Diazoxide preserves hypercapnia-induced arteriolar vasodilation after global cerebral ischemia in piglets.
Diazoxide (Diaz), an activator of mitochondrial ATP-sensitive K+ (mitoKATP) channels, is neuroprotective, but the mechanism of action is unclear. We tested whether Diaz preserves endothelium-dependent (hypercapnia) or -independent [iloprost (Ilo)] cerebrovascular dilator responses after ischemia-reperfusion (I/R) in newborn pigs and whether the effect of Diaz is sensitive to 5-hydroxydecanoate (5-HD), an inhibitor of mitoKATP channels. Anesthetized, ventilated piglets (n = 48) were equipped with closed cranial windows. Changes in diameter of pial arterioles were determined with intravital microscopy in response to graded hypercapnia (5-10% CO2 - 21% O2-balance N2, n = 25) or Ilo (0.1-1 microg/ml, n = 18) before and 1 h after 10 min of global I/R. Experimental groups were pretreated with vehicle, NS-398 (a selective cyclooxygenase-2 inhibitor, 1 mg/kg), Diaz (3 mg/kg), or 5-HD (20 mg/kg) + Diaz. Potential direct effects of Diaz and 5-HD on hypercapnic vasodilation were also tested in the absence of I/R (n = 5). To confirm the direct effect of Diaz on mitochondria, mitochondrial membrane potential in cultured piglet cerebrovascular endothelial cells was monitored using Mito Tracker Red. Hypercapnia resulted in dose-dependent pial arteriolar vasodilation, which was attenuated by approximately 70% after I/R in vehicle- and NS-398-treated animals. Diaz and 5-HD did not affect the CO2 response. Diaz significantly preserved the postischemic vasodilation response to hypercapnia, but not to Ilo. Diaz depolarized mitochondria in cultured piglet cerebrovascular endothelial cells, and 5-HD completely abolished the protective effect of Diaz, both findings indicate a role for mitoKATP channels. In summary, preservation of arteriolar dilator responsiveness by Diaz may contribute to neuroprotection.
Domoki
Ferenc
F
Dept. of Physiology, Faculty of Medicine, Univ. of Szeged, Szeged, Dóm tér 10, H-6720 Hungary. domoki@phys.szote.u-szeged.hu
Kis
Béla
B
Nagy
Krisztina
K
Farkas
Eszter
E
Busija
David W
DW
Bari
Ferenc
F
D000818:Animals; D000831:Animals, Newborn; D001160:Arterioles / Q000187:drug effects / Q000503:physiopathology; D001794:Blood Pressure / Q000187:drug effects; D002545:Brain Ischemia / Q000503:physiopathology*; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003652:Decanoic Acids / Q000494:pharmacology; D003981:Diazoxide / Q000494:pharmacology*; D005260:Female; D006880:Hydroxy Acids / Q000494:pharmacology; D006935:Hypercapnia / Q000503:physiopathology*; D008297:Male; D009578:Nitrobenzenes / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D013552:Swine; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D003652:Decanoic Acids; D006880:Hydroxy Acids; D009578:Nitrobenzenes; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013449:Sulfonamides; D014665:Vasodilator Agents; C117780:mitochondrial K(ATP) channel; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C052853:5-hydroxydecanoic acid; D003981:Diazoxide