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 µg/ml) enhanced this effect at all concentrations of PGE₂. Nicotine (2 µg/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.

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