title: Prostaglandin E2 in human placenta: its vascular effects and activation of prostaglandin E2 formation by nicotine and cotinine.
abstract: Tobacco smoking by pregnant women increases the frequency of spontaneous abortions and preterm births. Human labor is associated with enhanced intrauterine phospholipid metabolism and production of prostaglandin E2 (PGE2) which induces labor, initiates uterine contractions and maintains the homeostasis of placental blood flow. Therefore, we studied: (a) the influence of nicotine and cotinine on the effects of PGE2 on placental vasculature in perfused human placental cotyledon, and (b) the activation of placental phospholipase A2 (PLA2) by nicotine and cotinine using 1-palmitoyl-2-[1-14C]arachidonyl-phosphatidylethanolamine (PE, 2.2 nmol) as substrate. These studies revealed that: (1) increasing concentrations of PGE2 (10- 150 ng/ml) increased umbilical perfusion pressure by 170 +/- 10% (n = 6) of control (100%). Cotinine (2 microg/ml) enhanced this effect at all concentrations of PGE2. Nicotine (2 microg/ml) prevented the effect of PGE2; (2) both cotinine (EC50 470-500 fmol/l) and nicotine (EC50 18-32 pmol/l) activated PLA2 in human placental tissues. These observations indicated that cotinine was more potent than in nicotine activating PLA2 and potentiating the vasoconstrictive effects of PGE2 on fetal placental circulation. Nicotine activates nicotinic receptors and releases placental acetylcholine, a vasodilator of placental arteries. Acetylcholine stimulates muscarinic receptors of endothelial cells resulting in the release of endothelium-derived relaxing factor (EDRF), and possibly nitric oxide. Therefore, nicotine prevents or abolishes the vasoconstrictive effects of PGE2 through the release of EDRF. Cotinine is inactive at nicotinic and muscarinic receptors. Therefore, accumulation of cotinine, the major metabolite of nicotine, in fetal circulation may contribute to production of PGE2 and induction of preterm labor and spontaneous abortions.
authors.affiliation: Departments of Anesthesiology and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn. 37232-4125, USA.
authors.forename: B V
authors.initials: BV
authors.lastname: Rama Sastry
authors.forename: M E
authors.initials: ME
authors.lastname: Hemontolor
authors.forename: M
authors.initials: M
authors.lastname: Olenick
mesh_terms: D000328:Adult; D003367:Cotinine / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D010920:Placenta / Q000187:drug effects* / Q000502:physiology; D011247:Pregnancy; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D018722:Nicotinic Agonists; D009538:Nicotine; D010741:Phospholipases A; D054467:Phospholipases A2; D003367:Cotinine; D015232:Dinoprostone