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(Stroke. 1999;30:2713.)
© 1999 American Heart Association, Inc.

Original Contributions

Mitochondrial Potassium Channel Opener Diazoxide Preserves Neuronal-Vascular Function After Cerebral Ischemia in Newborn Pigs

Ferenc Domoki, MD; James V. Perciaccante, MD; Roland Veltkamp, MD; Ferenc Bari, PhD David W. Busija, PhD

From the Department of Physiology and Pharmacology (F.D., R.V., F.B., D.W.B.), Department of Pediatrics (J.V.P.), and Stroke Research Center (R.V.), Wake Forest University School of Medicine, Winston-Salem, NC; and Department of Physiology, Albert Szent-Györgyi Medical University, Szeged, Hungary (F.D., F.B.).

Correspondence to David W. Busija, PhD, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1010. E-mail dbusija{at}wfubmc.edu

Background and Purpose—N-Methyl-D-aspartate (NMDA) elicits neuronally mediated cerebral arteriolar vasodilation that is reduced by ischemia/reperfusion (I/R). This sequence has been preserved by pretreatment with the ATP-sensitive potassium (K_ATP) channel opener aprikalim, although the mechanism was unclear. In the heart, mitochondrial K_ATP channels (mitoK_ATP) are involved in the ischemic preconditioning-like effect of K⁺ channel openers. We determined whether the selective mitoK_ATP channel opener diazoxide preserves the vascular dilation to NMDA after I/R.

Methods—Pial arteriolar diameters were determined with the use of closed cranial window/intravital microscopy in anesthetized piglets. Vascular responses to NMDA were assessed before and 1 hour after 10 minutes of global cerebral ischemia induced by raising intracranial pressure. Subgroups received 1 of the following pretreatments before I/R: vehicle; 1 to 10 µmol/L diazoxide; and coapplication of 100 µmol/L 5-hydroxydecanoic acid (5-HD), a K_ATP antagonist with diazoxide.

Results—NMDA-induced dose-dependent pial arteriolar dilation was not affected by diazoxide treatment only but was severely attenuated by I/R. In contrast, diazoxide dose-dependently preserved the NMDA vascular response after I/R; at 10 µmol/L, diazoxide arteriolar responses were unaltered by I/R. The effect of diazoxide was antagonized by coapplication of 5-HD with diazoxide. Percent preservation of 100 µmol/L NMDA–induced vasodilation after I/R was 53±19% (mean±SEM, n=8) in vehicle-treated controls versus 55±10%, 85±5%, and 99±15% in animals pretreated with 1, 5, and 10 µmol/L diazoxide (n=8, n=8, and n=12, respectively) and 60±15% in the group treated with 5-HD+diazoxide (n=5).

Conclusions—The mitoK_ATP channel opener diazoxide in vivo preserves neuronal function after I/R, shown by pial arteriolar responses to NMDA, in a dose-dependent manner. Thus, activation of mitoK_ATP channels may play a role in mediating the protective effect of other K⁺ channel openers.

Editorial Comment

Robert M. Bryan, Jr, PhD, Guest Editor

Department of Anesthesiology, Baylor College of Medicine, Houston, Texas

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