Cerebrospinal fluid adrenomedullin levels in patients with pre-eclampsia

Abstract

Pre-eclampsia is a syndrome that affects nearly all the maternal organ systems, and the only management is the termination of the pregnancy. Increased vascular reactivity and vasoconstriction with endothelial damage appears as the final common pathway in the pathogenesis of pre-eclampsia (1). Adrenomedullin (AM) is a multifunctional bioactive 52-amino-acid vasorelaxant peptide with a single disulfide bridge between residues 16 and 21 and belongs to the calcitonin gene-related peptide family (2). It is produced 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 reflects degrees of tissue vascularity. Plasma levels of AM are elevated in a normal pregnancy (3). This increase has a range of biological actions including embryogenesis, vasodilatation, regulation of blood pressure and increased placental and cerebral blood flow (3,4). The concentration of cerebrospinal fluid (CSF)-AM is lower than plasma AM (3). While plasma AM increases from the first to third trimester, no change in CSF-AM concentration is seen, suggesting independent regulation of AM in the CSF and plasma (3). In view of the physiological features of AM, disturbance of CSF-AM may contribute to the central effects of pre-eclampsia. In the present study, we investigated whether CSF-AM levels change in patients with pre-eclampsia. As far as we know, this is the first report on CSF-AM levels in patients with pre-eclampsia. We studied 12 normotensive pregnant women, and 12 patients with pre-eclampsia. In all subjects, CSF samples were collected during spinal anesthesia at a cesarean section. Before the administration of local anesthetic to the subdural space, 2 ml of CSF was taken. Hemorrhagic samples were excluded from the study. AM was analyzed in CSF samples using reverse-phase high-performance liquid chromatography (C-18 column, 4.6 × 250 mm, Cecil 1100, Supelco, Cambridge, UK). The Mann–Whitney U-test was used in the statistical analysis. Results were given as median and range (Table I). The age and gestational weeks of the groups were similar. Systolic and diastolic pressures were significantly higher in the pre-eclamptic group. Infants' birth weights were significantly lower in the pre-eclamptic group. CSF-AM levels (28.1 pg/l; range, 24.4–34.1) were significantly higher in the pre-eclamptic group compared with the normotensive pregnancies (18.1 pg/l; range, 16.2–20.1, p < 0.05). AM receptors have been demonstrated in choroid plexus, blood vessels, astrocytes and other cell types of the brain. In the rat brain, CGRP1 and three different receptors (RDC-1 mRNA, L1 and CRLR) were found using in situ hybridization (5). AM acts via specific AM receptors for some responses and via CGRP1 receptors for vascular effects. However, the effects of AM in cerebral vessels have been poorly defined. Baskaya et al. (6) showed the vasodilator effects of AM in the cerebral vessels. Another study reported that AM might have a role in preventing ischemic brain injury (7). Intracerebral administration of AM increases sympathetic nerve activity and preganglionic sympathetic discharge, and stimulates hypertension in conscious rats (8). Interestingly, it has been recently demonstrated that AM has no effect on the blood–brain barrier (9) when injected peripherally. Thus, the cerebral effect of AM is dissociated from its effect on the blood–brain barrier. But there is no report on how the blood–brain barrier behaves during pre-eclampsia. It is probable that altered cerebral hemodynamics are responsible for the central effect of pre-eclampsia, because pre-eclampsia can cause an impairment of maternal cerebral circulation which is mainly a consequence of vasospasm (10) and hypoxic brain damage. The present preliminary clinical investigation demonstrated that CSF-AM levels are significantly higher in patients with pre-eclampsia than in normotensive pregnant women. The mechanism and physiological role of increased CSF-AM in pre-eclampsia is not known. We speculate that in pre-eclampsia, increased production of CSF-AM may compensate for the increased synthesis and release from the injured endothelium of other vasoactive substances. Increased CSF-AM levels lead to vasodilatation (6), increase cerebral blood flow (3), prevent ischemia (7) and may prevent eclampsia. Alternatively increased CSF-AM concentrations may have an important role in the regulation of blood flow through the cerebral microvessels or may reflect the degree of cerebral endothelial cell damage. Address for correspondence: Onder Celik Department of Obstetrics and Gynecology Turgut Ozal Medical Center Inonu University 44069 Malatya Turkey e-mail: oncelik@inonu.edu.tr