Open AccessTargeted Disruption of K ATP Channels Aggravates Cardiac Toxicity in Cocaine Abuse
Author(s) -
Reyes Santiago,
Kane Garvan C.,
Zingman Leonid V.,
Yamada Satsuki,
Terzic Andre
Publication year - 2009
Publication title -
clinical and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.303
H-Index - 44
eISSN - 1752-8062
pISSN - 1752-8054
DOI - 10.1111/j.1752-8062.2009.00145.x
Subject(s) - cardiotoxicity , medicine , toxicity , cardiac toxicity , cocaine abuse , pharmacology , cardiomyopathy , heart failure , bioinformatics , psychiatry , biology
Cocaine is the most frequently used illicit drug among individuals seeking emergency‐room care, with fatal outcome most often attributable to the cardiovascular manifestations of drug abuse. While the symptomatic presentations of cocaine toxicity are increasingly understood, the molecular determinants that define outcome remain largely unknown. Here, we report that the susceptibility to cocaine‐induced cardiotoxicity is genetically regulated. Targeted deletion of the KCNJ11 ‐encoded Kir6.2 pore‐forming subunit of sarcolemmal K ATP channels resulted in amplified vulnerability to the toxic effects of chronic cocaine abuse. Under the hyperadrenergic stress, imposed by daily 3‐week‐long intraperitoneal administration of 30 mg/kg cocaine in Kir6.2‐knockout mice, failure to maintain cardiac homeostasis translated into decreased exercise tolerance revealed by poor treadmill stress performance, and dilated hypokinetic left hearts with aggravated cellular hypertrophy and pathognomonic characteristics of chronic cocaine‐induced cardiac toxicity. This study therefore reveals a previously unrecognized role of Kir6.2‐encoded K ATP channels in determining cardiovascular outcome in chronic cocaine abuse, identifying a novel molecular determinant of cocaine cardiotoxicity.