Pilot Study for the Development of Transient Forearm Endothelial Dysfunction

Endothelial dysfunction denotes abnormal contractile function of the inner lining of blood vessels. Endothelial dysfunction is associated with hypertension, hypercholesterolemia, atherosclerosis and diabetes and is an independent risk factor for cardiovascular disease. In normal physiology, endothelial cells synthesize and release factors that modulate blood vessel growth, inflammation, homeostasis, and vascular tone. Recently, endothelial dysfunction has been recognized as an early event in ischemia-reperfusion (IR) injury. IR injury causes damage to tissue and is important in many settings including acute coronary artery occlusions and cerebral ischemia. A model to examine the physiology of IR induced endothelial dysfunction and to test pharmacologic agents to prevent IR induced endothelial dysfunction is of paramount importance given the rise in cardiovascular and cerebrovascular disease. Recently in Protocol 06-H-0024, our group found that 20 minutes of ischemic stress causes no absolute endothelial dysfunction to the forearm using venous plethysmography to measure blood flow, despite numerous publications that support this model. We believe that the previously published data are based on a computational error resulting in an erroneous data interpretation (discussed in the introductory section of this proposal). Using NMR spectroscopy in protocol 06-H-0024 we have found that by adding exercise to exhaustion (usually 1 to 2 minutes of concentric exercise) to a 15-minute period of forearm ischemia results in a significantly more robust metabolic stress to the forearm, than 20 minutes of ischemia alone. Given the potential utilization of the restoration of endothelial function as a therapeutic strategy, we propose this pilot study to examine whether 15 minutes of ischemia with exercise to exhaustion (usually 1-2 minutes of concentric exercise) will cause transient IR dependent blunting of endothelial vasodilation as measured by venous plethysmography. In this study, an extension of Protocol 06-H-0024, we hypothesize that in human subjects the addition of concentric exercise to exhaustion, as a means to deplete high energy phosphate stores, will contribute to the development of transient endothelial dysfunction when performed in parallel with a 15-minute forearm ischemic stress. The establishment of a human system to enable the study of transient forearm vessel endothelial dysfunction will enable us to explore therapeutic interventions to protect against endothelial dysfunction.