Patients with hypertension (HTN) are characterized by an exaggerated blood pressure response and premature fatigue during physical activities. An abnormal exercise pressor reflex (EPR) mediated by neural feedback from mechano- and/or metabosensitive group III and IV muscle afferents might contribute to these abnormalities. However, even in health, our understanding of the exact role and relative contribution of group III/IV afferents to the circulatory control and the development of fatigue during exercise is incomplete. By studying both HTN patients and well-matched healthy controls (CTRLs), we will evaluate the impact of HTN on the relative contribution of these muscle afferents to the circulatory control and the development of central and peripheral fatigue during exercise. The proposed studies will also examine the impact of HTN on muscle morphometry and contraction-induced intramuscular (whole muscle and muscle interstitium) metabolic changes, gene expression and protein levels of metabosensitive receptors on muscle afferents, and the functional impact of these changes in terms of fatigue. Specifically, we will use lumbar intrathecal fentanyl to block the central projection of group III/IV muscle afferents during voluntary and passive exercise (no concomitant effect on feedforward drive). This proven approach will enable us to evaluate and distinguish between the effects of group III and IV muscle afferents on blood pressure, leg blood flow, and cardiac output during large and small muscle mass exercise (bicycle and knee-extension), and the development of central and peripheral fatigue (femoral nerve stimulation techniques). We will also conduct morphometric and metabolite analysis on pre/post-exercise muscle biopsies and dialysate (resulting from intramuscular microdialysis during exercise) to evaluate alterations in intrinsic muscle characteristic as a potential factor determining metaboreflex abnormalities in HTN. Furthermore, we will determine the mRNA and protein levels of ASIC3, P2X, EP4 and TRPV1 receptors in human dorsal root ganglion neurons of HTN patients and CTRLs. Finally, to determine the specific contribution of these metabosensitive molecular receptors to the development of central fatigue in HTN and CTRLs, we will perform an intramuscular infusion of a metabolite soup into the unfatigued quadriceps muscle. We have designed the soup to specifically activate ASIC3, P2X, and TRPV1 receptors and have verified it's specificity in published animal and human studies. Based on recent findings suggesting greater metaboreceptor-mediated reflexes in HTN vs CTRLs, we expect, following the intramuscular soup infusion, greater central fatigue in HTN vs CTRLs. The results from this analysis will contribute to a better understanding of the role of metaboreceptors as a potential mechanism underlying central fatigue and reflex abnormalities characterizing exercising HTN patients. Combined, this research will provide new insight into the impact of HTN on the EPR and group III and IV- mediated afferent feedback and associated consequences for the neuro-circulatory response and fatigue during physical activities.

Public Health Relevance

This research in humans with hypertension will provide new information on the mechanisms accounting for the excessive blood pressure response, altered blood flow, and high fatigability characterizing these patients during physical activity. We will focus on the role of nerves originating in working limb muscles in determining these abnormalities and the associated disability and high mortality in this population. The results from our research will identify potential targets for therapeutic interventions with the overall purpose of improving the quality of life of patients with hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL116579-06A1
Application #
9448443
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Sopko, George
Project Start
2013-04-01
Project End
2022-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Utah
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Hureau, Thomas J; Romer, Lee M; Amann, Markus (2018) The 'sensory tolerance limit': A hypothetical construct determining exercise performance? Eur J Sport Sci 18:13-24
Broxterman, Ryan M; Layec, Gwenael; Hureau, Thomas J et al. (2018) Response. Med Sci Sports Exerc 50:1719
Broxterman, Ryan M; Hureau, Thomas J; Layec, Gwenael et al. (2018) Influence of group III/IV muscle afferents on small muscle mass exercise performance: a bioenergetics perspective. J Physiol 596:2301-2314
Andrade, David C; Arce-Alvarez, Alexis; Toledo, Camilo et al. (2018) Revisiting the physiological effects of exercise training on autonomic regulation and chemoreflex control in heart failure: does ejection fraction matter? Am J Physiol Heart Circ Physiol 314:H464-H474
Ansdell, Paul; Thomas, Kevin; Howatson, Glyn et al. (2018) Deception Improves Time Trial Performance in Well-trained Cyclists without Augmented Fatigue. Med Sci Sports Exerc 50:809-816
Hureau, Thomas J; Weavil, Joshua C; Thurston, Taylor S et al. (2018) Identifying the role of group III/IV muscle afferents in the carotid baroreflex control of mean arterial pressure and heart rate during exercise. J Physiol 596:1373-1384
Wray, D Walter; Amann, Markus; Richardson, Russell S (2017) Peripheral vascular function, oxygen delivery and utilization: the impact of oxidative stress in aging and heart failure with reduced ejection fraction. Heart Fail Rev 22:149-166
Broxterman, Ryan M; Layec, Gwenael; Hureau, Thomas J et al. (2017) Bioenergetics and ATP Synthesis during Exercise: Role of Group III/IV Muscle Afferents. Med Sci Sports Exerc 49:2404-2413
Broxterman, Ryan M; Layec, Gwenael; Hureau, Thomas J et al. (2017) Skeletal muscle bioenergetics during all-out exercise: mechanistic insight into the oxygen uptake slow component and neuromuscular fatigue. J Appl Physiol (1985) 122:1208-1217
Sidhu, Simranjit K; Weavil, Joshua C; Mangum, Tyler S et al. (2017) Group III/IV locomotor muscle afferents alter motor cortical and corticospinal excitability and promote central fatigue during cycling exercise. Clin Neurophysiol 128:44-55

Showing the most recent 10 out of 34 publications