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

Abstract

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.

Cocaine Constriction of Rat Basilar Artery in situ: Roles of Nitric Oxide and Endothelin-1

“…In this regard, we demonstrated that ET receptor antagonist inhibited cocaine constriction in rabbit basilar artery in situ [9]. Consistent with the dependency of cocaine constriction on ET-1 release [9] are the findings of increased ET-1 release from cultured endothelial cells following 100 µmol/l cocaine for 3 h [10].…”

“…While species differences may underlie this difference, it should also be considered that the lower contractile efficacy of cocaine in the rabbit basilar artery [9] as compared to the basilar artery in the rat (present results) may play a role. In any case, the present findings point to the varied contractile mechanisms utilized by cocaine to elicit constriction in cerebral and peripheral vessels.…”

“…The general lack of ET-1 involvement in cocaine constriction of the rat basilar artery, based on the weak and variable inhibition of the constriction by an ET A/B receptor antagonist, was unexpected since we previously demonstrated that cocaine constriction of the rabbit basilar artery in situ was ET-1-mediated [9]. While species differences may underlie this difference, it should also be considered that the lower contractile efficacy of cocaine in the rabbit basilar artery [9] as compared to the basilar artery in the rat (present results) may play a role.…”

“…In this regard, we demonstrated that ET receptor antagonist inhibited cocaine constriction in rabbit basilar artery in situ [9]. Consistent with the dependency of cocaine constriction on ET-1 release [9] are the findings of increased ET-1 release from cultured endothelial cells following 100 µmol/l cocaine for 3 h [10]. Others also reported that cocaine increased ET-1 release from cultured endothelial cells, although the shortest periods of cocaine exposure investigated were 6 h (1 µmol/l cocaine) [8] and 24 h (0.1 µmol/l cocaine) [11].…”

“…Thus, the initial purpose of this study was to investigate (1) in a cerebral vessel whether cocaine constriction involved lowered NO and (2) whether constriction to a cerebral vessel, other than the rabbit basilar artery [9], was also ET-1-mediated. This investigation, therefore, utilized the rat basilar artery and was performed in an in situ cranial window preparation.…”