Oxidative stress and enhanced sympathetic vasoconstriction in contracting muscles of nitrate‐tolerant rats and humans
- 15 January 2012
- journal article
- clinical trial
- Published by Wiley in Journal Of Physiology-London
- Vol. 590 (2), 395-407
- https://doi.org/10.1113/jphysiol.2011.218917
Abstract
Sympathetic vasoconstriction is normally attenuated in exercising muscle, but this functional sympatholysis is impaired in rats with hypertension or heart failure due to elevated levels of reactive oxygen species (ROS) in muscle. Whether ROS have a similar effect in the absence of cardiovascular disease or whether these findings extend to humans is not known. We therefore tested the hypothesis that chronic treatment with nitroglycerin (NTG) to induce nitrate tolerance, which is associated with excessive ROS production, impairs functional sympatholysis in healthy rats and humans. NTG treatment increased ethidium fluorescence in rat muscles and urinary F(2)-isoprostanes in humans, demonstrating oxidative stress. In vehicle-treated rats, sympathetic nerve stimulation (1 to 5 Hz) evoked decreases in femoral vascular conductance at rest (range, -30 to -63%) that were attenuated during hindlimb contraction (range, -2 to -31%; P < 0.05). In NTG-treated rats, vasoconstrictor responses were similar at rest, but were enhanced during contraction (range, -17 to -50%; P < 0.05 vs. vehicle). Infusion of the ROS scavenger tempol restored sympatholysis in these rats. In humans, reflex sympathetic activation during lower body negative pressure (LBNP) evoked decreases in muscle oxygenation in resting forearm (-12 ± 1%) that were attenuated during handgrip exercise (-3 ± 1%; P < 0.05). When these subjects became nitrate tolerant, LBNP-induced decreases in muscle oxygenation were unaffected at rest, but were enhanced during exercise (-9 ± 1%; P < 0.05 vs. before NTG). Collectively, these data indicate that functional sympatholysis is impaired in otherwise healthy nitrate-tolerant rats and humans by a mechanism probably involving muscle oxidative stress.This publication has 58 references indexed in Scilit:
- Modulation of postjunctional α‐adrenergic vasoconstriction during exercise and exogenous ATP infusions in ageing humansJournal Of Physiology-London, 2011
- Functional sympatholysis is impaired in hypertensive humansJournal Of Physiology-London, 2011
- Sedentary aging increases resting and exercise-induced intramuscular free radical formationJournal of Applied Physiology, 2010
- Translating the oxidative stress hypothesis into the clinic: NOX versus NOSJournal of Molecular Medicine, 2009
- Exercise-Induced Oxidative Stress: Cellular Mechanisms and Impact on Muscle Force ProductionPhysiological Reviews, 2008
- Reactive Oxygen Species Impair Sympathetic Vasoregulation in Skeletal Muscle in Angiotensin II–Dependent HypertensionHypertension, 2006
- Augmented leg vasoconstriction in dynamically exercising older men during acute sympathetic stimulationJournal Of Physiology-London, 2003
- Augmented leg vasoconstriction in dynamically exercising older men during acute sympathetic stimulationJournal Of Physiology-London, 2003
- Role of superoxide dismutase in in vivo and in vitro nitrate toleranceBritish Journal of Pharmacology, 1999
- Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance.JCI Insight, 1995