DIRECT EFFECTS OF COCAINE ON THE PREGNANT HUMAN UTERUS

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Cocaine use in pregnancy is a serious health hazard associated with a premature labor rate of approximately 25%. Unfortunately, little is known about how cocaine might augment uterine contractility and thus cause premature labor. The objectives of this investigation are to determine if cocaine has direct effects on the pregnant human uterus which increase contractility, and to identify the cellular mechanisms of cocaine's effects. The study will have two areas of concentration: First, to determine if cocaine acutely augments the contractile response to various agonists (catecholamines, prostaglandins and oxytocin), uterine strips from pregnant women will be evaluated in vitro using a muscle bath contraction apparatus. Using known tocolytic agents and other probes (alpha- and beta-adrenoceptor agonists and antagonists, prostaglandin inhibitors, calcium-channel blockers, magnesium sulfate), the specific contractile system(s) affected by cocaine, and the most effective way to block these effects will be identified. Chronic cocaine effects will be evaluated by examining uterine strips from pregnant humans who have taken cocaine during their pregnancy. The second area of concentration will be evaluation of the cellular mechanisms of cocaine's effects using slices, minces and membrane preparations of endometrium and myometrium. Cocaine's ability to alter uptake and deactivation will be evaluated by measuring intracellular levels of catecholamines and metabolites after exposure of cells to radiolabeled catecholamines. Cocaine's effect on alpha-adrenoceptors interactions will be evaluated by receptor binding studies, as well as agonist-induced production of prostaglandins and inositol trisphosphate. The acute and chronic effects of cocaine on beta-adrenoceptor function and concentration will be evaluated by receptor binding studies and cyclic AMP assay. Thus, this study will investigate the direct effects of cocaine that increase contractility of the pregnant human uterus and the mechanisms of these effects. This information will help clarify the relationship between cocaine use and premature labor, and provide a rational approach to the treatment of cocaine-associated premature labor.