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(Stroke. 2003;34:1015.)
© 2003 American Heart Association, Inc.

Original Contributions

Opening of Mitochondrial ATP-Sensitive Potassium Channels Is a Trigger of 3-Nitropropionic Acid–Induced Tolerance to Transient Focal Cerebral Ischemia in Rats

Takashi Horiguchi, MD; Bela Kis, PhD; Nishadi Rajapakse, BS; Katsuyoshi Shimizu, MD David W. Busija, PhD

From the Department of Physiology and Pharmacology (T.H., B.K., N.R., D.W.B.) and Molecular Medicine Graduate Program (N.R.), Wake Forest University School of Medicine, Winston-Salem, NC, and Department of Neurosurgery, Tachikawa Hospital, Tokyo, Japan (K.S.).

Correspondence to Takashi Horiguchi, MD, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1083. E-mail takaholy{at}aol.com

Background and Purpose— The role of mitochondrial ATP-sensitive potassium channels (mitoK_ATP) in ischemic tolerance has been well documented in heart, but little work has been done in brain. To investigate the involvement of mitoK_ATP activation in chemical preconditioning in brain, we examined the effect of 5-hydroxydecanoate (5-HD), a selective mitoK_ATP blocker, on neurotoxin 3-nitropropionic acid (3-NPA)–induced ischemic tolerance to transient focal cerebral ischemia in rats.

Methods— Male Wistar rats were administrated 3-NPA (20 mg/kg IP; n=16) or vehicle (saline; n=16) 3 days before temporary occlusion (120 minutes) of the middle cerebral artery; 5-HD (40 mg/kg IP; n=16) was injected 20 minutes before 3-NPA administration. Infarct volumes were measured 4 days after reperfusion. To directly investigate whether chemical preconditioning activates mitoK_ATP, we tested the effect of prior incubation with 1 mmol/L 5-HD on 300 µmol/L 3-NPA–induced alterations of mitochondrial membrane potential (_m) in cultured neurons and astrocytes using the fluorescent dye tetramethylrhodamine ethyl ester.

Results— Treatment with 3-NPA exhibited a 16% reduction (P<0.05) and 23% reduction in infarct volume (P<0.01) for total brain and cortex, respectively. Pretreatment with 5-HD completely abolished the neuroprotective effect of chemical preconditioning. In cultured cells, 3-NPA resulted in mitochondrial depolarization. This change of _m was completely blocked by 5-HD pretreatment.

Conclusions— These results strongly suggest that opening of mitoK_ATP plays a key role as the trigger in the development of 3-NPA–induced ischemic tolerance in brain.

Key Words: brain ischemia • middle cerebral artery occlusion • mitochondria • potassium channels • rats

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