Targeted disruption of K(ATP) channels aggravates cardiac toxicity in cocaine abuse

Santiago Reyes; Garvan C Kane; Leonid V Zingman; Satsuki Yamada; Andre Terzic

doi:10.1111/j.1752-8062.2009.00145.x

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Targeted disruption of K(ATP) channels aggravates cardiac toxicity in cocaine abuse

Journal article

Open access

Targeted disruption of K(ATP) channels aggravates cardiac toxicity in cocaine abuse

Santiago Reyes, Garvan C Kane, Leonid V Zingman, Satsuki Yamada and Andre Terzic

Clinical and translational science, Vol.2(5), pp.361-365

10/2009

DOI: 10.1111/j.1752-8062.2009.00145.x

PMCID: PMC3747562

PMID: 20443920

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https://doi.org/10.1111/j.1752-8062.2009.00145.xView

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Abstract

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.

Humans

Mice, Inbred C57BL

Potassium Channels, Inwardly Rectifying - chemistry

Mice, Knockout

Potassium - chemistry

Animals

Cocaine-Related Disorders - metabolism

Models, Biological

Heart - drug effects

Myocytes, Cardiac - metabolism

Mice

Potassium Channels, Inwardly Rectifying - metabolism

Physical Conditioning, Animal

Disease Models, Animal

Hypertrophy

Details

Title: Subtitle: Targeted disruption of K(ATP) channels aggravates cardiac toxicity in cocaine abuse
Creators: Santiago Reyes - Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
Garvan C Kane
Leonid V Zingman
Satsuki Yamada
Andre Terzic
Resource Type: Journal article
Publication Details: Clinical and translational science, Vol.2(5), pp.361-365
DOI: 10.1111/j.1752-8062.2009.00145.x
PMID: 20443920
PMCID: PMC3747562
NLM abbreviation: Clin Transl Sci
eISSN: 1752-8062
Grant note: HL064822 / NHLBI NIH HHS R01 HL064822 / NHLBI NIH HHS
Language: English
Date published: 10/2009
Academic Unit: Internal Medicine
Record Identifier: 9984094497802771

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