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

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 289; no. 1; pp. H368 - H373
• Main Authors: Domoki, Ferenc, Kis, Bela, Nagy, Krisztina, Farkas, Eszter, Busija, David W, Bari, Ferenc
• Format: Journal Article
• Language: English
• Published: United States 01.07.2005
• Subjects: Animals; Animals, Newborn; Arterioles - drug effects; Arterioles - physiopathology; Blood Pressure - drug effects; Brain Ischemia - physiopathology; Cells, Cultured; Cerebrovascular Circulation - drug effects; Cyclooxygenase Inhibitors - pharmacology; Decanoic Acids - pharmacology; Diazoxide - pharmacology; Female; Hydroxy Acids - pharmacology; Hypercapnia - physiopathology; Male; Nitrobenzenes - pharmacology; Potassium Channel Blockers - pharmacology; Potassium Channels - drug effects; Sulfonamides - pharmacology; Swine; Vasodilation; Vasodilator Agents - pharmacology
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00887.2004

Departments of 1 Physiology and 3 Anatomy, Faculty of Medicine, University of Szeged, Szeged, Hungary; and 2 Department 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% CO 2 -21% O 2 -balance N 2 , 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 CO 2 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 Address for reprint requests and other correspondence: F. Domoki, Dept. of Physiology, Faculty of Medicine, Univ. of Szeged, Szeged, Dóm tér 10, H-6720 Hungary (E-mail: domoki{at}phys.szote.u-szeged.hu )