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Stimulation of the ADRB3 Adrenergic Receptor Induces Relaxation of Human Placental Arteries: Influence of Preeclampsia¹

Laboratory of Cardiovascular Physiopathology and Pharmacology,³ Faculty of Medicine, 21079 Dijon Cedex, France UPRES EA220-Pharmacology,⁴ UFR Biomédicale des Saints Pères, 75006 Paris, France INSERM U427,⁵ Faculté de Pharmacie, 75006 Paris, France Department of Pharmacology,⁶ University of Valencia, 46010 Valencia, Spain Department of Gynaecology,⁷ CHU du Bocage, 21000 Dijon, France Department of Obstetrics and Gynecology,⁸ Port-Royal Cochin Hospital, 75014 Paris, France

ABSTRACT

Preeclampsia, which complicates 3–8% of pregnancies, is one of the leading causes of neonatal morbidity and mortality. Its pathophysiology remains unclear. The aim of the present study was to investigate the presence and the role of ß₂- and ß₃-adrenergic receptors (ADRB2 and ADRB3, respectively) in human placental arteries and to assess the influence of preeclampsia on ADRB responsiveness. SR 59119A, salbutamol, and isoproterenol (ADRB3, ADRB2, and nonselective ADRB agonists, respectively) induced a concentration-dependent relaxation of placental artery rings obtained from women with uncomplicated or preeclamptic pregnancies. SR 59119A-induced relaxation was unaffected by the blockade of ADRB1 and ADRB2 by 0.1 µM propranolol but was significantly decreased by the blockade of ADRB1, ADRB2, and ADRB3 by 10 µM propranolol. Both SR 59119A and salbutamol were associated with a significant increase in cAMP production that was significantly inhibited by pretreatment with 0.1 µM propranolol only for salbutamol. SR 59119A-induced relaxation (E_max = 28% ± 5% vs. 45% ± 4%, respectively) and cAMP production (2.7 ± 0.5 vs. 4.9 ± 0.4 pmol/mg of protein, respectively; P < 0.01) were decreased in arteries obtained from preeclamptic compared to normotensive women. Both ADRB2 and ADRB3 transcripts were expressed at the same level between arteries from normotensive and preeclamptic women. Western blot analysis, however, revealed a decreased expression of the ADRB3 immunoreactive protein in arteries from preeclamptic compared to normotensive women. We suggest the presence of functional ADRB2 and ADRB3 in human placental arteries. Even if preeclampsia is associated with an impairment of the ADRB3 responsiveness, ADRB3 agonists may have future pharmaceutical implications in the management of pregnancy-related disorders.

catecholamines, cyclic adenosine monophosphate, cyclic guanosine monophosphate, placenta, pregnancy

¹ Supported, in part, by the Fondation pour la Recherche Médicale and, in part, by the grant SAF2003–07206-C02 (Spain).

² Correspondence: M. Bardou, Faculty of Medicine, LPPCE, 7 Bd Jeanne d'Arc, BP 87900, 21079 Dijon Cedex, France. FAX: 33 3 80 39 32 93; marc.bardou{at}u-bourgogne.fr