title: Ecgonine methyl ester, a major cocaine metabolite, causes cerebral vasodilation in neonatal sheep.
abstract: Maternal cocaine abuse has been associated with fetal and neonatal neurologic abnormalities, including hemorrhagic cerebral infarctions, but the mechanisms for cocaine's cerebral effects are unknown. We previously showed that acute cocaine injection causes cerebral vasodilation in cats and immature sheep; others have shown that cocaine causes cerebral vasoconstriction in piglets and in pressurized neonatal sheep arteries. Although methodologic and species differences may explain these conflicting results, we tested another possibility; that is, that ecgonine methyl ester (EME), a major cocaine metabolite in sheep, causes cerebral vasodilation and may account, in part, for cocaine's vascular effects. We studied the cerebral effects of a single i.v. injection of EME (2.5 mg/kg) in eight chronically catheterized, unanesthetized neonatal sheep (4 +/- 2 d old). We measured cerebral hemisphere blood flow (CBF) using radiolabeled microspheres, mean arterial pressure, heart rate, and arteriovenous oxygen content, and we calculated cerebral oxygen consumption (CMRo2) and cerebrovascular resistance at baseline and 0.5, 2, 5, and 60 min after EME injection. EME injection had no systemic effects, including no changes in mean arterial pressure, heart rate, or arterial blood gases. Within 0.5 min of injection, EME caused a 21% decrease in cerebrovascular resistance, which remained decreased for 60 min. CBF increased by 20% at 0.5, 2, and 5 min. Blood flow to brain regions other than the cerebral hemispheres paralleled changes in CBF, with cerebellar flow remaining increased at 60 min. There was no change in CMRo2. There was a small, but physiologically insignificant, decrease in arterial oxygen content. We conclude that EME causes cerebral vasodilation in neonatal sheep and may account, in part, for cocaine's cerebral vascular effects.
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-3200, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Pane
authors.forename: R J
authors.initials: RJ
authors.lastname: Traystman
authors.forename: C A
authors.initials: CA
authors.lastname: Gleason
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000098:blood supply*; D002415:Cats; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D003042:Cocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D009294:Narcotics / Q000494:pharmacology*; D009928:Organ Specificity; D010100:Oxygen / Q000097:blood; D010101:Oxygen Consumption / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D012756:Sheep; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation
chemical_list: D009294:Narcotics; D003042:Cocaine; D010100:Oxygen; C034524:ecgonine methyl ester