In this application, we propose a series of experiments designed to Inelp us better understand blood pressure adjustments to exercise in patients with peripheral arterial disease (PAD). Recently obtained pilot data suggests that the pressor response to plantar flexion may be increased in PAD and that reactive oxygen species (ROS) contribute to this enhanced pressor response. In an effort to better understand the role oxidative stress plays in evoking the exercise pressor reflex (EPR) in the absence of chronic arterial disease, we have performed pilot studies in normal humans. These pilot data suggest that ROS contribute to the ischemic potentiation of the EPR. Moreover, chronic cigarette smoldng and acute hyperoxia, both conditions associated with oxidative stress, augment the ischemic accentuation. In this application, we examine the following questions: 1) Are pressor responses to unilateral rhythmic plantar flexion exercise increased in humans with PAD? We hypothesize that pressor responses to exercise will be augmented during exercise by both the """"""""symptomatic"""""""" and """"""""asymptomatic"""""""" limbs of subjects with unilateral ischemic leg pain with walking (i.e. intermittent claudication). This effect will be greater in the symptomatic limb and this effect will be seen at very low workloads (0.5 kg plantar flexion at 30 contractions per minute), even before symptoms of claudication are noted. 2) Does oxidative stress play a role in evoking the pressor response in PAD? Based on pilot data, we hypothesize that oxidative stress does play an important role in evoking the pressor reflex in PAD. We speculate that an intravenous infusion of the antioxidant, ascorbic acid, will markedly lesson the pressor response to plantar flexion in subjects with intermittent claudication. 3) In the absence of chronic limb ischemia, do ROS contribute to the EPR? We hypothesize that in normal volunteers, oxidative stress leads to ischemic accentuation of the reflex. When handgrip is performed by cigarette smokers or during acute hyperoxia, oxidative stress will be augmented and the ability of the antioxidant ascorbic acid to reduce the pressor response will be enhanced as compared to non-smokers.

Public Health Relevance

In PAD, autonomic reflex and vascular adjustments are understudied and of major clinical significance. PAD is common and lethal. Moreover, it is often a harbinger of other life threatening diseases (coronary and cerebral atherosclerosis). In severe PAD, blood pressure rises dramatically with walking. We postulate that autonomic processes contribute to the augmented pressor response. By better understanding this phenomenon we will better understand how to prevent, treat, and extend the life of those with PAD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL096570-04
Application #
8502529
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$317,644
Indirect Cost
$112,050
Name
Pennsylvania State University
Department
Type
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Muller, Matthew D; Li, Zhijun; Sica, Christopher T et al. (2016) Muscle oxygenation during dynamic plantar flexion exercise: combining BOLD MRI with traditional physiological measurements. Physiol Rep 4:
Cui, Jian; Blaha, Cheryl; Sinoway, Lawrence I (2016) Whole body heat stress attenuates the pressure response to muscle metaboreceptor stimulation in humans. J Appl Physiol (1985) 121:1178-1186
Li, Zhijun; Muller, Matthew D; Wang, Jianli et al. (2016) Dynamic characteristics of T2*-weighted signal in calf muscles of peripheral artery disease during low-intensity exercise. J Magn Reson Imaging :
Ross, Amanda J; Gao, Zhaohui; Luck, Jonathan Carter et al. (2016) Coronary Exercise Hyperemia Is Impaired in Patients with Peripheral Arterial Disease. Ann Vasc Surg :
Copp, Steven W; Kim, Joyce S; Ruiz-Velasco, Victor et al. (2016) The mechano-gated channel inhibitor GsMTx4 reduces the exercise pressor reflex in decerebrate rats. J Physiol 594:641-55
Clark, Christine M; Monahan, Kevin D; Drew, Rachel C (2016) Omega-3 polyunsaturated fatty acid supplementation attenuates blood pressure increase at onset of isometric handgrip exercise in healthy young and older humans. Physiol Rep 4:
Stone, Audrey J; Kaufman, Marc P (2015) The exercise pressor reflex and peripheral artery disease. Auton Neurosci 188:69-73
Clark, Christine M; Monahan, Kevin D; Drew, Rachel C (2015) Aging augments renal vasoconstrictor response to orthostatic stress in humans. Am J Physiol Regul Integr Comp Physiol 309:R1474-8
Copp, Steven W; Stone, Audrey J; Li, Jianhua et al. (2015) Role played by interleukin-6 in evoking the exercise pressor reflex in decerebrate rats: effect of femoral artery ligation. Am J Physiol Heart Circ Physiol 309:H166-73
Muller, Matthew D; Drew, Rachel C; Ross, Amanda J et al. (2015) Inhibition of cyclooxygenase attenuates the blood pressure response to plantar flexion exercise in peripheral arterial disease. Am J Physiol Heart Circ Physiol 309:H523-8

Showing the most recent 10 out of 64 publications