An engineered cocaine hydrolase blunts and reverses cardiovascular responses to cocaine in rats

There is increasing evidence that human plasma butyrylcholinesterase can lower the toxicity of cocaine overdose. Recently, 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 cardiovascular responses to cocaine. Anesthetized rats were instrumented 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 with CocE (3 mg/kg i.v.) reduced cocaine's pressor effect, whereas delayed treatment with CocE rapidly restored normal mean blood pressure. CocE had no hemodynamic effects in control animals not treated with cocaine. The finding that CocE can oppose pre-established physiologic actions of cocaine suggests that similar or improved hydrolases might help rescue patients from the life-threatening toxicity of drug overdose. Altamirano C and Lockridge O (1999) Association of tetramers of human butyrylcholinesterase is mediated by conserved aromatic residues of the carboxy terminus. Chem Biol Interact 119-120:53-60. Beckman KJ, Parker RB, Hariman RJ, Gallastegui JL, Javaid JI, and Bauman JL (1991) Hemodynamic and electrophysiological actions of cocaine: effects of sodium bicarbonate as an antidote in dogs. Circulation 83:1799-1807.