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

Domoki, Ferenc and Kiss, B. and Nagy, K. and Bari, Ferenc (2005) Diazoxide preserves hypercapnia-induced arteriolar vasodilation after global cerebral ischemia in piglets. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 289 (1). H368-H373. ISSN 0363-6135

Text 1169721.pdf Restricted to Registered users only Download (1MB) | Request a copy

Abstract

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% O-2-balance N-2, n=25) or Ilo (0.1-1 mu g/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 similar to 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.

Actions (login required)

Edit Item