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Plasma concentration of 2-methoxyestradiol (2-ME) and placental expression of catechol-O-methyltransferase(COMT) are elevated in normal pregnancy, but reduced in women with preeclampsia (PE). Women with PE and fetal growth restriction (FGR)exhibit decreased utero-placental blood flow. Catechol-O-methyltransferase knockout mice (COMT-/-) and female CBA/J mice mated with male DBA/2 mice (CBA/J × DBA/2)show many signs of PE during pregnancy and deliver growth-restricted pups. 2-ME is known to induce significant vasorelaxation of uterine arteries from pregnant mice. We hypothesized that 2-ME administration during pregnancy will lead to an increase in uterine artery blood flow velocity in COMT-/- and CBA/J × DBA/2 mice and therefore ameliorate PE-like signs and rescue fetal growth in these animal models. Pregnant COMT-/- and their controls (C57BL/6),and CBA/J × DBA/2 and their controls (CBA/J × BALB/c),were injected subcutaneously daily with 10 ng of 2-ME or vehicle (olive oil) from gestational day (GD) 12.5 to 17.5. There was no significant effect of genotype/strain or treatment on maternal blood pressure, uterine artery blood flow velocity or fetal growth. A perturbed phenotype only occurred in the COMT-/- mice in regard to umbilical artery flow velocity, proteinuria and 2-ME levels. Administration of 2-ME led to normalization ofumbilical artery blood flow velocity and proteinuria in COMT-/- mice. The utility of 2-ME in cases of PE and FGR needs to be further explored in PE models that exhibit more severe disease phenotypes.

A technique for the perfusion of the rat adrenal cortex is described. With tissue culture Medium 199 the preparation was responsive in terms of steroid production to both ACTH and K+ ions. Production of corticosterone and 18-hydroxydeoxycorticosterone (18-hydroxy-DOC) was stimulated by ACTH when it was administered at rates between 5 μu./min and 5 mu./min. Increasing the K+ ion concentration of the perfusate from 3·6 to 5·4 and 8·9 mmol/l stimulated the production of aldosterone, 18-hydroxycorticosterone and deoxycorticosterone, although not of corticosterone or 18-hydroxy-DOC. This preparation has been used to study further the mechanism of secretion of corticosterone and 18-hydroxy-DOC. Thus, production of these two steroids was measured at different perfusion flows, varying between 0·1 and 0·6 ml/min, with different levels of ACTH stimulation. Corticosterone production was significantly (P < 0·001) increased by increasing flows both under control conditions and when ACTH was administered at constant rates of 50 μu./min or 1 mu./min. Production of 18-hydroxy-DOC was not affected by flow either under control conditions or with 50 μu. ACTH/min. However, when ACTH was administered at 1 mu./min, 18-hydroxy-DOC production was also significantly (P < 0·001) increased by flow. The results are consistent with those obtained in previous in-vitro studies and have been interpreted as suggesting that the main mechanism of corticosterone secretion is simple diffusion. In contrast, 18-hydroxy-DOC secretion, at least at sub-maximal levels of stimulation, appears to require a more complex process.