Abnormal diazoxide‐induced vasodilation of middle cerebral arteries following transient focal cerebral ischemia in rats

Abstract

Diazoxide (DZ), a mitochondrial KATP channel activator, elicits arterial vasodilation by increasing the generation of mitochondria-derived reactive oxygen species that stimulate calcium sparks and calcium activated K+ channels. We evaluated the DZ-induced vasodilation in rat middle cerebral arteries (MCA) following transient focal cerebral ischemia. Male Wistar rats were subjected to cerebral ischemia by MCA occlusion (MCAO, 90 minutes) followed by reperfusion (48 hours). Vascular reactivity of isolated MCAs was assessed by videomicroscopy. DZ (100 μmol) induced vasodilation was intact in ipsilateral MCAs while it was diminished in contralateral MCAs (% relaxation: 31±5 in contrateral MCAs versus 55±10 in ipsilateral MCAs and 69±6 in MCAs from Wistar rats not exposed to MCAO, p<0.05). Similarly, vasodilation to bradykinin (10 μmol) was reduced in contralateral MCAs (27±8%, p<0.05) compared to ipsilateral (68±6%). In contrast, pressure induced constriction was decreased in ipsilateral MCAs compared to contralateral. Nitroprusside (100 μmol) induced vasodilation was intact in all MCAs. Thus, cerebral ischemia diminishes DZ induced as well as endothelium-dependent vasodilation in contralateral MCAs despite intact myogenic tone and smooth muscle dependent vasodilation. Diminished mitochondria-derived ROS or calcium sparks appear to mediate impaired vasodilation to DZ.