The role played by oxidative stress in evoking the exercise pressor reflex in health and simulated peripheral artery disease

Abstract

Contraction of muscle evokes the exercise pressor reflex (EPR), which is expressed partly by increases in heart rate and arterial pressure. Patients with peripheral artery disease (PAD) show an exaggerated EPR, sometimes report pain when walking and are at risk for cardiac arrthymias. Previous research suggested that reactive oxygen species (ROS) mediate the exaggerated EPR associated with PAD. To examine the effects of ROS on the EPR, we infused a superoxide scavenger, tiron, into the superficial epigastric artery of decerebrated rats. In some, we simulated PAD by ligating a femoral artery for 72 h before the experiment. The peak EPR in 'ligated' rats during saline infusion averaged 31 ± 4 mmHg, whereas the peak EPR in these rats during tiron infusion averaged 13 ± 2 mmHg (n = 12; P < 0.001); the attenuating effect of tiron on the EPR was partly reversed when saline was reinfused into the superficial epigastric artery (21 ± 2 mmHg; P < 0.01 vs. tiron). The peak EPR in 'ligated' rats was also attenuated (n = 7; P < 0.01) by infusion of gp91ds-tat, a peptide that blocks the activity of NAD(P)H oxidase. Tiron infusion had no effect on the EPR in rats with patent femoral arteries (n = 9). Western blots showed that the triceps surae muscles of 'ligated' rats expressed more Nox2 and p67phox, which are components of NADPH oxidase, compared to triceps surae muscles of 'freely perfused' rats. Tiron added to muscle homogenates reduced ROS production in vitro. The results of the present study provide further evidence indicating that ROS mediates the exaggeration of EPR in rats with simulated PAD.

Local Injections of Superoxide Dismutase Attenuate the Exercise Pressor Reflex in Rats with Femoral Artery Occlusion

“…It is noted that in this prior study tempol or tiron was trapped in the muscles and ~10–15 min later the hindlimb muscle was reperfused and contracted. However, tiron was shown to attenuate the exercise pressor reflex in occluded rats when it was constantly infused into the hindlimbs while the hindlimb muscles were contracting (Harms et al, 2017 ). Infusion of tiron also attenuated muscle activity of NADPH oxidase (Harms et al, 2017 ).…”

“…However, tiron was shown to attenuate the exercise pressor reflex in occluded rats when it was constantly infused into the hindlimbs while the hindlimb muscles were contracting (Harms et al, 2017 ). Infusion of tiron also attenuated muscle activity of NADPH oxidase (Harms et al, 2017 ). The method and period to deliver the antioxidants was likely to lead to the different effects of the antioxidants on the reflex.…”

“…However, in animals with heart failure and PAD, ROS is likely to play a role in modulating the exercise pressor reflex. It has been reported that the BP response to static muscle contraction was enhanced via an OS mechanism in rat models of heart failure and PAD (Koba et al, 2009 ; Harms et al, 2017 ). Of note, among the metabolic receptors engaged in the amplified exercise pressor reflex in PAD, transient receptor potential channel A1 (TRPA1) is responding to ROS (Bandell et al, 2004 ; Trevisani et al, 2007 ; Bessac et al, 2008 ; Kim et al, 2016 ).…”

“…In addition, tiron (a mimetic of SOD) was observed to attenuate the exercise pressor reflex in occluded rats after it was given acutely into arterial blood supply of the hindlimb muscles (Harms et al, 2017 ). Another study showed that tempol (another SOD mimetic), but not tiron had effects on the reflex in occluded rats (McCord et al, 2011 ).…”

The exercise pressor reflex and active O 2 transport in peripheral arterial disease

“…This is due, in part, to a greater responsiveness of these fibers to controlled levels of external input, such as capsaicin (Tsuchimochi et al, 2010) and muscle stretch (Kempf et al, 2018). Additionally, oxidative stress and stimulation of acid-sensing ion channels (by changes in pH balance) have been reported to play significant roles in evoking the exaggerated pressor response in both human and animal models of PAD (Tsuchimochi et al, 2011;Muller et al, 2012;Farrag et al, 2017;Harms et al, 2017;Xing et al, 2018). Therefore, the initial decrease in muscle oxygenation observed in our study, and others (Ledermann et al, 2006), would likely contribute to the exaggerated stimulation of these Group III and IV afferents via the aforementioned mechanisms.…”