The goal of this revised renewal is to continue to investigate how neural and local factors interact to regulate blood flow to human skeletal muscles. The investigators have shown that mental stress evokes atropine sensitive, nitric oxide (NO)-dependent vasodilation in human forearm muscles. Sympathoexcitatory maneuvers (e.g., contralateral ischemic handgrip exercise) can also cause marked NO-dependent atropine sensitive forearm vasodilation after alpha-adrenergic blockade of the forearm. These observations initially led the investigators to hypothesize that there is neurally mediated NO release in conscious humans governed in part by sympathetic-cholinergic nerves. They have now shown that sympathetic withdrawal also contributes to forearm vasodilation during mental stress. This suggests that during mental stress changes in forearm flow and systemic arterial pressure can mechanically stimulate the vascular endothelium to release NO via local cholinergic mechanisms. In this proposal, the investigators explore these alternative mechanisms of NO release by addressing the following specific aims: (1) Is NO-mediated forearm vasodilation observed during contralateral ischemic handgrip exercise after local anesthetic block of the stellate ganglion? (2) Is the forearm vasodilation seen during mental stress after stellate ganglion block NO mediated and atropine sensitive? (3) Is there evidence for vasodilator nerve traffic when mental stress is performed during systemic phenylephrine infusions that raise arterial pressure? (4) Can sympathoexcitatory maneuvers cause NO-dependent vasodilation in the leg? The proposed studies are feasible and address novel concepts in humans. They will allow the investigators to determine the mechanisms responsible for NO-mediated vasodilation during sympathoexcitatory maneuvers (Aims 1-3) and explore their potential whole-body hemodynamic significance (Aim 4). These vasodilating mechanisms may have significance in a variety of disease states associated with endothelial and autonomic dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL046493-06A2
Application #
2487332
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1992-01-17
Project End
2002-08-31
Budget Start
1997-09-30
Budget End
1998-08-31
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Van Iterson, Erik H; Johnson, Bruce D; Joyner, Michael J et al. (2017) V?o2 kinetics associated with moderate-intensity exercise in heart failure: impact of intrathecal fentanyl inhibition of group III/IV locomotor muscle afferents. Am J Physiol Heart Circ Physiol 313:H114-H124
Limberg, Jacqueline K; Malterer, Katherine R; Mikhail Kellawan, J et al. (2017) Potentiation of the NO-cGMP pathway and blood flow responses during dynamic exercise in healthy humans. Eur J Appl Physiol 117:237-246
Keller-Ross, Manda L; Johnson, Bruce D; Carter, Rickey E et al. (2016) Improved Ventilatory Efficiency with Locomotor Muscle Afferent Inhibition is Strongly Associated with Leg Composition in Heart Failure. Int J Cardiol 202:159-66
Harvey, Ronee E; Hart, Emma C; Charkoudian, Nisha et al. (2015) Oral Contraceptive Use, Muscle Sympathetic Nerve Activity, and Systemic Hemodynamics in Young Women. Hypertension 66:590-7
Van Iterson, Erik H; Snyder, Eric M; Joyner, Michael J et al. (2015) Intrathecal fentanyl blockade of afferent neural feedback from skeletal muscle during exercise in heart failure patients: Influence on circulatory power and pulmonary vascular capacitance. Int J Cardiol 201:384-93
Joyner, Michael J; Casey, Darren P (2015) Regulation of increased blood flow (hyperemia) to muscles during exercise: a hierarchy of competing physiological needs. Physiol Rev 95:549-601
Casey, Darren P; Ranadive, Sushant M; Joyner, Michael J (2015) Aging is associated with altered vasodilator kinetics in dynamically contracting muscle: role of nitric oxide. J Appl Physiol (1985) 119:232-41
Joyner, Michael J; Casey, Darren P (2014) Muscle blood flow, hypoxia, and hypoperfusion. J Appl Physiol (1985) 116:852-7
Casey, Darren P; Shepherd, John R A; Joyner, Michael J (2014) Sex and vasodilator responses to hypoxia at rest and during exercise. J Appl Physiol (1985) 116:927-36
Taylor, Jennifer L; Hines, Casey N; Nicholson, Wayne T et al. (2014) The effect of ageing and indomethacin on forearm reactive hyperaemia in healthy adults. Exp Physiol 99:859-67

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