A ROLE FOR NORADRENALINE IN PREECLAMPSIA - TOWARDS A UNIFYING HYPOTHESIS FOR THE PATHOPHYSIOLOGY

Objective To compare plasma catecholamine (noradrenaline and adrenalin e) levels in pre-eclamptic to normotensive pregnancy, and to study the activity of synthetic enzymes for catecholamines in placental and tro phoblastic cell cultures. We postulated that catecholamines might be a n important signal secreted by the fetoplacental unit in pre-eclampsia . Methods We recruited 12 women with pre-eclampsia and 12 pregnant wom en with nonproteinuric hypertension undergoing delivery by caesarean s ection, 23 normotensive women undergoing elective caesarean section at term, and 26 normotensive primigravid women with ongoing pregnancies at gestations equivalent to those women with pre-eclampsia, We measure d venous blood concentrations of catecholamines. Following delivery, w e studied tyrosine hydroxylase (the rate limiting enzyme for catechola mine synthesis) activity in placental tissue of these women as well as from four eclamptic women not in the observer study. We used Northern blot analysis to quantify mRNA for tyrosine hydroxylase and dopamine- beta-hydroxylase (D-beta-H, a non-rate-limiting synthetic enzyme for c atecholamine) in placental tissue, as well as in trophoblast cells in primary culture and trophoblast cell lines. Results Venous blood conce ntrations of noradrenaline were significantly higher in pre-eclamptic women compared with normotensive women. Tyrosine hydroxylase activity was greater in placental tissue from pre-eclamptic and eclamptic compa red with normotensive pregnancies, as were mRNA levels for this enzyme . The mRNA levels for the non-rate-limiting D-beta-H in women with pre -eclampsia were similar to those in normotensive pregnancies. First tr imester trophoblast cells in primary culture and trophoblast cell line s transcript mRNA for tyrosine hydroxylase and D-beta-H. Conclusions T rophoblasts have the capacity to secrete catecholamines, and we found increased activity of the rate-limiting synthetic enzyme in placental tissue from pre-eclamptic pregnancies. We postulate that the higher le vels of catecholamines we found in the plasma of women with pre-eclamp sia might be of placental origin. We hypothesise that in pre-eclampsia ischaemic trophoblast tissue secretes catecholamines as a physiologic al signal to increase maternal blood flow to the fetoplacental unit, w hich itself is spared the vasoconstrictor effects of catecholamines (p lacental vessels are known to be unresponsive to catecholamines). Howe ver, since the basic pathology-defective trophoblast invasion-is not c orrected, the increased blood flow fails to resolve the ischaemia, and the secretion of catecholamines is therefore sustained or even enhanc ed. Noradrenaline is known to cause lipolysis. This results in breakdo wn of triglycerides to free fatty acids, which are oxidized to lipid p eroxides. The latter are cytotoxic and cause widespread endothelial ce ll damage and dysfunction, culminating in the clinical syndrome of pre -eclampsia.