RESUMEN
Maternal smoking during pregnancy causes reduction of fetal breathing movements, an effect attributed to nicotine in fetal blood. Nicotine is metabolized to cotinine which has a long plasma half-life and exhibits slow clearance across membrane barriers. It is also known to activate placental phospholipase-A2-like enzymes, resulting in formation of prostaglandins. Therefore, we studied transport of nicotine in isolated perfused cotyledon of normal human term placenta. The placental cotyledon was perfused with aerated (21% O2, 5% CO2) Krebs-Ringer bicarbonate buffer (pH 7.4, 37 degrees C) containing 2% albumin on both maternal (230 ml, 15 ml/min, 35 mm Hg) and fetal (93 ml, 1.75 ml/min, 70 mm Hg) sides in a closed recirculating system. Nicotine (2 mg) was added to the maternal perfusate; perfusate samples (1 ml) were collected from both sides at regular intervals and analyzed for nicotine and cotinine by high-pressure liquid chromatography. This study gave the following results: (1) In about 60-80 min, 18.6% of the nicotine added to the maternal perfusate was transferred to the fetal perfusate, and the maternal/fetal concentration ratio reached 1.0. These results show rapid placental transfer of nicotine, consistent with its high lipid solubility. (2) Less than 1% is metabolized to cotinine in placenta. The ratio of cotinine concentrations in maternal and fetal perfusates reached 1.0 in about 40 min. These studies were also verified using 14C-nicotine. (3) Maximal reduction in fetal breathing movements occurs at about 30 min, and recovery occurs at 90 min after tobacco smoking by the mother. These observations agree with the rate of placental transfer of nicotine. (4) When nicotine was added on the fetal side, part of it was metabolized to cotinine. However, the maximal concentration of cotinine was twice higher on fetal than on maternal side. These observations suggest that accumulation of cotinine on fetal side may activate prostaglandin formation and trigger spontaneous abortions in pregnant smokers.
Asunto(s)
Cotinina/metabolismo , Intercambio Materno-Fetal , Nicotina/metabolismo , Placenta/metabolismo , Adulto , Antipirina/análisis , Antipirina/metabolismo , Cotinina/análisis , Femenino , Humanos , Técnicas In Vitro , Nicotina/análisis , Perfusión/métodos , EmbarazoRESUMEN
There is periparturitional increase of prostaglandin E2 (PGE2) in the plasma and amniotic fluid of humans. PGE2 increases uterine contractions and also increases uterine blood flow to sustain the contractions. A question arises as to what role PGE2 plays in human placental circulation. It may regulate feto-placental blood flow and closure of placental resistance vessels at parturition. Therefore, we have investigated (a) the release of PGE2 into fetal and maternal circulations, and (b) the influence of PGE2 on the feto-placental pressure in the isolated perfused cotyledon of normal human term placenta. The placental cotyledon was perfused with aerated. (21% O2, 5% CO2) Krebs-Ringer bicarbonate buffer (pH 7.4, 37 degrees C) containing 2% albumin on both maternal (230 ml, 12 ml/min., 0.6" Hg) and fetal (93 ml, 1.75 ml/min., 1.75" Hg) sides in a closed recirculating system. In one group of cotyledons, perfusion samples (2 ml) were collected at regular intervals from both perfusates for 3 hrs. and PGE2 was determined in aliquots (0.5 ml) of samples by a specific radioimmunoassay. In a second set of cotyledons, exogenous PGE2 was administered into fetal perfusate, and pressure was monitored as a function of time. These experiments gave the following results: 1) During the initial 20 min., a constant level of PGE2 (2.3-4.4 pg/ml) was maintained in both perfusates. At 3 hrs., the concentrations increased to about 110 ng/ml on the fetal side and 30 ng/ml on the maternal side. The total amount of PGE2 accumulated in the fetal and maternal reservoirs reached to 10.16 and 7.03 ng, respectively. 2) PGE2 (10-150 ng/ml) increased the feto-placental perfusion pressure in a concentration dependent manner. At 150 ng/ml, the pressure increased to 125-240% of control pressure observed at the beginning of the experiment. These studies suggest that a) placental trophoblast has the capacity for the synthesis and release of PGE2 into fetal and maternal circulations; b) PGE2 exhibits differential effects in the placental and uterine blood vessels, vaso-constriction in placental vessels and vasodilation in uterine blood vessels, and (c) PGE2 exhibits dual effects on blood vessels possibly by activating two different subtypes of PG-receptors.
Asunto(s)
Dinoprostona/fisiología , Placenta/fisiología , Adulto , Dinoprost/metabolismo , Dinoprostona/metabolismo , Femenino , Humanos , Técnicas In Vitro , Trabajo de Parto/fisiología , Intercambio Materno-Fetal/genética , Perfusión , Placenta/irrigación sanguínea , Embarazo , Presión , Receptores de Prostaglandina/clasificación , Receptores de Prostaglandina/fisiología , Contracción Uterina/fisiología , Útero/irrigación sanguínea , Útero/fisiología , Vasoconstricción/fisiología , Vasodilatación/fisiologíaRESUMEN
Nicotine is oxidized to its major metabolite, cotinine, which has a long biological half-life (19-24 h). The plasma concentration of cotinine has been used as an index of tobacco smoke exposure. Cotinine possibly increases the turnover rate of platelet-activating factor (PAF) because it is a potent activator of PAF hydrolase, and it may play a significant role in tobacco-induced arterial thrombosis. Therefore, we studied the distribution and retention of nicotine as it was metabolized to cotinine in the rat. Nicotine (1 mg/kg, 5 microCi/kg) was administered into the femoral vein of male Sprague-Dawley rats under nembutal anesthesia. At different times (5-60 min) after nicotine administration, nicotine and its metabolite, cotinine, were determined by HPLC in plasma, liver, kidney, heart and brain. Within 5-10 min after administration, nicotine concentrations reached peak values in plasma (2,160 pmol/ml) and the organs analyzed. The plasma level of nicotine decreased by 50% within 20 min (half-time) after its intravenous administration. The half-time of nicotine in the brain was about 50 min. The half-times of nicotine for the other organs were about 20-25 min. The major metabolite, cotinine, accumulated in plasma, and by about 30 min the concentrations of nicotine and cotinine in plasma were about equal (890-1,000 pmol/ml). While cotinine accumulated in plasma, nicotine was eliminated by the kidney. While the nicotine concentrations decreased with time in all organs, cotinine concentrations remained constant. These observations indicate that nicotine is renally eliminated or metabolized to cotinine while cotinine exhibits a long retention time and accumulates in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)