PROSTANOID BIOSYNTHESIS BY BLOOD MONOCYTES OF CHILDREN WITH HYPERPROSTAGLANDIN-E SYNDROME

Hyperprostaglandin E syndrome (HPS), the prenatal variant of Bartter's syndrome, is characterized by a marked and selective stimulation of p rostaglandin E (PGE(2)) synthesis. In the study group WS patients show ed increased urinary levels of PGE(2), an index of renal, and of 11 ,1 5-dioxo-2,3,4,5,20-pentanor-19-carboxyprostanoic acid (PGE-M), an inde x of systemic PGE(2) synthesis of 470% and of 570%, respectively. In a ddition, plasma concentration of PGE-M was also elevated 6.3-fold when compared with a control group. The urinary levels of other prostanoid s were unaltered. During indomethacin treatment in both groups prostan oid excretion rates were suppressed to similar levels. To investigate the origin of stimulated prostanoid biosynthesis in HPS patients CD14( +) monocytes were isolated from plasma samples, and the prostanoid syn thesis was analyzed. The pattern and amounts of metabolites synthesize d from endogenous arachidonic acid pools did not vary significantly be tween monocytes of the HPS and the control group. Thromboxane A(2) (TX A(2)) was formed as the major prostanoid product. Using PGH(2) as an e xogenous substrate, again no difference in PGE(2) biosynthesis was obs erved, indicating no difference in PGE-synthetic activity between both groups. Additionally, mRNA expression analysis of CD14(+) monocytes v ia RT-PCR delineated the constitutive expression of cyclooxygenase-1, cyclooxygenase-2, and thromboxane synthase mRNA in cells from HPS pati ents and controls without statistical differences between these two gr oups. In conclusion, our data show that monocytes are not the source f or the increased PGE(2) biosynthesis in children with HPS, and a genet ic defect in PGE synthesis can be excluded as the primary event in the pathogenesis in HPS.