Human placental norepinephrine transporter mRNA: expression and correlation with fetal condition at birth.

The purpose of this study was to determine the primary form of human placental norepinephrine transporter (hNET) mRNA expressed in the human placenta and to compare the level of expression in normal pregnancies and in pregnancies complicated by drug exposure or other forms of physiological derangement. We used the hNET cDNA to measure RNA extracted from placenta and examined placental RNA following complicated and uncomplicated pregnancies. To compare transporter expression and its relation to fetal condition at birth, umbilical arterial plasma catecholamine levels, umbilical arterial blood gases and placental transporter mRNA level were compared by linear regression analysis. Uncomplicated pregnancies had a higher level of placental norepinephrine transporter mRNA than complicated pregnancies. An inverse relationship between umbilical cord norepinephrine level and transporter expression was demonstrated. We conclude that placental transporter expression represents an important and newly described metabolic function of the placenta. Placental catecholamine clearance mediated via the placental NET may be important in the pathophysiology of disorders associated with placental dysfunction, impaired placental blood flow or intrauterine growth retardation. This may also explain the adverse effects of drugs, such as cocaine, which block catecholamine transport.

The contribution of transporter-dependent uptake to fetal catecholamine clearance.

These studies were designed to determine the contribution of cocaine-sensitive, transporter-dependent, reuptake mechanisms to the intrauterine norepinephrine clearance rate in chronically catheterized fetal sheep. Baseline norepinephrine clearance and appearance rates were 125 +/- 20 ml/kg/min and 85 +/- 11 ng/kg/min, respectively. Transporter-dependent clearance represented 40% of the intrauterine clearance rate. The effects of chronic cocaine administration on fetal catecholamine clearance and appearance rate were then determined in animals treated with daily infusion of saline or cocaine. The total intrauterine clearance rate and the transport-dependent component of intrauterine clearance decreased significantly following the week of drug or placebo treatment, p < 0.05. This was associated with a threefold increase in circulating catecholamine concentrations in both groups of animals, p < 0.05. These results demonstrate that intrauterine catecholamine clearance is highly dependent on transporter-dependent mechanisms. Chronic intrauterine stress, manifested by increased circulating norepinephrine, is associated with a significant decrease in norepinephrine clearance and may be important in the pathogenesis of the adverse effects of stress on the fetus and of drugs like cocaine, which block catecholamine reuptake.

Placental norepinephrine clearance: in vivo measurement and physiological role.

The intrauterine clearance rate of catecholamines is higher than in newborn animals or in adults. The separate contributions of the fetus and placenta to this clearance are not known. The placenta is a site of expression of the amine plasma membrane transporters that mediate this process. To determine the physiological role of this placental transporter in vivo, we studied fetal sheep at 123 days with common umbilical vein (UV), fetal arterial (AO), and venous catheters. Tritiated norepinephrine ([3H]NE) was infused to determine the kinetics of placental and fetal NE appearance and clearance rates. Umbilical flow was determined by [3H]NE infusion. Placental and total (fetal-placental) NE clearance rates were determined by measurement of [3H]NE from simultaneously drawn UV and AO samples. Total clearance was 99 +/- 8 ml.kg-1.min-1. Placental fractional [3H]NE extraction was 21% and accounted for 48% of total clearance. Fetal plasma NE production rate was 85 +/- 20 ng.kg-1.min-1. We conclude that placental catecholamine clearance is an important metabolic function of the placenta. This mechanism for clearance of the high fetal production rate of catecholamines is vital for fetal homeostasis. We speculate that derangements in placental catecholamine clearance may explain the exaggerated adverse effects on the fetus of drugs like cocaine, which block catecholamine transport.