Diazoxide preconditioning attenuates global cerebral ischemia-induced blood-brain barrier permeability.
Brain edema formation due to blood-brain barrier (BBB) disruption is a major consequence of cerebral ischemia. Previously, we demonstrated that targeting mitochondrial ATP-sensitive potassium channels (mitoK(ATP)) protects neuronal tissues in vivo and in vitro, however, the effects of mitoK(ATP) openers on cerebral endothelial cells and on BBB functions have never been examined. We investigated the effects of mitoK(ATP) channel opener diazoxide on BBB functions during ischemia/reperfusion injury (I/R). Rats were treated with 6, 20 or 40 mg/kg diazoxide ip for 3 days then exposed to global cerebral ischemia for 30 min. BBB permeability was assessed by administering Evan's-blue (EB) and Na-fluorescein (NaF) at the beginning of the 30 min reperfusion. I/R increased BBB permeability for the large molecular weight EB (ng/mg) in the cortex (control: 146 +/- 12, n = 7; I/R: 1049 +/- 152, n = 11) which was significantly attenuated in diazoxide-treated rats (575 +/- 99, n = 9; 582 +/- 104, n = 8; 20 and 40 mg/kg doses). Diazoxide pretreatment also significantly inhibited the extravasation of the low molecular weight NaF. Edema formation in the cortex was also decreased after diazoxide pretreatment. In cultured cerebral endothelial cells, diazoxide depolarized the mitochondrial membrane, suggesting a direct diazoxide effect on the endothelial mitochondria. Our results demonstrate that preconditioning of cerebral endothelium with diazoxide protects the BBB against ischemic stress.
Lenzsér
Gábor
G
Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, NC 27157-1010, USA. glenzser@wfubmc.edu
Kis
Béla
B
Bari
Ferenc
F
Busija
David W
DW
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000098:blood supply* / Q000187:drug effects; D001929:Brain Edema / Q000517:prevention & control*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D002199:Capillary Permeability / Q000187:drug effects; D003981:Diazoxide / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D015221:Potassium Channels / Q000819:agonists; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control
D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D003981:Diazoxide