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This Article Full Text Full Text (PDF) All Versions of this Article: 289/1/H368    most recent 00887.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (7) Citing Articles via Google Scholar Google Scholar Articles by Domoki, F. Articles by Bari, F. Search for Related Content PubMed PubMed Citation Articles by Domoki, F. Articles by Bari, F.

Diazoxide preserves hypercapnia-induced arteriolar vasodilation after global cerebral ischemia in piglets

Departments of ¹Physiology and ³Anatomy, Faculty of Medicine, University of Szeged, Szeged, Hungary; and ²Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina

Submitted 27 August 2004 ; accepted in final form 13 February 2005

Diazoxide (Diaz), an activator of mitochondrial ATP-sensitive K⁺ (mitoK_ATP) 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 mitoK_ATP 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 µg/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 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 mitoK_ATP channels. In summary, preservation of arteriolar dilator responsiveness by Diaz may contribute to neuroprotection.

pial arteriole; iloprost; NS-398; 5-hydroxydecanoate; intravital microscopy; endothelium

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