Pharmacological preconditioning ameliorates neurological injury in a model of spinal cord ischemia.
BACKGROUND
Pharmacological openers of mitochondrial ATP-sensitive potassium (mitoKATP) channels have been shown to mimic ischemic preconditioning (IPC) in both the brain and myocardium. We hypothesized that similar endogenous mechanisms exist in the spinal cord and that diazoxide, a potent mitoKATP opener, could reduce neurologic injury after aortic cross-clamping in a model of spinal cord ischemia.


METHODS
The infra-renal aorta was cross-clamped in 45 male New Zealand white rabbits for 20 minutes. Control animals received no pretreatment. Diazoxide-treated animals were dosed (5 mg/kg) 15 minutes before cross-clamp. A third group underwent 5 minutes of IPC 30 minutes before cross-clamp. Two groups received KATP antagonists, 5-hydroxydecanoic acid (5-HD, 20 mg/kg) or glibenclamide (1.0 mg/kg), before diazoxide administration. Systemic hypotension was induced in a final group with excess isoflurane. Tarlov Scoring was used to assess neurologic function at 24 and 48 hours, after which, the spinal cords were procured for histopathological analysis.


RESULTS
Tarlov scoring demonstrated marked improvement in the Diazoxide group compared with control at 24 hours (p < 0.02) and 48 hours (p < 0.009). Moreover, no further neurologic injury occurred in this group at 7 days. IPC-treated animals showed neurologic improvement but were not significantly different from controls. Further, administration of glibenclamide was effective in antagonizing diazoxide's protective effect.


CONCLUSIONS
Administration of diazoxide resulted in significant improvement in neurologic outcome in this model. This protective effect improved outcome at both early and late time points. Further, the antagonistic effect of glibenclamide implicates diazoxide's ATP-dependent potassium channel agonism as the mechanism of protection. Overall, this study suggests that diazoxide may be useful in the prevention of neurologic injury after thoracic aneurysm surgery.
Caparrelli
David J
DJ
Division of Cardiac Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA.
Cattaneo
Stephen M
SM
Bethea
Brian T
BT
Shake
Jay G
JG
Eberhart
Charles
C
Blue
Mary E
ME
Marbán
Eduardo
E
Johnston
Michael V
MV
Baumgartner
William A
WA
Gott
Vincent L
VL
D000818:Animals; D003981:Diazoxide / Q000494:pharmacology*; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology; D009336:Necrosis; D009460:Neurologic Examination / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D015221:Potassium Channels; D011817:Rabbits; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D020760:Spinal Cord Ischemia / Q000473:pathology / Q000503:physiopathology*
D008565:Membrane Proteins; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D003981:Diazoxide