Adrenomedullin expression during hypoxia in fetal sheep R. I. Jensen, A. M. Carter, O. Skøtt and B. L. Jensen Department of Physiology and Pharmacology, University of Southern Denmark, Odense, Denmark Received 28 June 2004, accepted 26 August 2004 Correspondence: A. M. Carter, Department of Physiology and Pharmacology, University of Southern Denmark, Winsloewparken 21, Third Floor, DK-5000 Odense, Denmark. Abstract Aim: We asked how adrenomedullin (AM), a vasodilator peptide, was dis- tributed in fetal sheep organs and whether expression of AM would be upregulated in response to moderate acute fetal hypoxia in vivo. Methods: In four sheep at day 126–130 of gestation, nitrogen was added to the inspired air by tracheal infusion to reduce fetal arterial oxygen content for a period of 4 h. Control fetuses were from four ewes given a tracheal infusion of room air. Fetal and maternal blood samples were taken prior to and during hypoxia/sham hypoxia. Fetal tissue samples were frozen for RNA analysis and fixed for immunohistochemistry. Results: In hypoxic fetuses, arterial oxygen content was significantly reduced to 50% compared with sham fetuses with no change in arterial pH in either group. Plasma ACTH levels rose significantly at 2 and 4 h in hypoxic fetuses only. Initial plasma concentrations of AM in control and hypoxic fetuses were 457  20 and 430  35 pg mL )1 and did not change during the experiment. The relative abundance of AM mRNA was placental cotyledons  lung > cerebral cortex @ renal cortex > left ventricle @ right ventricle > adrenal gland > renal medulla > aorta @ liver. Immunohistochemical staining for AM confirmed distinct labelling in organs with significant expression. AM mRNA level increased significantly in cerebral cortex of hypoxic fetuses. Conclusion: Our results show expression of AM in placenta and in several fetal organs in late gestation sheep. AM may participate in the cerebral vasodilatation that is an integral part of the fetal response to hypoxia. Keywords growth, hypoxaemia, pregnancy. The vasodilator peptide adrenomedullin (AM) was originally characterized in human pheochromocytoma cell extracts by its ability to initiate cAMP production in target cells (Kitamura et al. 1993). AM is widely distributed in adult tissues, including the pulmonary and cardiovascular systems, urogenital tract and central nervous system (Sakata et al. 1993). As no single glandular source of AM has been identified, it is thought to act in a paracrine fashion. AM has been associated with states of cellular growth, as it is widely expressed during fetal development (Montuenga et al. 1997) and in various human malignancies (e.g. Martinez et al. 1995). A significant role for AM during fetal development has been established in rodents. Thus, administration of an AM antagonist to pregnant rats led to fetal growth restriction and pathological changes in the placenta (Witlin et al. 2002). Homo- zygous deletion of the AM gene was embryonically lethal causing significant defects in the cardiovascular system (Caron & Smithies 2001). AM thus appears important for normal development of heart and vessels, but in general, little is known about which organs express significant amounts of AM in the fetus and about the physiologic regulation of AM expression and secretion in the fetus. In order to identify sites of AM expression and potential sources of AM release in the fetus we screened an array of late gestation sheep fetal organs for AM expression and determined the cellular localization of AM in these organs. AM has been demonstrated in human fetal lung (Marinoni et al. 1999) and in fetal membranes and placenta (Marinoni et al. 1998, Kanenishi et al. 2001). AM is elevated in Acta Physiol Scand 2005, 183, 219–228 Ó 2005 Scandinavian Physiological Society 219