Role of cyclooxygenase-2 in hyperprostaglandin E syndrome/antenatal Bartter syndrome.
BACKGROUND
Hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS) is a congenital salt-losing tubulopathy with an induced expression of cyclooxygenase-2 (COX-2) in the macula densa probably leading to hyperreninemia. Inhibition of stimulated prostaglandin E2 (PGE2) formation with indomethacin results in a significant improvement of clinical symptoms and is therefore standard therapy. Using the COX-2 selective inhibitor rofecoxib, we investigated the role of COX-2 in the pathophysiology of HPS/aBS.


METHODS
Six clinically well-characterized patients with HPS/aBS (3 girls) were enrolled into the study. Four patients had mutations in the renal potassium channel ROMK, one patient in the furosemide-sensitive cotransporter NKCC2, whereas in one patient no molecular abnormality could be detected. Median age was 15.8 years (range: 9.1 to 19.0 years). Patients were evaluated on indomethacin treatment, 3 days after indomethacin withdrawal, and after 4 days of treatment with rofecoxib. Therapeutic drug monitoring was performed.


RESULTS
COX-2-selectivity of rofecoxib was confirmed in vivo and ex vivo. Both indomethacin and rofecoxib ameliorated clinical symptoms, the typical laboratory findings, and significantly suppressed PGE2 and PGE-M excretion to normal values while it was elevated under withdrawal conditions. Rofecoxib suppressed hyperreninemia to a similar extent as indomethacin.


CONCLUSIONS
In patients with HPS/aBS, excessive PGE2 synthesis and hyperreninemia is dependent on COX-2 activity. This observation proves the stimulatory role of COX-2 on renin-secretion in salt-depletion in humans. Clinical long-term efficacy and potential side effects of rofecoxib need to be evaluated in a larger cohort of HPS/aBS-patients.
Reinalter
Stephan C
SC
Department of Pediatrics, Philipps-University Marburg, Deutschhausstrasse 12, D-35053 Marburg, Germany.
Jeck
Nikola
N
Brochhausen
Christoph
C
Watzer
Bernhard
B
Nüsing
Rolf M
RM
Seyberth
Hannsjörg W
HW
Kömhoff
Martin
M
D000293:Adolescent; D000328:Adult; D001477:Bartter Syndrome / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D002648:Child; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology*; D007783:Lactones / Q000627:therapeutic use*; D008297:Male; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011458:Prostaglandins E / Q000096:biosynthesis*; D012083:Renin / Q000097:blood; D013450:Sulfones; D013577:Syndrome
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D007783:Lactones; D008565:Membrane Proteins; D011458:Prostaglandins E; D013450:Sulfones; C116926:rofecoxib; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D012083:Renin