtenoth.Dirk@mh-hannover.de
authors.forename: Dirk O
authors.initials: DO
authors.lastname: Stichtenoth
authors.forename: Verena
authors.initials: V
authors.lastname: Marhauer
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tsikas
authors.forename: Frank-Mathias
authors.initials: FM
authors.lastname: Gutzki
authors.forename: Jürgen C
authors.initials: JC
authors.lastname: Frölich
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000031:analogs & derivatives / Q000652:urine; D000328:Adult; D000450:Aldosterone / Q000097:blood; D001835:Body Weight; D000068579:Celecoxib; D003404:Creatinine / Q000097:blood / Q000652:urine; D018592:Cross-Over Studies; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage; D015232:Dinoprostone / Q000096:biosynthesis* / Q000652:urine; D004232:Diuretics / Q000008:administration & dosage; D005260:Female; D005665:Furosemide / Q000008:administration & dosage; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D011188:Potassium / Q000097:blood / Q000652:urine; D011453:Prostaglandins / Q000096:biosynthesis / Q000652:urine; D011720:Pyrazoles / Q000008:administration & dosage*; D012083:Renin / Q000378:metabolism*; D012964:Sodium / Q000097:blood / Q000652:urine; D013449:Sulfonamides / Q000008:administration & dosage*; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000652:urine
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004232:Diuretics; D011453:Prostaglandins; D011720:Pyrazoles; D013449:Sulfonamides; D000450:Aldosterone; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C028290:2,3-dinor-6-ketoprostaglandin F1alpha; C060526:7-hydroxy-5,11-dioxotetranorprostane-1,16-dioic acid; D005665:Furosemide; D012964:Sodium; D003404:Creatinine; D012083:Renin; D000068579:Celecoxib; D015232:Dinoprostone; D011188:Potassium; D007213:Indomethacin