Mitochondrial potassium channel opener diazoxide preserves neuronal-vascular function after cerebral ischemia in newborn pigs

Background and Purpose-N-Methyl-D-aspartate (NMDA) elicits neuronally media ted cerebral arteriolar vasodilation that is reduced by ischemia/reperfusio n (I/R). This sequence has been preserved by pretreatment with the ATP-sens itive potassium (K-ATP) channel opener aprikalim, although the mechanism wa s unclear. In the heart, mitochondrial K-ATP channels (mitoK(ATP)) are invo lved in the ischemic preconditioning-like effect of K+ channel openers. We determined whether the selective mitoK(ATP) channel opener diazoxide preser ves the vascular dilation to NMDA after I/R. Methods-Pial arteriolar diameters were determined with the use of closed cr anial window/intravital microscopy in anesthetized piglets. Vascular respon ses to NMDA were assessed before and 1 hour after 10 minutes of global cere bral ischemia induced by raising intracranial pressure. Subgroups received 1 of the following pretreatments before I/R: vehicle; 1 to 10 mu mol/L diaz oxide; and coapplication of 100 mu mol/L 5-hydroxydecanoic acid (5-HD), a K -ATP antagonist with diazoxide. Results-NMDA-induced dose-dependent pial arteriolar dilation was not affect ed by diazoxide treatment only but was severely attenuated by I/R, In contr ast, diazoxide dose-dependently preserved the NMDA vascular response after I/R; at 10 mu mol/L, diazoxide arteriolar responses were unaltered by I/R. The effect of diazoxide was antagonized by coapplication of 5-HD with diazo xide. Percent preservation of 100 mu mol/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 mu mol/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 neuro nal function after I/R, shown by pial arteriolar responses to NMDA, in a do se-dependent manner. Thus, activation of mitoK(ATP) channels may play a rol e in mediating the protective effect of other K+ channel openers.