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

Abstract

The exercise pressor reflex is amplified in patients with peripheral artery disease (PAD) and in an experimental PAD model of rats induced by femoral artery occlusion. Heightened blood pressure worsens the restricted blood flow directed to the limbs in this disease. The purpose of this study was to determine the role played by muscle oxidative stress in regulating the augmented pressor response to static exercise in PAD. We hypothesized that limb ischemia impairs muscle superoxide dismutase (SOD) thereby leading to abnormal autonomic responsiveness observed in PAD animals, and a chronic compensation of SOD for anti-oxidation improves the exaggerated exercise pressor reflex. Our data show that femoral occlusion decreased the protein levels of SOD in ischemic muscle as compared with control muscle. Downregulation of SOD appeared to a greater degree in the oxidative (red) muscle than in the glycolytic (white) muscle under the condition of muscle ischemia. In addition, the exercise pressor response was assessed during electrically induced static contraction. The data demonstrates that the enhancement of the exercise pressor reflex was significantly attenuated after tempol (a mimetic of SOD, 30 mg over a period of 72 h) was administered into the occluded hindlimb. In the occluded rats, mean arterial pressure (MAP) response was 26 ± 3 mmHg with no tempol and 12 ± 2 mmHg with tempol application (P < 0.05 vs. group with no tempol; n = 6 in each group). There were no differences in muscle tension development (time-tension index: 12.1 ± 1.2 kgs with no tempol and 13.5 ± 1.1 kgs with tempol; P > 0.05 between groups). In conclusion, SOD is lessened in the ischemic muscles and supplement of SOD improves the amplified exercise pressor reflex, which is likely beneficial to the restricted blood flow to the limbs in PAD.

Superoxide Dismutase Administration: A Review of Proposed Human Uses

“…The study used the ligation of the femoral artery in rats as a model of PAD. This model causes an abnormal autonomic response that was significantly reduced after tempol administration [ 194 ].…”

Sympathetic Nerve Activity and Blood Pressure Response to Exercise in Peripheral Artery Disease: From Molecular Mechanisms, Human Studies, to Intervention Strategy Development

“…Moreover, PAD in human subjects is not solely a disease of large vessel obstruction, but it is a disease of large vessel obstruction in the setting of a chronic disease process (atherosclerosis) that is influenced by oxidative stress and inflammation [73]. Femoral artery occlusion increases products of oxidative stress in the hindlimb muscles of rats and activates inflammatory signals (i.e., IL-6 and TNF-α) [74][75][76] as shown in Figure 1. This also makes the femoral occlusion model reflective of human conditions.…”

“…Seventy-two hours of femoral artery occlusion increases products of oxidative stress in the hindlimb muscles of rats and activates inflammatory signaling pathways [74][75][76]. IL-6 also plays a role in regulating the exaggerated BP response to static exercise in PAD rats [169] likely via membrane-bound IL-6R or gp130 trans-signaling pathways assembled by soluble forms of IL-6R [163,170,171].…”

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.…”