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Drugs, such as cocaine, which may alter monoamine neurotransmitter responsiveness, could adversely affect the regulation of cerebral vasculature. Cocaine exhibits at least two mechanisms that may alter vascular responsiveness: synaptic uptake inhibition, which may augment response to stimulation, and Na+ channel inhibition, which may attenuate response. To help elicit the concentration-dependent effects of cocaine, the effects of cocaine on monoamine neurotransmitter responsiveness were studied in vitro on fetal sheep cerebral arteries (120 days gestation). The changes in diameter of segments of cannulated, pressurized fetal sheep cerebral artery were measured with a videomicroscaler system. Cumulative concentration-response curves (10(-10) to 10(-4)M) were generated for two monoamines, norepinephrine and serotonin, alone and in the presence of cocaine (10(-5) or 10(-4)M). Cocaine caused concentration-dependent alteration of response. At 10(-4)M, cocaine attenuated mean maximal norepinephrine-induced vasoconstriction 46.2% (P < 0.05). At 10(-5)M, cocaine increased sensitivity to norepinephrine (log EC50 decreased -6.63 +/- 0.09 to -7.11 +/- 0.03) and to serotonin (log EC50 decreased -7.24 +/- 0.04 to -7.81 +/- 0.09) (P < 0.05). The higher concentration of cocaine (10(-4)M) did not significantly decrease log EC50 norepinephrine. Cocaine (10(-4)M) also attenuated the response to single doses of norepinephrine (10(-6)M) and serotonin (10(-6)M) by 26.5% and 40.0%, respectively (P < or = 0.05). It is concluded that cocaine has concentration-dependent effects on vasoconstriction of the fetal sheep cerebral artery in vitro. This cocaine-induced alteration of cerebral vascular responsiveness to monoamines may be important in the regulation of fetal cerebral blood flow.

Prenatal cocaine exposure has been reported to cause neurovascular complications in the developing fetus. To determine the effect of cocaine on the fetal neurovasculature, we studied the in vitro response of fetal sheep cerebral arteries to cocaine and cocaine metabolites. The change in diameter of cannulated pressurized cerebral artery segments from fetal sheep was measured using a video microscaler system. Cumulative dose-response curves (10(-12)-10(-4) M) were generated for cocaine and the major cocaine metabolites in fetal sheep cerebral artery segments. Benzoylecgonine (> 10(-10) M) also caused concentration-dependent constriction, and cerebral artery segments were significantly more sensitive to benzoylecgonine than to cocaine and the other cocaine metabolites. Benzoylecgonine-induced vasoconstriction appeared to be mediated through alpha-adrenergic stimulation, predominantly through stimulation of alpha 1-adrenergic receptor subtypes. We conclude that cocaine and benzoylecgonine cause significant fetal cerebral artery vasoconstriction in vitro. Cocaine and benzoylecgonine-induced cerebral vasoconstriction may contribute to the perinatal neurovascular complications associated with prenatal cocaine exposure.

We studied hemodynamic responses to cocaine and two metabolites, cocaethylene (CE) and benzoylecgonine (BE), in five conscious ewes and fetuses, which were chronically instrumented to measure maternal and fetal aortic pressures, uterine artery blood flow (Qutr) and fetal common carotid artery blood flow (Qcar) to estimate cerebral blood flow. Conscious ewes of 121 to 128 days' (mean, 124 days) gestation received 1.0 mg/kg i.v. of cocaine (n = 12 doses), CE (n = 14) or BE (n = 12) and responses were compared to seven additional ewes and fetuses at 115 to 127 days' (mean, 122 days) gestation each given one 1.0 mg/kg i.v. of cocaine dose while anesthetized with halothane. In conscious ewes, cocaine, CE and BE all caused maternal and fetal hypertension. Qutr decreased 31% after cocaine, increased 37% after CE and was unaffected by BE. Cocaine induced fetal hypoxemia; fetal arterial blood gas tensions were unaffected by CE or BE. Fetal Qcar was reduced 51% at peak effect by cocaine (57 +/- 8 to 28 +/- 6 ml/min) and 46% by CE (65 +/- 7 to 33 +/- 6 ml/min), and was unaffected by BE because of variable subject response, although all three drugs increased calculated fetal cerebral vascular resistance. The cocaine-induced changes were attenuated or abolished in anesthetized sheep. Fetal/maternal peak serum concentrations were 100% for CE and only 2% for BE; amniotic fluid concentrations of CE were 10-fold higher than both fetal and maternal serum concentrations. Cocaine and cocaine metabolites have important effects on maternal and fetal hemodynamics and fetal cerebral blood flow which, for CE and BE, are not dependent on decreased uterine blood flow or fetal hypoxemia.