Cocaine and benzoylecgonine constrict cerebral arteries by different mechanisms.
This study was designed to determine possible mechanisms underlying the vasoconstrictor activity of cocaine and its principal metabolite, benzoylecgonine (BE) in cat isolated cerebral arteries. The arteries constricted significantly in response to single doses of cocaine, BE and norepinephrine (NE; (P < 0.05). After 6-OHDA treatment to remove adrenergic nerve endings, NE-induced constrictions were essentially unchanged from those before treatment. Denervated arteries exposed to cocaine dilated significantly (P < 0.05) but those exposed to BE constricted as much as before denervation. Following exposure to prazosin and yohimbine, arterial constrictions to NE and cocaine were significantly reduced from control (P < 0.05) but the BE-induced constriction was unchanged. Ryanodine eliminated the cocaine-induced contraction (P < 0.05) whereas verapamil eliminated the BE response (P < 0.05). These data suggest that while cocaine's vasoconstrictor action may be significantly mediated through adrenergic transmission, BE may act through a mechanism involving calcium (Ca2+) channels. Cocaine levels peak and decline in the body more rapidly than BE levels which can remain detectable for days. This study suggests there may also be different pharmacological mechanisms as well as temporal differences underlying the vasoreactivity of these two substances. Our findings may have implications for pharmacological management of cocaine-induced toxic vascular events.
Madden
J A
JA
Research Service, Zablocki Veterans Affairs Medical Center, Milwaukee, WI.
Konkol
R J
RJ
Keller
P A
PA
Alvarez
T A
TA
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002415:Cats; D002536:Cerebral Arteries / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D003042:Cocaine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D016627:Oxidopamine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D012433:Ryanodine / Q000494:pharmacology; D013563:Sympathectomy, Chemical; D014661:Vasoconstriction / Q000187:drug effects*; D014666:Vasomotor System / Q000502:physiology; D014700:Verapamil / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology
D012433:Ryanodine; D015016:Yohimbine; C005618:benzoylecgonine; D016627:Oxidopamine; D014700:Verapamil; D003042:Cocaine; D002118:Calcium; D009638:Norepinephrine; D011224:Prazosin