Integrative Cardiovascular Laboratories

The Nitric Oxide System

The release of nitric oxide through the oxidation of L-arginine by nitric oxide synthase plays a pivotal role in the maintenance of vascular homeostasis. In response to changes in hemodynamic forces (shear stress) or receptor stimulation (e.g. acetylcholine) nitric oxide is released from the vascular endothelium to promote relaxation of vascular smooth muscle. Endothelial dysfunction resulting from impaired nitric oxide synthesis is a prominent feature in several cardiovascular diseases, including hypertension, metabolic syndrome and diabetes. Given that L-arginine is the exclusive substrate of endothelial nitric oxide synthase, alterations in L-arginine availability may play a crucial role in regulating nitric oxide release. In this respect, endothelial cells express arginase that catalyzes the metabolism of L-arginine to L-ornithine and urea, raising the possibility that arginase and endothelial nitric oxide synthase may compete for substrate. Consistent with this proposal, inhibition of arginase activity stimulates nitric oxide production whereas overexpression of arginase inhibits nitric oxide synthesis in cultured endothelial cells. Moreover, recent findings indicate that increased arginase activity blocks nitric oxide synthesis in the corpus cavernosum and promotes erectile dysfunction in diabetes as well as endothelial dysfunction in aging, and following ischemia-reperfusion. In addition, a recent study found that upregulation of vascular arginase expression decreases nitric oxide-mediated dilation of coronary arterioles isolated from pigs with aortic coarctation hypertension.