Mitochondria mediated vasodilation by BMS‐191095, a selective mitochondrial K ATP channel activator

Mitochondrial depolarization and subsequent generation of reactive oxygen species (ROS) have been shown to trigger vasodilation via activation of ‘calcium sparks’ and large‐conductance calcium‐activated K + channels (BK Ca ). It is unclear if mitochondrial depolarization alone, independent of ROS, is capable of promoting vasodilation. Therefore, we determined the vasodilation induced by BMS‐191095 (BMS), a putative mitochondrial K ATP channel opener, in isolated cerebral arteries of Sprague‐Dawley (SD), Zucker obese (ZO) with mitochondrial dysfunction and the lean (ZL) control rats. In SD arteries, 50 μmol/L BMS depolarized mitochondria without producing ROS, and induced vasodilation (% relaxation) in endothelium‐intact arteries (53.1±4.4, n=12) that was diminished by endothelial denudation (36.6±3.9, n=8), nitric oxide (NO) synthase inhibition (27.4±5.3, n=6), and BK Ca blockade (21.3±2, n=11) (p<0.05). However, the vasodilation was unaffected by ROS scavenger (45.9±6.7, n=10). In ZO arteries, BMS‐induced vasodilation and mitochondrial depolarization were diminished compared to ZL arteries. Thus, mitochondrial depolarization induces vasodilation via ROS‐independent mechanisms mediated by endothelium, smooth muscle, NO and BK Ca . Finally, mitochondrial dysfunction associated with insulin resistance diminishes BMS‐induced vasodilation. Supported by HL‐077731, HL‐030260, HL‐065380.