The long term objectives of this application are to investigate the biologic response(s) produced by chemicals and drugs in the fetus and pregnant animal.
The specific aims of this application are to establish the magnitude which selected serotonergic drugs (2,5-dimethoxy-4-methyl-amphetamine (DOM), d-lysergic acid diethylamide (LSD) and cocaine constrict the umbilical and uterine vasculature. Each of these drugs has been shown to directly constrict isolated umbilical and uterine blood vessels while cocaine has also been shown to enhance the responses to serotonin. There is growing concern in the medical community that the recreational abuse of these drugs in reproductive aged women will have an adverse effect on the pregnancy and/or the fetus. Information is needed to understand the effect of these drugs on the maternal and fetal cardiovascular systems. In the chronically instrumented fetus, fetal heart rate and blood pressure, uterine blood flow and umbilical artery blood flow will be monitored. Fetal p02, pCO2, and pH monitoring will permit assessment of stress-like conditions produced as a result of the vasoconstriction. Depending on the intensity and duration of such an insult, the fetus may be harmed. The determination of drug concentrations and fetal plasma will permit pharmacokinetic modeling and importantly, correlation of concentration with pharmacologic effect. Specific serotonergic antagonists will be used in vivo and on isolated blood vessels to permit an in-depth analysis of the receptors mechanisms involved in the vasoconstriction. Both group and paired """"""""t"""""""" statistical analysis will be used in the analysis of dose-response and antagonism studies. The significance of the proposed research is that it will document under in vivo conditions the magnitude which these drugs of abuse can alter fetal hemodynamics and thereby explain their harmful effects on the fetus as well as demonstrate the usefulness of antagonists in blocking their hemodynamic effect(s).
