Progressive dysfunction of nitric oxide synthase in a lamb model of chronically increased pulmonary blood flow: a role for oxidative stress

摘要

Basal NO production by the vascular endothelium is integral to the maintenance of the normal low resistance state of the pulmonary vasculature, and dynamic alterations in NO production modulate vascular relaxation and constriction in response to various stimuli. NO is produced in vascular endothelial cells by nitric oxide synthase (NOS) from the oxidation of the guanidino nitrogen moiety of L-arginine. Once formed, NO diffuses into vascular smooth muscle cells where it activates soluble guanylate cyclase (sGC), which produces cGMP from GTP, resulting in smooth muscle relaxation through activation of a cGMP-dependent protein kinase (19, 25). Both animal and human studies indicate that abnormally increased pulmonary blood flow results in an early selective impairment of endo-thelium-dependent pulmonary vascular relaxation, suggestive of decreased NO bioavailability (11, 33)