Prostaglandin E-2 in human placenta: Its vascular effects and activation of prostaglandin E-2 formation by nicotine and cotinine

Tobacco smoking by pregnant women increases the frequency of spontaneous ab ortions and preterm births. Human labor is associated with enhanced intraut erine phospholipid metabolism and production of prostaglandin E-2 (PGE(2)) which induces labor, initiates uterine contractions and maintains the homeo stasis of placental blood flow. Therefore, we studied: (a) the influence of nicotine and cotinine on the effects of PGE(2) on placental vasculature in perfused human placental cotyledon, and (b) the activation of placental ph ospholipase A(2) (PLA(2)) by nicotine and cotinine using 1-palmitoyl-2-[1-C -14]arachidonyl-phosphatidylethanolamine (PE, 2.2 nmol) as substrate. These studies revealed that: (1) increasing concentrations of PGE(2) (10-150 ng/ ml) increased umbilical perfusion pressure by 170 +/- 10% (n = 6) of contro l (100%). Cotinine (2 mu g/ml) enhanced this effect at all concentrations o f PGE(2). Nicotine (2 mu g/ml) prevented the effect of PGE(2); (2) both cot inine (EC50 470-500 fmol/l) and nicotine (EC50 18-32 pmol/l) activated PLA( 2) in human placental tissues. These observations indicated that cotinine w as more potent than in nicotine activating PLA(2) and potentiating the vaso constrictive effects of PGE(2) on fetal placental circulation. Nicotine act ivates nicotinic receptors and releases placental acetylcholine, a vasodila tor 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 PGE(2) through the release of EDR F. Cotinine is inactive at nicotinic and muscarinic receptors. Therefore, a ccumulation of cotinine, the major metabolite of nicotine, in fetal circula tion may contribute to production of PGE(2) and induction of preterm labor and spontaneous abortions.