Pathogenetic role of cyclooxygenase-2 in hyperprostaglandin E syndrome/antenatal Bartter syndrome:: Therapeutic use of the cyclooxygenase-2 inhibitor nimesulide

Patients with hyperprostaglandin E syndrome/antenatal Bartter syndrome typically have renal salt wasting, hypercalciuria with nephrocalcinosis, and secondary hyperaldosteronism. Antenatally, these patients have fetal polyuria, leading to polyhydramnios and premature birth. Hyperprostaglandin E syndrome/antenatal Bartter syndrome is accompanied by a pathologically elevated synthesis of prostaglandin E-2, thought to be responsible for aggravation of clinical symptoms such as salt and water loss, vomiting, diarrhea, and failure to thrive. In this study administration of the cyclooxygenase-2 (COX2) specific inhibitor nimesulide to patients with hyperprostaglandin E syndrome/antenatal Bartter syndrome blocked renal prostaglandin E-2 formation and relieved the key parameters hyperprostaglandinuria, secondary hyperaldosteronism, and hypercalciuria. Partial suppression of serum thromboxane B-2 synthesis resulting from platelet COX-1 activity and complete inhibition of urinary 6-keto-prostaglandin F-1 alpha, reflecting endothelial COX-2 activity, indicate preferential inhibition of COX-2 by nimesulide. Amelioration of the clinical symptoms by use of nimesulide indicates that COX-2 may lay an important patho. genetic role in hyperprostaglandin E syndrome/antenatal Bartter syndrome. Moreover, on the basis of our data we postulate that COX-2-derived prostaglandin E-2 is an important mediator for stimulation of the renin-angiotensin-aldosterone system in the kidney.