Regulation of Exercise Blood Flow: Role of Free Radicals

Joel D Trinity; Ryan M Broxterman; Russell S Richardson

doi:10.1016/j.freeradbiomed.2016.01.017

. Author manuscript; available in PMC: 2017 Sep 1.

Published in final edited form as: Free Radic Biol Med. 2016 Feb 10;98:90–102. doi: 10.1016/j.freeradbiomed.2016.01.017

Regulation of Exercise Blood Flow: Role of Free Radicals

Joel D Trinity ^1,², Ryan M Broxterman ^1,², Russell S Richardson ^1,^2,³

PMCID: PMC4975999 NIHMSID: NIHMS762148 PMID: 26876648

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: Redox Balance, Oxidative Stress, Hyperemia, Antioxidant, Vascular Function, Vasodilation, Skeletal Muscle

Introduction

Despite the continual discovery of potent vasoactive molecules such as nitric oxide (NO), prostaglandins, endothelium derived hyperpolarizing factor (EDHF), adenosine triphosphate (ATP) [1–4], the identification of the mechanisms essential to the regulation of blood flow during exercise in humans has proven to be a difficult and arduous task [5]. Indeed, concurrent inhibition of multiple vasodilatory pathways during exercise has yielded significant, albeit modest, changes in blood flow [6–8]. Additionally, limitations in the ability to target specific enzymatic isoforms and pharmacologically dissect vasodilatory pathways during exercise in humans may be contributing to these disparate findings [9–12]. Based on these findings it may be concluded that either the underlying mechanism of exercise hyperemia has yet to be identified or adequately inhibited during in-vivo human experimentation or that the regulation of blood flow during exercise involves the complex interaction of numerous compensatory and redundant pathways that control the balance between vasodilation and vasoconstriction in the human vasculature.

Much attention has been focused on elucidating specific mechanisms regulating blood flow, with the ultimate goal of identifying a “master regulator”. When considering that blood flow is determined by the integration of central (cardiac output, mean arterial pressure) and peripheral hemodynamics (vascular conductance or resistance) and the multitude of factors that regulate these processes during exercise, it is unlikely that a single molecule will encompass the properties of a master regulator. Indeed, thus far, this notion is supported by many elegant investigations utilizing pharmacological dissection of specific vasodilatory pathways [6–8, 13–18]. However, when considering the overall goal of increased blood flow during exercise, to match oxygen delivery and oxygen demand, it becomes evident that even minor modifications in blood flow in the intact human may have significant consequences in terms of physical performance [19]. The impact of these alterations is likely to be most relevant during high intensity aerobic exercise or during exercise under conditions of compromised vascular function such as with aging and disease.

Active skeletal muscle demands a large increase in blood flow during exercise, increasing by 100-fold compared to resting values [20, 21]. As such, the skeletal muscle vascular bed is arguably the most important vascular bed in terms of the regulation of blood flow during exercise. The regulation of blood flow to this “sleeping giant” is important to maintain adequate oxygen and nutrient delivery to meet the energetic demands of the skeletal muscle during exercise [22], as inadequate oxygen delivery compromises exercise performance and accelerates the development of fatigue [23]. Importantly, minor changes in oxygen delivery have profound consequences in human performance, especially in conditions where components of the oxygen cascade are operating at near maximal capacity or have been altered by disuse, aging, or disease [24–28]. However, blood flow to other vital organs, including the brain and the heart, is of critical importance and small alterations in oxygen and nutrient delivery can have a profound impact on function and performance. Additionally, the skin, second only to the active skeletal muscle in regards to vasodilatory capacity, participates in critical thermoregulatory processes that are directly linked to exercise performance. Clearly, the regulation of blood flow during exercise requires a coordinated and integrated approach to adequately deliver oxygen and nutrient rich blood throughout the body.

The ubiquitous nature and potential vasoactive properties of free radicals is becoming increasingly appreciated. Indeed, NO, first identified 35 years ago as endothelium-derived relaxing factor by Furchgott and Zawadski [1] and later determined to be NO by Ignarro et al. [2], is actually a reactive nitrogen species (RNS) or free radical. NO certainly has potent vasodilatory properties and has, in fact, been a strong contender for the title of “master regulator” of blood flow. However, although still commonly discussed, the source and complex role of NO in vascular function and blood flow regulation is not the focus of this review and the reader is directed to several excellent reviews on this topic [29–31]). Instead, this review will focus on the regulation (or modification) of blood flow during exercise by other RNS and reactive oxygen species (ROS) such as peroxynitrite (ONOO⁻), superoxide (O₂⁻), hydroxyl radical (OH⁻), and lipid radicals that promote oxidative stress. Ultimately this depends on several factors including the free radical species, the interaction of the free radical with vasodilators (or vasoconstrictors), possible direct effects of the radical on the vasculature, and the underlying redox balance. Here, the interaction of these factors will be addressed as they relate to the regulation of blood flow during exercise in health, aging, and disease as it appears that the underlying redox status dictates how an exercise-induced increase in free radicals promote or impair vasodilation (Figure 1).

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.

When information regarding the exercise associated regulation of blood flow is limited, free radical regulation of basal blood flow will be reviewed. Furthermore, to gain additional mechanistic insight into the possible regulatory roles of free radicals during exercise, investigations evaluating the control of isolated blood vessels will be discussed. Additionally, this review will extend beyond blood flow control in skeletal muscle as important insight may be gained from understanding how free radicals contribute to blood flow regulation in the vasculature of the heart, skin, and brain. As a complete overview of the factors that regulate blood flow during exercise is beyond the scope to this review, the reader is referred to the many excellent reviews on this topic [32–37].

Sources of free radicals

Over the last 30 years, our understanding and appreciation of free radical biology has changed a great deal. Indeed, these highly reactive molecules, characterized by an unpaired electron, were originally viewed as toxic by-products of in vivo chemistry, but are now considered critical regulators of cell signaling and play essential roles in facilitating the damage and adaptations that accompany exercise [38–45]. Importantly, the production of free radicals is augmented during exercise in proportion to the severity of exercise intensity. Seminal work by Davies et al., [46] provided the first electron paramagnetic resonance (EPR) spectroscopic evidence of increased free radical production during exhaustive exercise in animals [46]. These findings have been translated to humans in a series of innovative studies by Bailey and colleagues [47, 48] utilizing isolated knee extension exercise and ex-vivo spin trapping of blood and skeletal muscle (Figure 2). The production of free radicals is clearly augmented during exercise; however, the source(s) of these free radicals remains equivocal.

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].

Early investigators proposed that skeletal muscle mitochondria were the primary source of free radical production during exercise [46]. It was estimated that during exercise 2–5% of oxygen consumed during oxidative phosphorylation was converted to O₂⁻ during the transfer of electrons through the complexes of the electron transport chain (ETC) [42, 49–52]. This hypothesis centered on the notion that during state 3 mitochondrial respiration, when electron flux through the ETC is maximized, the potential for electrons to bypass the respiratory complexes and aberrantly reduce oxygen, producing O₂⁻, would also be maximized [53, 54]. Contrary to this concept, it has recently been documented that ROS production is actually lowest during state 3 respiration, as the oupling of electron transfer to ATP production is optimized [55, 56]. Thus, the early estimates that 2–5% of oxygen consumed is converted to ROS have been re-evaluated, and it is now more commonly accepted that as little as 0.15% of consumed oxygen is converted to ROS [57]. While the contribution of skeletal muscle mitochondria to ROS production during exercise is somewhat equivocal, several studies, utilizing mitochondrial targeted antioxidants, have provided compelling evidence that mitochondria-derived ROS contribute to vascular endothelial dysfunction with age in murine models [58, 59] and that even the thin endothelial cell layer may be a significant source of free radicals [60]. Therefore, the location of the mitochondria, skeletal muscle versus endothelial cells or vascular smooth muscle, may be a critical factor in deciphering the source of free radicals during exercise and how free radicals impact blood flow.

In addition to endothelial cell and smooth muscle mitochondria, the vasculature contains several enzymatic sources of free radicals including nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase), xanthine oxidase (XO), and nitric oxide synthases (NOS) [43, 60–62] that, each, likely contribute to the exercise-induced increase in free radicals. Indeed, elevations in blood flow and shear stress, as well as biochemical changes in the metabolic milieu of the blood that occur with exercise increase the activity of these enzymes resulting in increased free radical production [63, 64]. Animal studies using specific enzymatic inhibitors (allopurinol, apocynin) reveal important roles of these enzymes in the exercise-induced production of free radicals [65].

Overall, multiple sources, both enzymatic and mitochondria-based, contribute to the exercise-induced increase in free radicals such as O₂⁻, ONOO⁻, and OH⁻. Importantly, these free radicals possess inherent vasoactive properties or are capable of altering the bioavailability of other vasoactive molecules, such as NO. Under normal healthy conditions, acute exposure to elevated free radicals, as occurs with exercise, induces the upregulation of endogenous antioxidant enzyme systems that are capable of combating the potential deleterious effect of heightened free radicals [66]. However, when the production of free radicals outweighs the system’s ability to neutralize these reactive molecules, oxidative stress ensues. Oxidative stress, a condition defined by a redox imbalance in which pro-oxidant forces outweigh antioxidant capacity, has been linked to damage and dysfunction associated with normal aging and the development of cardiovascular and metabolic disease [67, 68]. As will become evident throughout this review, the underlying level of oxidative stress is a critical factor that directly impacts the physiological role of free radicals in the context of blood flow regulation.

Free Radical Regulation of Vascular Function

The regulation of vascular tone and skeletal muscle blood flow are inherently linked. However, a complex, and often underappreciated, paradox exists whereby the control of conduit artery diameter and skeletal muscle blood flow may occur independently. This differential regulation of macro- (conduit) and micro-vascular (resistance arteries/arterioles and capillaries) tone may be due to distinct mechanisms contributing to the regulatory processes, made possible by the fact that modest changes in conduit vessel diameter do not regulate blood flow to the active skeletal muscle. This concept is supported by several studies reporting a vasoactive role of free radicals in the regulation of conduit artery diameter (specifically, the brachial artery), without a simultaneous change in skeletal muscle blood flow [69, 70]. Similarly, NOS inhibition can attenuate movement induced hyperemia in the leg without altering femoral artery diameter [71]. While a complete discussion of the many factors that contribute to the regulation of vascular function and blood flow is beyond the scope of this review, this background information is important as free radicals and oxidative stress impact both macro- and microvascular function. With these concepts establishing a conceptual framework, this section will focus on the regulation of vascular tone by free radicals during exercise with a specific emphasis on the in vivo assessment of conduit artery vasodilatory capacity. Ancillary studies utilizing isolated blood vessels to directly examine mechanisms of free radical regulation of vascular tone will also be discussed.

A series of investigations by our group revealed interesting, and somewhat unexpected, findings regarding the regulation of vasomotor tone during exercise in healthy individuals with low oxidative stress. Utilizing an oral antioxidant cocktail of Vitamins C, E, and alpha lipoic acid, our group [69, 70] reported impaired exercise-induced brachial artery vasodilation following treatment with the supplemental antioxidants (Figure 3A), that attenuated circulating free radicals during exercise [70]. Similarly, following 6-weeks of single leg knee extension exercise training which lowered oxidative stress in older adults, training-induced improvements in resting blood pressure and brachial artery vasodilation (Figure 3B), assessed by flow mediated dilation evoked by both post cuff occlusion hyperemia and during progressive handgrip exercise, were abolished with concomitant antioxidant consumption [69, 72]. Similar findings in isolated rat arterioles confirm a critical role of ROS in flow induced vasodilation [73]. Overall, these findings reveal that in the absence of disease and underlying oxidative stress, free radicals are critically involved in the regulation of vascular tone and act as pro-oxidant vasodilators.

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].

H₂O₂ and ONOO⁻, a non-radical species and a RNS, respectively, are two reactive species that have been identified as vasodilatory under certain conditions [43]. Following the generation of O₂⁻, this highly reactive molecule can react directly with NO to form ONOO⁻ or combine with O₂⁻ dismutase (SOD) resulting in molecular oxygen and H₂O₂ [74]. The rate of reaction for O₂⁻ with NO is two-fold greater than O₂⁻ with SOD, thus creating a biochemical competition between SOD and NO [75]. While the damaging potential of ONOO⁻ outweighs that of H₂O₂, both possess vasodilatory properties. Depending on the chemical environment, these free radicals can play a causative role in oxidative stress and associated damage, or, conversely, contribute to vasodilation. For instance, peroxy-based radicals induced a dose-dependent decrease in blood pressure in healthy rodents that was abolished following antioxidant treatment [76], but have also been linked to lipid peroxidation, platelet aggregation, mitochondrial DNA damage, and endothelial dysfunction [77]. Furthermore, under physiological conditions, H₂O₂ acts as a vasodilator [78] and regulator of eNOS levels during exercise training; however, under pathophysiological conditions with high oxidative stress, H₂O₂ evokes a contractile or vasoconstrictor response in the vascular smooth muscle [79].

Contrary to the pro-oxidant vasodilatory role of free radicals observed in healthy individuals, under conditions of underlying oxidative stress that typically accompany aging and disease, free radicals contribute to impaired vascular function, thus perpetuating sustained peripheral vasoconstriction. As previously discussed, exercise is associated with elevated free radical production. Importantly, when exercise is performed with a background of oxidative stress or when the exercise-induced increase in free radicals surpasses the systems natural antioxidant defense mechanisms, vasodilatory capacity may be impaired. In these circumstances, oxidative stress can enhance endothelin-1 activity [80, 81], potentiate angiotensin II-mediated vasoconstriction [82], augment sympathetically mediated vascular tone [83], suppress cyclooxygenase-2 mediated vasodilation [84], and attenuate NO bioavailability [85, 86].

Clearly, free radicals have the potential to impact peripheral resistance, and therefore blood flow, as both vasoconstrictor and vasodilator pathways are altered by these highly reactive molecules. In healthy older men, the aforementioned oral antioxidant cocktail reduced free radicals and concomitantly restored brachial artery vasodilation during progressive handgrip exercise and following ischemic cuff occlusion [69, 72]. Interestingly, following a 6-week exercise training regimen, the free radical-induced improvements in endothelial function were ameliorated, suggesting an upregulation of endogenous antioxidant defenses that were capable of improving the redox balance in these individuals. Improved endothelial dependent dilation following infusion or oral administration of high doses of Vitamin C alone or combined with other antioxidants have been reported in older individuals [87, 88] and patients with hypertension [89], COPD [90], CAD [91], and diabetes [92]. These improvements in endothelial function with exogenous antioxidants likely occur as a result of quenching free radicals, thereby minimizing their reaction with NO or by improving NOS coupling through tetrahydrobiopterin (BH4), a critical co-factor required for the chemical stabilization of NOS. Indeed, BH4 alone has been reported to improve endothelial function [93].

Based on the aforementioned studies it is clear that, under certain conditions, reducing oxidative stress with exogenous antioxidants improves redox balance and vascular function. However, large scale interventional studies often fail to report improvements in health related outcome measures following oral antioxidant consumption [94]. One reason for this dichotomy between well-controlled mechanistic studies and large interventional investigations may be rooted in the inability of large scale studies to adequately target the individually quite variable levels of oxidative stress with non-specific oral antioxidants. An alternative and relatively new approach to combat oxidative stress is to directly target mitochondria-derived ROS production [95–97]. Based on their chemical structure, mitochondria targeted antioxidants directly attenuate free radicals produced by mitochondria. Several animal studies report complete restoration of endothelial function following treatment with mitochondrial targeted antioxidants [58, 59]. While early findings are promising, additional research is required to determine if these mitochondria specific antioxidants exhibit any impact on measures of exercise-induced vascular function. Additionally, under conditions of minimal background oxidative stress, where endogenous antioxidants are capable of remediating the deleterious effect of free radicals, the impact of these mitochondria targeted antioxidants may prove detrimental.

In summary, free radicals are important regulators of vascular tone and under normal, healthy, conditions with low oxidative stress and redox balance and contribute to vasodilation during exercise and following tissue ischemia. However, when the redox balance is shifted in favor of oxidative stress, which typically occurs in aging and disease, free radicals are associated with impaired vascular function. Interestingly, likely due to augmented endogenous antioxidants, exercise training corrects derangements in vascular function caused by augmented oxidative stress. Moreover, when exogenous antioxidants are administered post aerobic exercise training, the exercise-induced improvements in vascular function, as measured by conduit artery vasodilation, are further negated, supporting a vasodilatory role of free radicals in conditions of low oxidative stress.

Free Radical Regulation of Skeletal Muscle Blood Flow

At a given blood pressure, blood flow to the active vascular bed is inversely related to the tone of the resistance vessels (arterioles) in the arterial tree, as described by Ohm’s law (Flow = Pressure /Resistance). As discussed in the previous section, it should be note that the resistance vessels of the microvasculature and not the larger conduit vessels dictate blood flow. According to Ohm’s law blood pressure is clearly a critical determinant of blood flow. However, blood pressure is dictated by relative exercise intensity [98]. Thus, when comparing a trained athlete and an untrained individual at the same relative exercise intensity, the higher blood flow of the well-trained athlete is primarily regulated by reductions in vascular resistance [98]. Moreover, in accordance with Poiseuille’s Law, changes in vessel diameter are magnified to the fourth power. Indeed, the ability of the resistance vasculature to vasodilate in response to the release of autocrine and paracrine factors (e.g. NO, prostaglandins, EDHF, and ATP) plays a critical role in regulating skeletal muscle blood flow, especially during exercise when sympathetic nervous system activity is augmented [99–101]. This section focuses on the role free radicals play in the regulation of skeletal muscle blood flow by the regulation of resistance vessel tone.

Mechanistic investigations examining the regulation of blood flow by free radicals have, generally, been constrained to small muscle mass exercise paradigms, typically handgrip, knee extension, or plantar flexion exercise. Unlike whole-body dynamic exercise, such as running and cycling, skeletal muscle perfusion during these small muscle mass exercises is not limited by central hemodynamics [20, 21]. Thus, high levels of skeletal muscle perfusion can be attained and a reductionist approach adopted to elucidate mechanisms contributing to the regulation of skeletal muscle blood flow. In young healthy individuals, the impact of free radicals on blood flow regulation during handgrip exercise appears to be minimal to non-existent. Several investigations by our group and others observed no change in forearm blood flow during dynamic handgrip exercise in healthy young adults following the inhibition of free radical accumulation/production with oral antioxidant administration [69, 70]. However, during dynamic handgrip exercise in hyperoxic conditions (100% oxygen) those individuals that exhibited the greatest hyperoxia-induced attenuation in forearm blood flow experienced a restoration of blood flow following Vitamin C infusion [102]. Additionally, following sustained isometric handgrip exercise, Vitamin C augmented post contraction hyperemia by 50% [103]. Of note, unlike the majority of the studies that report no impact of ROS on blood flow regulation in healthy young individuals, both of these studies induced a condition of elevated ROS production (hyperoxia and ischemia) that was subsequently ameliorated with Vitamin C. Compared to arm exercise, typically handgrip, which has been relatively well-studied, there is a paucity of information regarding free radical regulation of blood flow during leg exercise in healthy young individuals.

While the impact of free radicals on skeletal muscle blood flow appears to be minimal in healthy young individuals under conditions of normal redox balance, free radicals seem to be important in the control of hyperemia during dynamic small muscle mass exercise in populations exhibiting underlying evidence of oxidative stress. Specifically, during steady-state dynamic handgrip exercise in older individuals, Vitamin C infusion restored blood flow through an NO-dependent mechanism (Figure 4) [104, 105]. In a recent follow-up study, it was documented that the oral administration of Vitamin C similarly restored forearm blood flow in older individuals through local vasodilatory pathways and not a global sympatholytic effect of Vitamin C [106]. Interestingly, oxygen consumption was also improved following Vitamin C supplementation. Taken together, these findings provide convincing evidence that attenuating the level of free radicals augments blood flow in older individuals, a population associated with oxidative stress. The concomitant increases in blood flow and oxygen uptake may translate to improved exercise performance, ultimately leading to increased physical activity and improved peripheral vascular function.

(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].

In contrast to the aforementioned studies in the forearm, we recently reported no impact of oral antioxidants on leg blood flow or leg vascular conductance during isolated knee extension exercise in healthy older adults [107]. However, in age-matched patients with chronic obstructive pulmonary disease (COPD), the oral antioxidants did improve leg blood flow, leg vascular conductance, and leg oxygen consumption [107]. Interestingly, COPD is associated with elevated oxidative stress, above and beyond that reported for normal healthy aging, as evidenced by attenuated antioxidant capacity and elevated markers of inflammation, which were selectively improved by the antioxidants only in the patients with COPD. This suggests that the healthy age-matched controls may not have been exposed to chronic elevations in oxidative stress. In a separate series of studies conducted under basal conditions, Vitamin C infusion improved leg blood flow in older men and postmenopausal women [108, 109]. These changes in leg blood flow were correlated with oxidized low density lipoprotein, a marker of oxidative stress, providing further support for the concept that an elevated level of background oxidative stress may be required to observe improved skeletal muscle blood flow following antioxidant administration.

Overall, the contribution of free radicals to the regulation of skeletal muscle blood flow to the arms, and, although less well studied, to some extent the legs, appears to be minimal in healthy individuals under normal conditions. However, due to the paucity of research examining the role of free radicals in the regulation of leg blood flow in young healthy individuals, additional investigations are required to determine if free radicals critically contribute to the hyperemic and vasodilatory response of the leg in this population. In contrast, under conditions of elevated oxidative stress including aging and disease, free radicals are important in the control of blood flow during exercise in both the arms and the legs (Figure 5), as exogenous administration of antioxidants lessens free radical levels and restores skeletal muscle blood flow. Unfortunately, due to limited methodological approaches, a quantitative assessment of the necessary fall in free radicals to negatively impact cellular signaling in conditions of elevated oxidative stress is unavailable in the current literature.

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.

Free Radical Regulation of Coronary Blood Flow

During exercise, the increased demand for nutrient and oxygen rich blood throughout the body is fundamentally achieved by the augmented work of the heart, resulting in a 5 to 6 fold increase in cardiac output and myocardial metabolic demand during maximal aerobic exercise [98]. The myocardium relies almost exclusively on the aerobic oxidation of substrates to meet the energetic demands of contraction [110], which increases due to the rise in heart rate and stroke volume with exercise intensity [111]. Therefore, the regulation of blood flow through the coronary vasculature to the myocardium determines not only the performance of the heart, but also the entire body, as inadequate myocardial blood flow will detrimentally impact the ability of the heart to reach maximal pumping capacity which may occur with cardiovascular disease. Our understanding of how free radicals contribute to the regulation of coronary blood flow during exercise is severely limited. The lack of information on this topic stems from the difficulty in attaining such measures during exercise, especially in healthy humans. However, a recent investigation by Hays et al. [112] reported that coronary vasodilation during ischemic handgrip exercise in healthy humans is primarily NO-mediated (Figure 6). Although not directly examined in this study, factors that attenuate NO-bioavailability and alter redox balance, including free radicals, would be expected to impair coronary vasodilation, mimicking the attenuated vasodilation exhibited by patients with coronary artery disease during ischemic handgrip exercise. Despite this recent finding, there is still a lack of information regarding the regulation of the coronary vasculature during dynamic exercise in healthy populations. However, both in vivo and in vitro investigations in clinically relevant conditions provide evidence that free radicals are important regulators of coronary blood flow and vascular tone.

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].

Coronary blood flow and vascular tone can be assessed during cardiac catheterization using routine angiographic techniques or with sophisticated imaging methods. In individuals reporting atypical chest pain but no evidence of coronary artery disease, intracoronary infusion of reduced glutathione improved coronary endothelial function by suppressing acetylcholine (ACh)-induced vasoconstriction [113]. In a similar study, intracoronary Vitamin C infusion abolished ACh-induced vasoconstriction in spastic, but not control, coronary arteries [114]. Additionally, in smokers, Vitamin C administered either orally or by intracoronary infusion restored coronary microcirculatory function and coronary flow reserve, respectively [115, 116]. Finally, Vitamin C effectively abolished the reduction in coronary blood flow induced by elevated free radical production during hyperoxia (100% oxygen) in patients with ischemic heart disease [117]. Although there is a dearth of information regarding normal healthy hearts under normal redox balance conditions, taken together, the available in vivo assessments reveal an integral role of free radicals in the regulation of the coronary vasculature and the decrements in coronary endothelial function and coronary blood flow that accompany oxidative stress and disease.

Interestingly, in vitro several studies utilizing isolated human coronary resistance vessels report an important vasodilatory role of H₂O₂ in the microvasculature of the myocardium [118, 119]. Specifically, H₂O₂, derived from vascular endothelial mitochondrial respiration, evoked significant flow induced dilation in isolated coronary arteries [118]. Treatment of these arterioles with catalase to minimize H₂O₂ resulted in attenuated flow induced dilation. One caveat, however, of these studies [118, 119], is that the coronary vessels were obtained from patients with coronary artery disease; therefore, these findings may not be generalizable to the normal or healthy regulation of coronary function, as oxidative stress was likely elevated in these individuals.

In summary, both in vivo and in vitro investigations provide evidence of a regulatory role of free radicals in the coronary vasculature (Figure 5). Lowering free radical levels with oral or infused antioxidants appears to improve in vivo function of the coronary vessels when oxidative stress is present. A vasodilatory role of H₂O₂ has also been reported in isolated arteries obtained from patients with coronary artery disease; however, the role of free radicals in regulation of healthy human coronary vessels function is largely unknown and requires future research.

Free Radical Regulation of Skin Blood Flow

The vasodilatory capacity of the cutaneous circulation is second only to skeletal muscle. During whole body passive heating, it has been estimated that blood flow to the skin may reach between 7 and 8 L/min, a substantial portion of the total cardiac output [120]. During exercise, blood flow to the skin is increased in order to dissipate heat by sweating, as core temperature rises. During exercise in the heat, when core temperature is increased and the temperature gradient between the skin and core falls, the demand for skin blood flow places a tremendous burden on the cardiovascular system, which can significantly impact exercise performance [121].

The regulation of skin blood flow is unique as it is reflexively controlled by two branches of the sympathetic nervous system [122]. During the initial rise in core temperature, the onset of cutaneous vasodilation is mediated by withdrawal of adrenergic vasoconstriction and is further augmented by active vasodilation regulated by the sympathetic co-transmission of ACh and an unknown neurotransmitter [123, 124]. One benefit of the cutaneous circulation, from a research perspective, is that it is easily accessible, thus allowing for the simultaneous interrogation of multiple experimental sites. Combining pharmacological interventions with microdialysis and laser Doppler flowmetry, investigators have been able to perform well-controlled and mechanistic studies aimed at identifying the factors regulating skin blood flow.

Numerous vasodilator pathways are involved in the regulation of skin blood flow [readers are referred to several excellent reviews regarding this topic [33, 125, 126]]. Importantly, in young healthy individuals, up to 40% of the total vasodilatory response appears to be NO-dependent [127, 128]. Therefore, factors that attenuate NO bioavailability, including free radicals, are expected to negatively impact cutaneous vasodilation, and vice versa, factors that increase NO bioavailability are expected to increase skin blood flow. Unfortunately, the number of studies that have systematically investigated the role of free radicals during exercise is surprisingly low; therefore, much of our current understanding is based on whole body and local heating protocols, with only a few exceptions. Although not a direct assessment of free radicals on skin blood flow, exercise trained athletes, characterized by an elevated maximal oxygen consumption, exhibited increased antioxidant capacity as well as superior cutaneous microvascular function compared to sedentary individuals, as measured by stimulated peripheral skin blood flow [129]. While the capacity for augmented cutaneous vasodilation is present in well-trained athletes with elevated endogenous antioxidant levels, further increasing antioxidant capacity via exogenous supplementation may not result in additional improvements in skin blood flow during exercise. Indeed, following 7 days of polyphenol antioxidant supplementation, well-trained endurance athletes did not exhibit improved skin blood flow, thermoregulatory capacity, or exercise performance during prolonged exercise in the heat (Figure 7) [130]. Based on these findings, exercise training-induced increases in endogenous antioxidant capacity and associated increases in cutaneous microvascular function yield improved skin blood flow that is not further augmented with exogenous antioxidants. Furthermore, attenuating the normal increase in free radicals, specifically H₂O₂, may actually have a negative impact on skin blood flow. Indeed, during local heating, inhibition of H₂O₂ production, reduced a portion of the vasodilatory response, suggesting that free radicals, may in part, participate in the normal skin blood flow response [131, 132].

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].

The capacity for cutaneous vasodilation in aged and diseased individuals is markedly lower than healthy age-matched controls, and several studies indicate that elevated oxidative stress is an important factor in this attenuated response. Indeed, impaired cutaneous microvascular function leading to attenuated vasodilation has been linked to attenuated NO bioavailability associated with elevated ROS, as decreasing O₂⁻ through the local administration of tempol, a SOD mimetic, restored cutaneous vasodilation in young smokers and patients with chronic kidney disease [133]. Moreover, inhibition of NADPH oxidase (apocynin) restored cutaneous vasodilation in the chronic kidney disease patients, suggesting an important role of this free radical producing enzymatic complex in the production of O₂⁻ [134]. Additionally, acute Vitamin C supplementation, alone or in combination with arginase, improved reflex cutaneous vasodilation during whole body heating in both older [135] and hypertensive [136] individuals. The mechanisms underlying the Vitamin C induced improvements in cutaneous vasodilation may be due to a direct effect of quenching ROS or by improving eNOS coupling through the chemical stabilization of BH4, an essential cofactor for eNOS. Importantly, BH4 independently improves cutaneous vasodilation through an NO-dependent mechanism in older subjects [137] and those with hypercholesterolemia [138]. Therefore, elevations in NO bioavailability, accomplished through direct or indirect means, result in enhanced cutaneous vasodilation in conditions of elevated oxidative stress.

Despite its unique regulation, the cutaneous circulation appears to mimic other vascular beds in regards to the regulation of blood flow by role of free radicals (Figure 5). Specifically, under normal healthy conditions, attempts to augment skin blood flow with exogenous antioxidants have been unsuccessful and a vasodilatory role of free radicals, specifically H₂O₂, has been reported. However, under conditions of known oxidative stress including aging, kidney disease, hypertension, and smoking, antioxidant mediated-improvements in NO bioavailability augmented skin blood flow during whole body and local heating. The role of free radicals in the regulation of skin blood flow during exercise is currently unknown and certainly worthy of future investigation.

Free Radical Regulation of Cerebral Blood flow

Traditionally, cerebral blood flow was thought to remain relatively constant across a range of blood pressures (60 to 150 mmHg) and be unaffected by exercise [35, 139–141]. However, this concept has been challenged as exercise-induced increases in cerebral blood flow during moderate intensity (< 60% of maximal oxygen consumption) exercise have been reported [142–147]. During higher intensity exercise (> 60% of maximal oxygen consumption), cerebral blood flow returns towards baseline as exercise-induced hyperventilation reduces the partial pressure of CO₂ in the arterial blood, resulting in cerebral vasoconstriction and indicating a potential mismatch between neuronal metabolism and activity and cerebral blood flow [148–150]. Methodological limitations in conjunction with technological advances in cerebral imaging likely contribute to the equivocal findings regarding the regulation of cerebral blood flow during exercise. However, despite these limitations, clear and fundamental differences exist in regards to cerebral and skeletal muscle hyperemia during exercise, with the latter exhibiting a linear increase in blood flow with exercise intensity in order match to perfusion and oxygen demand. Although a complete discussion of the factors regulating cerebral blood flow is beyond the scope of this review and the reader is referred to several excellent reviews for additional information [35, 151, 152]. This section of this review will highlight the existing knowledge regarding the contribution of free radicals to cerebral blood flow regulation during exercise. Additionally, insight collected from non-exercise related investigations will be presented to advance our understanding of the regulation of the cerebral vasculature by free radicals.

Similar to skeletal muscle, augmented free radical outflow from the cerebral vasculature has been directly documented using EPR spectroscopy. Following prolonged (9-hour) exposure to hypoxia, elevated free radical outflow was observed, as measured in blood obtained from the internal jugular vein [153]. In a separate study, intense exercise, evoking a systemic increase in oxidative-nitrosative stress, was associated with impaired cerebral autoregulation (Figure 8) [154]. Dynamic cerebral autoregulation refers to the inherent ability of cerebral blood vessels to maintain blood flow in response to rapid changes in arterial blood pressure via rapid counter-regulatory changes in the vascular resistance of cerebral arteries [155, 156]. Taken together, these studies, performed in healthy young physically active individuals, provide evidence that the free radical output across the cerebral vasculature is increased during exercise and that free radicals may, therefore, contribute to the regulation of cerebral blood flow.

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].

Although not specific to exercise, free radicals, at low concentrations, appear to have a vasodilatory role in the cerebral vasculature and act as important mediators and modulators of cell signaling [157]. Specifically, at low concentrations, O₂⁻, H₂O₂, and ONOO⁻ have vasodilatory properties [158–164], however, at high concentrations, these free radicals contribute to the oxidative stress that underlies cerebral vascular disease and injury [158, 165, 166].

Under conditions of redox imbalance supporting evidence for an inhibitory role of free radicals in the regulation of cerebral blood flow has been obtained from the assessment of cerebral autoregulation in humans and the direct evaluation of cerebral artery function in animal models of cerebrovascular dysfunction. During handgrip exercise, Type 2 Diabetics experienced impaired dynamic cerebral autoregulation that was correlated to markers of oxidative stress (Figure 9) [167]. Interestingly, this impaired cerebral autoregulation was only present during exercise and may confer an elevated risk of an adverse cerebral event in these patients, especially when coupled with exaggerated sympathetically mediated vasoconstriction and impaired vasodilator capacity during exercise. In young African Americans, a population characterized by increased incidence of cardiovascular disease, acute flavonal antioxidant consumption augmented the cerebral vasodilatory response following a hypercapnic stimulus [168]. The mechanisms contributing to this improved response were not directly assessed. However, the authors speculated that a reduction in NADPH oxidase activity leading to lower O₂⁻ production may have contributed to the improvement. Utilizing obese Zucker rats, cerebrovascular dysfunction has been linked to oxidative stress, as pretreatment with SOD restored all dilator responses assessed in the basilar artery [169]. Additionally, reducing angiotensin-II mediated oxidative stress in older mice with treatment of angiotensin-converting enzyme 2 (ACE2) restored vasodilatory capacity [170].

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].

In summary, exercise is associated with elevated free radical outflow from the cerebral vasculature. The direct impact of this exercise-induced increase in free radicals on cerebral blood flow regulation is largely unknown, but has been linked to impaired cerebral autoregulation following exhaustive exercise. In contrast, under basal conditions, low levels of free radicals are associated with vasodilation; however, under conditions of oxidative stress, free radicals evoke cerebrovascular dysfunction as measured by impaired cerebral autoregulation in humans and cerebral vascular dysfunction in animals that can be restored with antioxidant interventions (Figure 5).

Summary

Adequate delivery of blood flow to the active skeletal muscle, heart, skin, and brain is of critical importance during exercise, as minor alterations in oxygen and nutrient delivery can accelerate the development of fatigue and impair exercise performance. Importantly, free radicals possess vasoactive properties that contribute to the regulation of blood flow to these organs. The magnitude of this regulatory potential is highly dependent on the underlying redox state. In normal, healthy, conditions of low oxidative stress, when endogenous antioxidant defenses are capable of appropriately combating the exercise-induced increase in free radicals thus avoiding excessive oxidation and maintaining redox balance, free radicals promote optimal vasodilation and hyperemia. Interestingly, efforts to further attenuate free radical production or accumulation with exogenous antioxidants in normal, healthy conditions shifts the redox balance to a reduced state and negatively impacts vasodilatory capacity. Importantly, in contrast, when the redox balance is disturbed in favor of oxidative stress, as typically occurs with aging and disease, the exercise-induced elevation in free radicals impairs blood flow and vasodilatory capacity. Therefore, attempts to mitigate the negative impact of free radicals in older and diseased individuals through antioxidants typically improve vasodilation and blood flow during exercise. Figure 10 depicts our working hypothesis regarding the impact of alterations in redox balance and free radical regulation of blood flow during exercise. Based on the accumulated evidence, this working hypothesis appears to be remarkably preserved across skeletal muscle, heart, skin and brain (Figure 5). Overall, free radicals have important hemodynamic regulatory potential that extends to several vascular beds during exercise and, importantly, it is the underlying redox state that appears to dictate the vascular impact of these highly reactive molecules.

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].

Highlights.

Free radicals regulate skeletal, coronary, skin, and cerebral blood flow
Exercise-induced increases in free radicals can promote or impair blood flow
Underlying redox balance determines the vasoactive response of free radicals
Evidence linking free radicals, redox balance, and blood flow is reviewed

Acknowledgments

Funding: This work was supported by the National Institutes of Health (PO1 HL-091830, R01 HL118313), the United States Veterans Administration (RR&D E6910-R, E1433-P, E1697-R, E9275-L), and the American Heart Association (0835209N, 1850039).

Footnotes

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PERMALINK

Regulation of Exercise Blood Flow: Role of Free Radicals

Joel D Trinity

Ryan M Broxterman

Russell S Richardson

Abstract

Introduction

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

Sources of free radicals

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.

Free Radical Regulation of Vascular Function

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).

Free Radical Regulation of Skeletal Muscle Blood Flow

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

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.

Free Radical Regulation of Coronary Blood Flow

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.

Free Radical Regulation of Skin Blood Flow

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

Free Radical Regulation of Cerebral Blood flow

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

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.

Summary

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

Highlights.

Acknowledgments

Footnotes

References

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PERMALINK

Regulation of Exercise Blood Flow: Role of Free Radicals

Joel D Trinity

Ryan M Broxterman

Russell S Richardson

Abstract

Introduction

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

Sources of free radicals

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.

Free Radical Regulation of Vascular Function

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).

Free Radical Regulation of Skeletal Muscle Blood Flow

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

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.

Free Radical Regulation of Coronary Blood Flow

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.

Free Radical Regulation of Skin Blood Flow

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

Free Radical Regulation of Cerebral Blood flow

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

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.

Summary

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

Highlights.

Acknowledgments

Footnotes

References

ACTIONS

PERMALINK

RESOURCES

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Cited by other articles

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