Figure 2.
Under normal circumstances, NO is produced by eNOS on the endothelial cell using L-arginine as a substrate and tetrahydrobiopterin (BH4) as a cofactor. eNOS is inhibited by asymmetrical dimethylarginine, which itself is inhibited by DDAH. The vasodilating effects of NO is balanced by the vasoconstricting effects of Angiotensin II and Endothelin 1 on the Vascular Smooth Muscle Cells. Under circumstances of oxidative stress, ROS interact with 1) BH4, resulting in decreased activity of eNOS and decreased NO production; 2) DDAH, resulting in accumulation of ADMA and inhibition of NO production by eNOS; 3) NO itself, resulting in production of the peroxynitrite radical and further ROS. ET-1 and Ang-II increase ROS production via NADPH oxidase. The cumulative effect favors vasoconstriction.