Cocaine and benzoylecgonine constrict cerebral arteries by different mechanisms

Madden, Jane A.; Konkol, Richard J.; Keller, Peter M.; Alvarez, Tomas

doi:10.1016/0024-3205(94)00501-i

Cited by 55 publications

(28 citation statements)

References 22 publications

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“…6-Hydroxydopamine destruction of adrenergic nerve endings reversed cocaine constriction to dilatation in isolated feline middle cerebral artery (Madden et al 1995). Antagonism of both α 1 -and α 2 -adrenergic receptors with prazosin and yohimbine, respectively, also partially reversed the cocaine constriction (Madden et al 1995). In contrast, cocaine constriction of isolated canine, porcine, and ovine basilar artery and canine middle cerebral artery were unaltered by the α 1 -and α 2 -adrenergic receptor antagonist, phentolamine (He et al 1994).…”

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confidence: 90%

“…As in peripheral vessels, there is some evidence in cerebral vessels that cocaine elicits constriction via inhibition of norepinephrine uptake into adrenergic nerve terminals. 6-Hydroxydopamine destruction of adrenergic nerve endings reversed cocaine constriction to dilatation in isolated feline middle cerebral artery (Madden et al 1995). Antagonism of both α 1 -and α 2 -adrenergic receptors with prazosin and yohimbine, respectively, also partially reversed the cocaine constriction (Madden et al 1995).…”

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confidence: 91%

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Acute Cocaine Induces Endothelin-1–Dependent Constriction of Rabbit Basilar Artery

2007

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It has been postulated that ischemic stroke due to acute cocaine usage involves constriction of the cerebral vasculature. However, the mechanism underlying the constriction remains unclear. This study tested whether cocaine constriction was mediated via endothelin-1. Cocaine suffusion induced maintained constriction in the rabbit basilar artery in situ. The constriction was relaxed by PD145065, an endothelin A and B receptor antagonist. These results support the hypothesis that constriction of the cerebral vasculature due to acute cocaine exposure is via endothelin-1 release. Endothelin receptor antagonists may be of therapeutic benefit in cerebrovascular pathophysiologies involving cocaine constriction.

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confidence: 90%

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confidence: 91%

Acute Cocaine Induces Endothelin-1–Dependent Constriction of Rabbit Basilar Artery

2007

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“…The most abundant metabolite (40 -50%), benzoylecgonine, is produced by hydrolysis of the methyl ester of cocaine by human liver carboxylesterase-1 (Dean et al, 1991). Benzoylecgonine is inactive at monoamine transporters; however, it has some vasoconstrictive effects possibly mediated through interactions with Ca 2ϩ channels (Madden et al, 1995). Benzoylecgonine (t 1/2 ϭ 7 h) is the urinary metabolite measured in drug screens and may be the cause of latent chest pain associated with cocaine use.…”

Section: Introductionmentioning

confidence: 99%

The Ability of Bacterial Cocaine Esterase to Hydrolyze Cocaine Metabolites and Their Simultaneous Quantification Using High-Performance Liquid Chromatography-Tandem Mass Spectrometry

Brim¹,

Noon²,

Collins³

et al. 2011

Mol Pharmacol

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Cocaine toxicity is a widespread problem in the United States, responsible for more than 500,000 emergency department visits a year. There is currently no U.S. Food and Drug Administration-approved pharmacotherapy to directly treat cocaine toxicity. To this end, we have developed a mutant bacterial cocaine esterase (DM-CocE), which has been previously shown to rapidly hydrolyze cocaine into inert metabolites, preventing and reversing toxicity with limited immunogenic potential. Herein we describe the ability of DM-CocE to hydrolyze the active cocaine metabolites norcocaine and cocaethylene and its inability to hydrolyze benzoylecgonine. DM-CocE hydrolyzes norcocaine and cocaethylene with 58 and 45% of its catalytic efficiency for cocaine in vitro as measured by a spectrophotometric assay. We have developed a mass spectrometry method to simultaneously detect cocaine, benzoylecgonine, norcocaine, and ecgonine methyl ester to quantify the effect of DM-CocE on normal cocaine metabolism in vivo. DM-CocE administered to rats 10 min after a convulsant dose of cocaine alters the normal metabolism of cocaine, rapidly decreasing circulating levels of cocaine and norcocaine while increasing ecgonine methyl ester formation. Benzoylecgonine was not hydrolyzed in vivo, but circulating concentrations were reduced, suggesting that DM-CocE may bind and sequester this metabolite. These findings suggest that DM-CocE may reduce cocaine toxicity by eliminating active and toxic metabolites along with the parent cocaine molecule.

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“…Cocaine and its metabolites have been shown to be potent cerebral vasoconstrictors in animal models [26]. In almost 80% of long term cocaine users, a focal perfusion defect develops, which is a subtle form of cerebrovascular dysfunction, and may be secondary to cocaine-induced cerebral vasoconstriction [42,48].…”

Section: Discussionmentioning

confidence: 99%

Stroke in the young: relationship of active cocaine use with stroke mechanism and outcome

et al.

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Cocaine and benzoylecgonine constrict cerebral arteries by different mechanisms

Cited by 55 publications

References 22 publications

Acute Cocaine Induces Endothelin-1–Dependent Constriction of Rabbit Basilar Artery

Acute Cocaine Induces Endothelin-1–Dependent Constriction of Rabbit Basilar Artery

The Ability of Bacterial Cocaine Esterase to Hydrolyze Cocaine Metabolites and Their Simultaneous Quantification Using High-Performance Liquid Chromatography-Tandem Mass Spectrometry

Stroke in the young: relationship of active cocaine use with stroke mechanism and outcome

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