Prevention and reversal by cocaine esterase of cocaine-induced cardiovascular effects in rats.
The present study is the first to utilize bacterial cocaine esterase (CocE) to increase elimination of a lethal dose of cocaine and evaluate its cardioprotective effects. Rats received one of 5 treatments: CocE 1 min after saline; CocE 1 min after a lethal i.p. dose of cocaine; saline 1 min after a lethal i.p. dose of cocaine; CocE immediately after observing a cocaine-induced convulsion; and CocE 1 min after observing a cocaine-induced convulsion. Measures were taken of ECG, blood pressure, and cardiac troponin I (cTnI). The specificity of CocE against cocaine was determined by evaluating its actions against the cocaine analogue, WIN-35,065-2, which lacks an ester attack point for CocE. In addition, CocE's effects were compared with those of midazolam, a benzodiazepine often used to manage cocaine overdose. Whereas CocE alone had negligible cardiovascular effects, it blocked or reversed cocaine-induced QRS complex widening, increased QTc interval, ST elevation, bradycardia, and hypertension. When administered 1 min after cocaine, CocE inhibited myocardial damage; however, administered 1 min after a cocaine-induced convulsion (approximately 40s before cocaine-induced death), CocE did not block cTnI release, but did restore cardiac function. Midazolam blocked convulsions, but exhibited inadequate protection against cocaine-induced cardiotoxicity. The majority of rats given cocaine plus midazolam died. CocE did not prevent the lethal cardiovascular effects of WIN-35,065-2. In all likelihood, CocE rapidly and specifically reduced the body burden of cocaine and inhibited or reversed the cardiovascular consequences of high-dose cocaine. These results support CocE as a potential therapeutic avenue in cocaine overdose.
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Susan K
SK
Wood
Diwahar
D
Narasimhan
Ziva
Z
Cooper
Roger K
RK
Sunahara
James H
JH
Woods
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002265:Carboxylic Ester Hydrolases / Q000008:administration & dosage / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000209:etiology / Q000517:prevention & control*; D002408:Catheters, Indwelling; D003042:Cocaine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000150:complications / Q000188:drug therapy*; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000209:etiology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013686:Telemetry
D002316:Cardiotonic Agents; D002265:Carboxylic Ester Hydrolases; C019921:cocaine esterase; D003042:Cocaine