Regulation of exercise blood flow: Role of free radicals

Abstract

During exercise, oxygen and nutrient rich blood must be delivered to the active skeletal muscle, heart, skin, and brain through the complex and highly regulated integration of central and peripheral hemodynamic factors. Indeed, even minor alterations in blood flow to these organs have profound consequences on exercise capacity by modifying the development of fatigue. Therefore, the fine-tuning of blood flow is critical for optimal physical performance. At the level of the peripheral circulation, blood flow is regulated by a balance between the mechanisms responsible for vasodilation and vasoconstriction. Once thought of as toxic by-products of in vivo chemistry, free radicals are now recognized as important signaling molecules that exert potent vasoactive responses that are dependent upon the underlying balance between oxidation-reduction reactions or redox balance. Under normal healthy conditions with low levels of oxidative stress, free radicals promote vasodilation, which is attenuated with exogenous antioxidant administration. Conversely, with advancing age and disease where background oxidative stress is elevated, an exercise-induced increase in free radicals can further shift the redox balance to a pro-oxidant state, impairing vasodilation and attenuating blood flow. Under these conditions, exogenous antioxidants improve vasodilatory capacity and augment blood flow by restoring an "optimal" redox balance. Interestingly, while the active skeletal muscle, heart, skin, and brain all have unique functions during exercise, the mechanisms by which free radicals contribute to the regulation of blood flow is remarkably preserved across each of these varied target organs.

Keywords: Antioxidant; Hyperemia; Oxidative stress; Redox balance; Vascular function; Vasodilation.

Figure 1. A conceptual schematic of the proposed critical link between redox balance and the regulation of blood flow by free radicals during exercise

Shifting the underlying redox status such that an imbalance is created may determine whether free radicals promote or impair vasodilation in the vasculature. Optimal vasodilation is defined as the precise matching of oxygen delivery and oxygen demand coupled with the appropriate pressor response to adequately perfuse the active tissue.

Figure 2. The relationship between net PBN (α-phenyl-tert-butylnitrone) spin-adduct outflow (venous – arterial difference), a direct measure of free radical outflow, and single-leg oxygen uptake during dynamic single-leg knee extension exercise performed at 25 and 70% of work rate maximum

Data were collected in a heterogeneous group of 7 healthy men (48 ± 25 yr). Each exercise intensity was continued for 3 min to achieve steady-state pulmonary VO₂. Modified from [43].

Figure 3. The impact of oral antioxidant administration on brachial artery diameter during progressive handgrip exercise in young (A) and old (B) subjects and old subjects post-training (C)

Young subjects exhibited a progressive linear increase in brachial artery diameter under control (placebo) conditions and in these subjects the administration of an oral antioxidant significantly blunted exercise-induced vasodilation. Old subjects, exhibited impaired vasodilation under control conditions that was restored following antioxidant administration. Following 6-weeks of single-leg knee extension training, old subjects demonstrated a training-induced improvement in vasodilation and in these subjects the administration of an oral antioxidant significantly blunted exercise-induced vasodilation. Data were collected in 8 young (26 ± 2 yr) and 8 older (71 ± 6 yr) healthy subjects. The oral antioxidant consisted of “over the counter” Vitamins C, E, and α-lipoic acid administered in 2 doses separated by 30 min, with the first dose ingested 2 hours before the graded handgrip exercise protocol. The first dose consisted of 300 mg of α-lipoic acid, 500 mg of Vitamin C, and 200 IU of Vitamin E, whereas the second included 300 mg of α-lipoic acid, 500 mg of Vitamin C, and 400 IU of Vitamin E. Modified from [69].

Figure 4. The Ascorbic acid-induced improvement in forearm blood flow during handgrip exercise in older subjects

(A) Young (n = 14, 22 ± 1 yr) and old (n = 14, 65 ± 2 yr) subjects performed rhythmic dynamic handgrip exercise at 10% of MVC (20 contractions per min). Older subjects exhibited attenuated forearm blood flow during the first 6 min of handgrip exercise (* P = 0.06 – 0.09 for minutes 1–6). Ascorbic acid infusion commenced at min 5 of handgrip exercise. Forearm blood flow gradually increased in the old, but not the young subjects, during ascorbic acid infusion († P < 0.05 vs. steady-state exercise within older group for minutes 7–15). Modified from Kirby et al. 2009. (B) A follow-up study, performed by the same group, utilized the same handgrip paradigm with the addition of intra-arterial L-NMMA (NG-monomethyl-L-arginine) infusion to inhibit endothelial nitric oxide synthase activity in the old (n = 14, 64 ± 3 yr) subjects. Inhibition of endothelial nitric oxide synthase abolished the ascorbic acid-induced improvement in forearm blood flow. * P < 0.05 vs. within-trial steady-state exercise condition. Modified from [73].

Figure 5. A schematic of the critical link between redox balance by the exercise-induced increase in free radicals that likely plays a role in the regulation of blood flow to active skeletal muscle, heart, brain, and skin

Under conditions of high oxidative stress and redox imbalance free radicals generated during exercise impair vasodilation and contribute to attenuated blood flow in the active skeletal muscle, heart, brain, and skin. Under conditions of low oxidative stress and optimal redox balance free radicals generated during exercise promote vasodilation and contribute to augmented blood flow in the active skeletal muscle, heart, brain, and skin. Optimal vasodilation is defined as the precise matching of oxygen delivery and oxygen demand coupled with the appropriate pressor response to adequately perfuse the active tissue.

Figure 6. Contribution of nitric oxide (NO) to coronary artery cross-sectional area (CSA), flow velocity (CFV), and blood flow (CBF) during ischemic handgrip exercise in healthy adults

Healthy coronary arteries respond to endothelial-dependent stressors with an increase in CSA, CFV, and CBF. Intravenous infusion of L-NMMA significantly blunted these responses indicating a significant NO contribution (n = 10, 31 ± 9 yr). Modified from [142].

Figure 7. The impact of polyphenol antioxidant supplementation on estimated skin blood flow (SkBF) during prolonged cycling exercise in the heat

Twelve healthy well-trained male cyclists (27± 5yr) cycled in the heat (31.5°C, 55% relative humidity) following 7-days of placebo or polyphenol antioxidant supplementation. Exercise intensity started at 40% of VO₂max and increased by 10% of VO₂max every 5 min until min 20. At min 20, exercise intensity was adjusted to 5% above lactate threshold and maintained until min 50. Polyphenol antioxidant supplementation had no effect of SkBF during exercise in the heat. * P < 0.05 compared to previous value. Modified from [160].

Figure 8. Exercise-induced changes in ascorbate radical (A^•−) production and associated changes in cerebral autoregulation index (ARD)

Eight physically active healthy men (35±7 yrs) exercised (semi-recumbent cycling) to exhaustion. Changes from rest to exhaustion for A^•− were negatively correlated with ARI, suggesting a link between exercise-induced increases in free radicals and impaired dynamic cerebral autoregulation. Modified from [184].

Figure 9. Partial correlation plot in patients with Type Two Diabetes with and without hypertension demonstrating an inverse relationship between total reactive oxygen species (ROS) and rate of cerebral autoregulation (RoR) during 40% MVC handgrip exercise

Partial correlation was used to account for the potential confounding influence of lipids, body mass index, age, duration of the disease, fasting glucose, and HbA1c. Modified from [197].

Figure 10. Working hypothesis: Impact of alterations in redox balance on free radical-induced vasodilation

The impact of exercise-induced increases in free radicals on vasodilation is dependent upon the underlying redox status. In young and healthy aging conditions (●) free radicals produced during exercise contribute to optimal vasodilation (A). Under such conditions endogenous antioxidant enzymatic systems (including, but not limited to CAT [catalase] and SOD [superoxide dismutase]) are able to appropriately quench free radical production, thus avoiding excessive oxidation. In normal aging and disease states (■) the underlying redox balance is shifted towards a pro-oxidized state and free radicals produced during exercise contribute to impaired vasodilation (B). Interestingly, in normal aging and disease states (■) augmenting exogenous antioxidants shifts the redox balance and restores optimal vasodilation (A′). In contrast, augmenting exogenous antioxidants in young individuals creates a reduced redox state leading to impaired vasodilation (C) as the normal vasodilatory role of the free radicals produced during exercise is blocked. A similar hypothesis has been proposed for the link between redox balance and muscle force production [171].