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

Abstract

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.