SHORT REPORT

Cerebrospinal fluid adrenomedullin levelsin patients with pre-eclampsiaONDER CELIK

1, SEYMA HASCALIK1, MUHITTIN YUREKLI

2AND YUSUF TURKOZ

3

From the 1Department of Obstetrics and Gynecology, Inonu University Medical Faculty, 2Department of MolecularBiology, Inonu University Science Faculty and 3Department of Biochemistry, Inonu University Medical Faculty,Malatya, Turkey

Key words: cerebrospinal fluid; adrenomedullin; pre-eclampsia

Submitted 27 July, 2002Accepted 2 December, 2002

Pre-eclampsia is a syndrome that affects nearlyall the maternal organ systems, and the onlymanagement is the termination of the pregnancy.Increased vascular reactivity and vasoconstric-tion with endothelial damage appears as thefinal common pathway in the pathogenesis ofpre-eclampsia (1). Adrenomedullin (AM) is amultifunctional bioactive 52-amino-acid vaso-relaxant peptide with a single disulfide bridgebetween residues 16 and 21 and belongs to thecalcitonin gene-related peptide family (2). It isproduced and released from the adrenal gland,vascular endothelial cells, smooth muscle cells,macrophages, neurons and glial cells. Therefore,AM expression is seen in all tissues and reflectsdegrees of tissue vascularity. Plasma levels of AMare elevated in a normal pregnancy (3). Thisincrease has a range of biological actions includ-ing embryogenesis, vasodilatation, regulation ofblood pressure and increased placental and cere-bral blood flow (3,4). The concentration of cere-brospinal fluid (CSF)-AM is lower than plasmaAM (3). While plasma AM increases from thefirst to third trimester, no change in CSF-AMconcentration is seen, suggesting independentregulation of AM in the CSF and plasma (3). Inview of the physiological features of AM, disturb-ance of CSF-AM may contribute to the centraleffects of pre-eclampsia. In the present study, weinvestigated whether CSF-AM levels change inpatients with pre-eclampsia. As far as we know,

this is the first report on CSF-AM levels inpatients with pre-eclampsia.

We studied 12 normotensive pregnant women,and 12 patients with pre-eclampsia. In all subjects,CSF samples were collected during spinalanesthesia at a cesarean section. Before theadministration of local anesthetic to the subduralspace, 2 ml of CSF was taken. Hemorrhagicsamples were excluded from the study. AM wasanalyzed in CSF samples using reverse-phasehigh-performance liquid chromatography (C-18column, 4.6� 250 mm, Cecil 1100, Supelco,Cambridge, UK). The Mann–Whitney U-test wasused in the statistical analysis. Results were givenas median and range (Table I). The age and gesta-tional weeks of the groups were similar. Systolicand diastolic pressures were significantly higherin the pre-eclamptic group. Infants’ birth weightswere significantly lower in the pre-eclampticgroup. CSF-AM levels (28.1 pg/l; range, 24.4–34.1)were significantly higher in the pre-eclampticgroup compared with the normotensive pregnan-cies (18.1 pg/l; range, 16.2–20.1, p< 0.05).

AM receptors have been demonstrated in chor-oid plexus, blood vessels, astrocytes and other celltypes of the brain. In the rat brain, CGRP1 andthree different receptors (RDC-1 mRNA, L1 andCRLR) were found using in situ hybridization(5). AM acts via specific AM receptors for someresponses and via CGRP1 receptors for vasculareffects. However, the effects of AM in cerebral

# Acta Obstet Gynecol Scand 82 (2003)

Acta Obstet Gynecol Scand 2003; 82: 578--579 Copyright # Acta Obstet Gynecol Scand 2003

Printed in Denmark. All rights reservedActa Obstetricia et

Gynecologica ScandinavicaISSN 0001-6349

vessels have been poorly defined. Baskaya et al.(6) showed the vasodilator effects of AM in thecerebral vessels. Another study reported that AMmight have a role in preventing ischemic braininjury (7). Intracerebral administration of AMincreases sympathetic nerve activity and pregan-glionic sympathetic discharge, and stimulateshypertension in conscious rats (8). Interestingly,it has been recently demonstrated that AM hasno effect on the blood–brain barrier (9) wheninjected peripherally. Thus, the cerebral effect ofAM is dissociated from its effect on the blood–brain barrier. But there is no report on how theblood–brain barrier behaves during pre-eclampsia.It is probable that altered cerebral hemo-dynamics are responsible for the central effect ofpre-eclampsia, because pre-eclampsia can causean impairment of maternal cerebral circulationwhich is mainly a consequence of vasospasm(10) and hypoxic brain damage. The present pre-liminary clinical investigation demonstrated thatCSF-AM levels are significantly higher inpatients with pre-eclampsia than in normotensivepregnant women. The mechanism and physio-logical role of increased CSF-AM in pre-eclampsiais not known. We speculate that in pre-eclampsia,increased production of CSF-AM may compen-sate for the increased synthesis and release fromthe injured endothelium of other vasoactive sub-stances. Increased CSF-AM levels lead to vaso-dilatation (6), increase cerebral blood flow (3),prevent ischemia (7) and may prevent eclampsia.Alternatively increased CSF-AM concentrationsmay have an important role in the regulation ofblood flow through the cerebral microvessels ormay reflect the degree of cerebral endothelial celldamage.

References

1. Friedman SA, Taylor RN, Roberts JM. Pathophysiol-ogy of preeclampsia. Clin Perinatol 1991; 4: 661–82.

2. Kitamura K, Kangawa K, Kawamoto M, Ichiki Y,Nakamura S, Matsuo H, Eto T. Adrenomedullin: anovel hypotensive peptide isolated from human pheo-chromocytoma. Biochem Biophys Res Commun 1993;192: 553–60.

3. Nagata N, Kato J, Kitamura K, Kawamoto M, Tanaka N,Eto T, Takasaki M. Dissociation of adrenomedullinconcentrations in plasma and cerebrospinal fluid inpregnant and non-pregnant women. Eur J Endocrinol1998; 139: 611–4.

4. Kohno N, Hanemira T, Kano H, Horio T, Yokokawa K,Ikeda M, Minami M, Yasunari K, Yoshikawa J. Plasmaadrenomedullin concentrations in essential hyperten-sion. Hypertension 1996; 27: 102–7.

5. Oliver KR, Wainwright A, Heavens RP, Hill RG,SirinathsinghjiDJS.DistributionofnovelCGRP(1)recep-tor and adrenomedullin receptor mRNAs in the ratcentral nervous system. Mol Brain Res 1998; 57: 149–54.

6. Baskaya MK, Suzuki Y, Anzai M, Seki Y, Saito K,Takayasu M, Shibuya M, Sugita K. Effects of adreno-medullin, calcitonin gene-related peptide, and amylin oncerebral circulation in dogs. J Cereb Blood Flow Metab1995; 15: 827–34.

7. Dogan A, Suzuki Y, Koketsu N, Osuka K, Saito K,Takayasu M, Shibuya M, Yoshida J. Intravenous infu-sion of adrenomedullin and increase in regional cerebralblood flow and prevention of ischemic brain injury aftermiddle cerebral artery occlusion in rats. J Cereb BloodFlow Metab 1997; 17: 19–25.

8. Samson WK, Murphy TC, Resch ZT. Central mechan-isms for the hypertensive effects of preproadrenomedullin-derived peptides in conscious rats [Rapid Communi-cation]. Am J Physiol 1998; 43: R1505–R1509.

9. Kastin AJ, Akerstrom V, Hackler L, Pan W. Adreno-medullin and the blood–brain barrier. Horm Metab Res2001; 33: 19–25.

10. Demarin V, Rundek T, Hodek B. Maternal cerebralcirculation in normal and abnormal pregnancies. ActaObstet Gynecol Scand 1997; 76: 619–24.

Address for correspondence:Onder CelikDepartment of Obstetrics and GynecologyTurgut Ozal Medical CenterInonu University44069 MalatyaTurkeye-mail: oncelik@inonu.edu.tr

Table I. Patient characteristics and CSF-AM levels in pre-eclamptic and normotensive pregnancies

Pre-eclampsia(n¼ 12)

Control(n¼ 12) Significance

Age (years) 26.0 (22–33) 25.0 (19–28) NSGestational age at delivery (week) 36.4 (35–38) 37.0 (35–38) NSSystolic blood pressure (mmHg) 150.0 (140–160) 110.0 (100–145) p< 0.05*Distolic blood pressure (mmHg) 100.0 (90–110) 70.0 (60–90) p< 0.05*Parity 2.0 (1–3) 1.0 (1–3) p< 0.05*Birth weight (gm) 2900 (2200–3200) 3300 (2700–3500) p< 0.05*Proteinuria (mg/24 hr) 1847.5 (385–4400) 102.5 (60–240) p< 0.05*Adrenomedullin (pg/l) 28.1 (24.4–34.1) 18.13 (16.2–20.1) p< 0.05*

NS: not significant.*Statistically significant by the Mann–Whitney U-test (p< 0.05).Data were presented as median and range.

CSF-AM levels in patients with pre-eclampsia 579

# Acta Obstet Gynecol Scand 82 (2003)