Regulation of Nitric Oxide Bioavailability in Chronic Obstructive Pulmonary Disease: A Mechanistic Approach

Chronic Obstructive Pulmonary Disease (COPD) is among the leading causes of death worldwide. Although COPD is a disease of the lungs, recent evidence describes a multitude of systemic consequences including vascular endothelial function. Nitric Oxide is the primary vasodilator responsible for the regulation of vascular endothelial function. Non invasive assessment of reactive hyperemia induced flow-mediated dilation (FMD) of the brachial artery has been classified as a functional assay of NO bioavailability and has been shown to correlate with coronary artery endothelial function. Surprisingly, there is limited evidence investigating endothelial function in COPD. Thus, the overall objective of this proposal is to identify the role of NO bioavailability in regulating vascular endothelial function in patients with COPD and to provide insight into the molecular mechanisms involved. Our central hypothesis is that inflammation and oxidative stress both independently contribute to the reduction in NO bioavailability and vascular endothelial dysfunction in patients with COPD. To test the hypothesis that reductions in nitric oxide bioavailability contributes to vascular endothelial function in patients with COPD, brachial artery FMD, markers of inflammation and markers of oxidative stress will be determined in patients with COPD and healthy controls prior to and following 1) acute administration of tetrahydrobiopterine (BH4) supplementation to increase NO bioavailability, 2) the ingestion of a high-fat meal to decrease NO bioavailability, and 3) acute intra arterial infusion of L-NMMA to block NO production. To test the hypothesis that inflammation and oxidative stress both contribute to vascular endothelial dysfunction in patients with COPD, Salsalate, a clinically prescribed inhibitor of inflammation and a single dose oral antioxidant cocktail (Vitamin C, Vitamin E, and alpha lipoic acid) will be administered to inhibit inflammation and oxidative stress, respectively. The combination of the proposed physiology, pharmacology, and molecular tools provide a novel and innovative approach to exam the influence of NO bioavailability in patients with COPD. These findings will not only lead to further understanding of the molecular mechanisms associated with endothelial dysfunction in patients with COPD, they will provide insight into possible therapeutic interventions for the treatment of the 4th leading cause of death worldwide. (AHA Program: Scientist Development Grant)