脳塞栓症による血管内皮細胞障害と新規血管保護薬(誌上シンポジウム)  [in Japanese] Brain Embolism-induced Injury of Vascular Endothelial Cells and a Novel Vasoprotective Drug(Symposium Review)  [in Japanese]

Microsphere embolism-induced up-regulation of endothelial nitric oxide synthase (eNOS) in endothelial cells of brain microvessels was found after brain ischemia. The eNOS induction preceded disruption of the blood-brain barrier following ischemia. In vascular endothelial cells, microsphere embolism-induced eNOS expression was associated with protein tyrosine nitration, which is a marker of generation of peroxynitrite. To determine whether eNOS expression and protein tyrosine nitration in vascular endothelial cells mediates the blood-brain barrier disruption in the microsphere embolism brain, we tested the effect of a novel calmodulin-dependent NOS inhibitor, DY-9760e, which inhibits eNOS activity and in turn protein tyrosine nitration. Concomitant with inhibition of protein tyrosine nitration in vascular endothelial cells, DY-9760e significantly inhibited BBB disruption as assessed by Evans blue excretion. DY-9760e also inhibited cleavage of poly (ADP-ribose) polymerase as a marker of the apoptotic pathway in vascular endothelial cells. Taken together with previous evidence in which DY-9760e inhibited brain edema, microsphere embolism-induced eNOS expression in vascular endothelial cells likely mediates BBB disruption and in turn brain edema.