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.
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