An Engineered Cocaine Hydrolase Blunts and Reverses Cardiovascular Responses to Cocaine in Rats

There is increasing evidence that human plasma butyrylcho-linesterase can lower the toxicity of cocaine overdose. Re-cently, with structure-based protein engineering, we converted this enzyme into a more efficient cocaine hydrolase (CocE). When tested in rats, CocE shortened cocaine’s plasma half-life and decreased drug accumulation in heart and brain. Here, we have investigated the potential of CocE to antagonize cardio-vascular responses to cocaine. Anesthetized rats were instru-mented for continuous recording of blood pressure from the femoral artery. Cocaine (7 mg/kg i.v.) caused blood pressure to rise within 30 s by 25 to 37 mm Hg, but pressure returned to baseline within 60 s. These transient pressor responses were prolonged up to 5 min when vagal reflexes were blocked with atropine (1 mg/kg). Under such conditions, pretreatment wit