Alpha 1-acid glycoprotein reverses cocaine-induced sodium channel blockade in cardiac myocytes.
Alpha 1-acid glycoprotein (AAG) is an acute phase protein capable of binding basic drugs. This action explains its reversal of sodium channel blockade by drugs such as amitriptyline and quinidine. We report here the reversal of cocaine-induced sodium channel blockade by AAG. The sodium channel blocking property of cocaine is a major mechanism behind cocaine-induced sudden cardiac death, since sodium channels play a key role in the initiation and regulation of the heart beat. Voltage-gated sodium current (I(Na)) was recorded using whole-cell patch-clamp techniques. Guinea-pig cardiac ventricular myocytes were isolated and continuously perfused at room temperature with physiological solutions. At concentrations ranging from 5 to 320 microM cocaine showed a dose-dependent and reversible blockade of I(Na) with an IC50 of 45.9 microM. The addition of equimolar amounts of AAG to cocaine produced almost complete reversal of cocaine's effects, suggesting a single binding site for cocaine on the AAG molecule. With changes of peak I(Na) normalized against control as 1, cocaine at 20 and 40 microM reduced I(Na) to 0.62+/-0.042 (n = 6) and 0.57+/-0.052 (n = 9), respectively, and the addition of an equimolar concentration of AAG reversed I(Na) to 0.86+/-0.022 and 0.91+/-0.060, respectively.


CONCLUSIONS
AAG reverses cocaine-induced sodium channel blockade in a dose-dependent manner, indicating a therapeutic potential to reverse acute cocaine cardiac toxicity.
Ma
Yu-Ling
YL
Department of Cardiac Electrophysiology, National Heart and Lung Institute, Imperial College London, 10th Floor QEQM Wing, St. Mary's Hospital, London W21NY, UK. y.ma@imperial.ac.uk
Peters
Nicholas S
NS
Henry
John A
JA
D000818:Animals; D003042:Cocaine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004594:Electrophysiology; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology; D013287:Illicit Drugs / Q000633:toxicity*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009961:Orosomucoid / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism
D004338:Drug Combinations; D013287:Illicit Drugs; D009961:Orosomucoid; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D003042:Cocaine