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Impaired Diazoxide Induced Myocardial Ischemia Preconditioning in Insulin Resistant Rats Relates to Mitochondrial Dysfunction Involving Reactive Oxygen Species
Author(s) -
Katakam Prasad VG,
Jordan James E,
Tulbert Christina D,
Snipes James A,
Miller Allison W,
Busija David W
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a742
Subject(s) - diazoxide , reactive oxygen species , ischemia , mitochondrion , ischemic preconditioning , medicine , insulin , insulin resistance , endocrinology , pharmacology , chemistry , biochemistry
Diabetes has been associated with disproportionately greater morbidity and mortality following myocardial infarction. Previously, we showed that insulin resistance enhances the extent of damage following myocardial ischemia‐reperfusion (MI/R) and abolishes ischemic preconditioning (IPC). We investigated diazoxide induced IPC (one cycle of 5 min of ischemia and 5 min reperfusion) in the hearts of Zucker obese (ZO) and control lean rats (ZL). Methods Male rats were randomized to ZL‐IPC, ZL‐IPC+5‐hydroxydecanoate (5HD), ZL‐diazoxide, ZL‐diazoxide+5HD, ZO‐IPC, ZO‐IPC+5HD, ZO‐diazoxide and ZO‐diazoxide+5HD. Rats were subjected to 30 min of in vivo myocardial ischemia and 4 hr reperfusion at which time infarct size was quantitated. Production of reactive oxygen species (ROS) was measured in the isolated heart mitochondria by measuring hydroethidine fluorescence. Results ZO developed larger infarct sizes and failed to be protected by IPC compared to ZL. Diazoxide failed to protect the hearts in ZO compared to ZL. Mitochondrial K ATP blocker, 5HD, diminished the IPC and diazoxide induced protection in ZL while it had no effect in ZO. Isolated mitochondria in ZO generated greater amounts of ROS at baseline but failed to enhance ROS production in response to diazoxide compared to mitochondria from ZL. Conclusions Diazoxide failed to protect the hearts from ZO rats compared to ZL rats. This may be due to mitochondrial dysfunction related to ROS production in response to diazoxide and other stimuli.