Exercise Hyperemia Research Articles

Regulation of coronary resistance vessel tone in response to exercise

Exercise is a primary stimulus for increased myocardial oxygen demand. The ~6-fold increase in oxygen demand of the left ventricle during heavy exercise is met principally by augmenting coronary blood flow (~5-fold), as hemoglobin concentration and oxygen extraction (which is already ~70% at rest) increase only modestly in most species. As a result, coronary blood flow is tightly coupled to myocardial oxygen consumption over a wide range of physical activity. This tight coupling has been proposed to depend on periarteriolar oxygen tension, signals released from cardiomyocytes and the endothelium as well as neurohumoral influences, but the contribution of each of these regulatory pathways, and their interactions, to exercise hyperemia in the heart remain incompletely understood. In humans, nitric oxide, adenosine and K(ATP) channels each appear to contribute to resting coronary resistance vessel tone, but evidence for a critical contribution to exercise hyperemia is lacking. In dogs K(ATP)-channel activation together with adenosine and nitric oxide contribute to exercise hyperemia in a non-linear redundant fashion. In contrast, in swine nitric oxide, adenosine and K(ATP) channels contribute to resting coronary resistance vessel tone control in a linear additive manner, but do not appear to be mandatory for exercise hyperemia. Rather, exercise hyperemia in swine appears to involve β-adrenergic activation in conjunction with exercise-induced blunting of an endothelin-mediated vasoconstrictor influence. In view of these remarkable species differences in coronary vasomotor control during exercise, future studies are required to determine the system of vasodilator components that mediate exercise hyperemia in humans. This article is part of a Special Issue entitled "Coronary Blood Flow".

Ischemic exercise hyperemia in the human forearm: reproducibility and roles of adenosine and nitric oxide

The roles of local metabolites in reactive and exercise hyperemia remain incompletely understood. A maximum metabolic stimulus caused by ischemic exercise (IE) could potentially fully activate all vasodilator pathways and limit potential redundancy amongst vasoactive substances. We tested the hypotheses that IE elicits a reproducible hyperemic response in the forearm and that adenosine (ADO) and nitric oxide (NO) contribute to this response. In separate protocols, forearm blood flow (FBF) was measured with venous occlusion plethysmography following IE trials consisting of 5 min of ischemia and rhythmic forearm handgrip exercise (performed during last 2 min of ischemia). In protocol 1 (n = 8), FBF was measured after three trials of IE. In protocol 2 (n = 9), subjects performed IE during control (saline), aminophylline (APH; adenosine receptor antagonist), and combined APH/N (G)-monomethyl-L-arginine (L-NMMA; NOS inhibition) infusions. In protocol 1, coefficients of variation for total (area under the curve) ΔFBF and ΔFVC (forearm vascular conductance) following IE were 10.4 ± 1.0% and 14.9 ± 1.0%, respectively. In protocol 2, peak ΔFBF was similar for saline and APH trials. Peak ΔFBF for the APH+L: -NMMA trial was greater than that of the APH trial (P = 0.03), and peak ΔFVC was marginally non-significant (P = 0.053). Total ΔFBF (54.8 ± 3.9, 55.2 ± 5.4, and 60.4 ± 4.8 ml 100 ml(-1); P = 0.43) and ΔFVC (51.4 ± 3.5, 52.1 ± 5.5, and 56.5 ± 5.0 ml 100 ml(-1) 100 mmHg(-1); P = 0.52) were similar for saline, APH, and APH+L: -NMMA, respectively. Our data suggest that (1) the hyperemic response to IE is reproducible and (2) inhibition of ADO alone or combined ADO and NO does not blunt the hyperemic response following IE.

Does venous insufficiency impair the exercise-induced rise in arterial leg blood flow?

It has been shown that the leg muscle pump increases the immediate rise in arterial leg blood flow during upright exercise in healthy subjects. The present study is the first to investigate the muscle pump effect in exercise hyperaemia in patients with venous insufficiency, who should be lacking an optimally functioning muscle pump. Any muscle pump effect is more pronounced in an upright position because of gravitation. The exercise-induced rise in femoral artery flow (FF) (ultrasound Doppler) was thus compared in the supine and 30° head-up tilted position in 10 patients. Neither the transient nor the steady-state rise in FF showed any difference between positions. This is in contrast to the previous findings in healthy subjects, where the transient rise in FF was larger in the tilted position. The muscle pump effect in exercise hyperaemia seems to be reduced or lacking in these patients.

Peripheral microvascular response to muscle contraction is unaltered by early diabetes but decreases with age

Long-term or untreated diabetes leads to micro- and macrovascular complications. However, there are few tests to evaluate microvascular function. A postcontraction blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) technique was exploited to measure peripheral microvascular function in diabetics and healthy controls matched with respect to age, body mass index, and physical activity. Postcontraction BOLD microvascular response was measured following 1-s maximal isometric ankle dorsiflexion in individuals with diabetes mellitus type I [DMI, n = 15, age 33 ± 3 yr (means ± SE), median diabetes duration = 5.5 yr] and type II (DMII, n = 16, age 45 ± 2 yr, median duration = 2.4 yr); responses were compared with controls (CONI and CONII). Peripheral macrovascular function of the popliteal and tibial arteries was assessed during exercise hyperemia with phase contrast magnetic resonance angiography following repetitive exercise. There were no group differences as a result of diabetes in peripheral microvascular function (peak BOLD response: DMI = 2.04 ± 0.38% vs. CONI = 2.08 ± 0.48%; DMII = 0.93 ± 0.24% vs. CONII = 1.13 ± 0.24%; mean ± SE), but the BOLD response was significantly influenced by age (partial r = -0.384, P = 0.003), supporting its sensitivity as a measure of microvascular function. Eleven individuals had no microvascular BOLD response, including three diabetics with neuropathy and four controls with a family history of diabetes. There were no differences in peripheral macrovascular function between groups when assessing exercise hyperemia or the pulsitility and resistive indexes. Although the BOLD microvascular response was not impaired in early diabetes, these results encourage further investigation of muscle BOLD as it relates to peripheral microvascular health.

Augmented skeletal muscle hyperaemia during hypoxic exercise in humans is blunted by combined inhibition of nitric oxide and vasodilating prostaglandins

Exercise hyperaemia in hypoxia is augmented relative to the same level of exercise in normoxia. At moderate exercise intensities, the mechanism(s) underlying this augmented response are currently unclear. We tested the hypothesis that endothelium-derived nitric oxide (NO) and vasodilating prostaglandins (PGs) contribute to the augmented muscle blood flow during hypoxic exercise relative to normoxia. In 10 young healthy adults, we measured forearm blood flow (FBF; Doppler ultrasound) and calculated the vascular conductance (FVC) responses during 5 min of rhythmic handgrip exercise at 20% maximal voluntary contraction in normoxia (NormEx) and isocapnic hypoxia (HypEx; O2 saturation ∼85%) before and after local intra-brachial combined blockade of NO synthase (NOS; via N(G)-monomethyl-L-arginine: L-NMMA) and cyclooxygenase (COX; via ketorolac). All trials were performed during local α- and β-adrenoceptor blockade to eliminate sympathoadrenal influences on vascular tone and thus isolate local vasodilatation. Arterial and deep venous blood gases were measured and oxygen consumption (VO2) was calculated. In control (saline) conditions, FBF after 5 min of exercise in hypoxia was greater than in normoxia (345 ± 21 ml min(−1) vs. 297 ± 18 ml min(−1); P < 0.05). After NO–PG block, the compensatory increase in FBF during hypoxic exercise was blunted ∼50% and thus was reduced compared with control hypoxic exercise (312 ± 19 ml min(−1); P < 0.05), but this was not the case in normoxia (289 ± 15 ml min(−1); P = 0.33). The lower FBF during hypoxic exercise was associated with a compensatory increase in O2 extraction, and thus VO2 was maintained at normal control levels (P = 0.64–0.99). We conclude that under the experimental conditions employed, NO and PGs have little role in normoxic exercise hyperaemia whereas combined NO–PG inhibition reduces hypoxic exercise hyperaemia and abolishes hypoxic vasodilatation at rest. Additionally, VO2 of the tissue was maintained in hypoxic conditions at rest and during exercise, despite attenuated oxygen delivery following NO–PG blockade, due to an increase in O2 extraction at the level of the muscle.

Exercise Hyperemia and Acute Ascorbic Acid Infusion in Obesity and Metabolic Syndrome

Exercise hyperemia in obesity and metabolic syndrome (MetS) may be influenced by reactive oxygen species (ROS). We tested the hypothesis that Ascorbic Acid (AA) would increase skeletal muscle blood flow from steady-state exercise (SSE) levels in 11 obese adults (35±4 yrs, BMI 37±2 kg.m−2) and 12 adults with MetS (35±3 yrs, BMI 39±2 kg.m−2). An arterial catheter was inserted for continuous blood pressure monitoring and acute administration of AA. We measured forearm blood flow (FBF, Doppler Ultrasound of brachial artery) during 15 minutes of dynamic handgrip exercise (20 contractions.min−1 at 15% of maximal effort). AA was infused during the last 10 minutes of SSE. To account for differences in blood pressure (BP), forearm vascular conductance (FVC = FBF.BP−1) was assessed. Data are presented as Mean±SEM. Steady-state FVC was similar between groups (Obese 326±34, MetS 328±34 mL.min−1.100mmHg−1, p=0.49). Both groups increased plasma total antioxidant capacity with AA infusion (p=0.02). Acute AA administration significantly increased FVC from SSE levels in obese adults (16±4%, p<0.01) but changes were not statistically significant in MetS (12±7%, p=0.07). These results suggest ROS may limit exercise hyperemia in obese adults; an effect of AA was not detected in MetS. Support: NIH HL091397 (WGS), AHA 0815622G (JKL).

Integrated control of coronary blood flow in exercising swine by adenosine, nitric oxide and KATP channels

The mechanism of exercise‐induced coronary vasodilation remains incompletely understood. KATP channels in conjunction with nitric oxide (NO) and adenosine have been proposed to mediate exercise hyperemia in dogs but not in swine. Different results may have been due, in part, to different routes of administration of drugs to block these pathways. Hence, we studied the role of KATP channels together with NO and adenosine in exercise hyperemia in swine, using an identical drug dosing protocol and administration route that was previously shown to virtually abolish the exercise hyperemia in dogs. Swine exercised on a treadmill at 0–5 km/h, before and after blockade of KATP channels (glibenclamide, 50 μg/kg/min intracoronary (ic)), in the absence or presence of blockade of adenosine receptors (8‐phenyltheophylline, 8PT, 5 mg/kg iv) and NO‐synthase (nitro‐L‐arginine, NLA, 1.5 mg/kg, ic). Glibenclamide reduced myocardial O2 delivery and coronary venous O2 tension at rest and during exercise. Administration of 8PT + NLA reduced coronary venous O2 tension but did not enhance vasoconstriction to glibenclamide. Despite an increase in O2‐extraction to ~90% during combined NLA + 8PT + glibenclamide, exercise‐induced hyperemia was maintained. Thus, KATP channels, adenosine and NO do not appear to be critical for exercise coronary hyperemia, and act in a linear additive fashion, in swine.Supported by NHF Grant 2000T042

Combined inhibition of nitric oxide and vasodilating prostaglandins abolishes forearm vasodilatation to systemic hypoxia in healthy humans

We tested the hypothesis that nitric oxide (NO) and vasodilating prostaglandins (PGs) contribute independently to hypoxic vasodilatation, and that combined inhibition would reveal a synergistic role for these two pathways in the regulation of peripheral vascular tone. In 20 healthy adults, we measured forearm blood flow (Doppler ultrasound) and calculated forearm vascular conductance (FVC) responses to steady-state (SS) isocapnic hypoxia (O₂ saturation ~85%). All trials were performed during local α- and β-adrenoceptor blockade (via a brachial artery catheter) to eliminate sympathoadrenal influences on vascular tone and thus isolate local vasodilatory mechanisms. The individual and combined effects of NO synthase (NOS) and cyclooxygenase (COX) inhibition were determined by quantifying the vasodilatation from rest to SS hypoxia, as well as by quantifying how each inhibitor reduced vascular tone during hypoxia. Three hypoxia trials were performed in each subject. In group 1 (n = 10), trial 1, 5 min of SS hypoxia increased FVC from baseline (21 ± 3%; P < 0.05). Infusion of N(G)-nitro-L-arginine methyl ester (L-NAME) for 5 min to inhibit NOS during continuous SS hypoxia reduced FVC by -33 ± 3% (P < 0.05). In Trial 2 with continuous NOS inhibition, the increase in FVC from baseline to SS hypoxia was similar to control conditions (20 ± 3%), and infusion of ketorolac for 5 min to inhibit COX during continuous SS hypoxia reduced FVC by -15 ± 3% (P < 0.05). In Trial 3 with combined NOS and COX inhibition, the increase in FVC from baseline to SS hypoxia was abolished (~3%; NS vs. zero). In group 2 (n = 10), the order of NOS and COX inhibition was reversed. In trial 1, five minutes of SS hypoxia increased FVC from baseline (by 24 ± 5%; P < 0.05), and infusion of ketorolac during SS hypoxia had minimal impact on FVC (-4 ± 3%; NS). In Trial 2 with continuous COX inhibition, the increase in FVC from baseline to SS hypoxia was similar to control conditions (27 ± 4%), and infusion of L-NAME during continuous SS hypoxia reduced FVC by -36 ± 7% (P < 0.05). In Trial 3 with combined NOS and COX inhibition, the increase in FVC from baseline to SS hypoxia was abolished (~3%; NS vs. zero). Our collective findings indicate that (1) neither NO nor PGs are obligatory to observe the normal local vasodilatory response from rest to SS hypoxia; (2) NO regulates vascular tone during hypoxia independent of the COX pathway, whereas PGs only regulate vascular tone during hypoxia when NOS is inhibited; and (3) combined inhibition of NO and PGs abolishes local hypoxic vasodilatation (from rest to SS hypoxia) in the forearm circulation of healthy humans during systemic hypoxia.

Role of reactive oxygen species on blood pressure and exercise hyperemia in aging humans: effect of lifelong physical activity

This study examined whether reduced nitric oxide (NO) bioavailability, caused by formation of reactive oxygen species (ROS), is less in well-trained than in un-trained elderly individuals. We measured hemodynamics at rest and during one-leg knee-extensor exercise (12 W and 45 % of Wmax) in lifelong sedentary (SED; 63±4 years; Wmax of 45±4 W) and lifelong physically active (AC; 64±3 years; Wmax of 76±11 W) male subjects without (CON) or with infusion of the antioxidant N-acetylcysteine (NAC; 125mg kg-1 h-1 for 15 min followed by 25mg kg-1 h-1 until the termination of exercise) in order to scavenge ROS. During CON there was no difference in leg blood flow (LBF) at 12 W between SED and AC (1.72±0.08 and 1.64±0.06 l min-1, respectively) and infusion of NAC did not change LBF in either group. Mean arterial pressure (MAP) at rest and during exercise at 12 W was lower (P<0.05) in both AC and SED during NAC infusion, whereas MAP also decreased (P<0.05) during 45 % of Wmax in AC. Infusion of NAC increased (P<0.05) leg vascular conductance at 12 W in AC. These results indicate that an elevated formation of ROS affects the bioavailability of NO leading to elevations in blood pressure in both lifelong sedentary and physically active individuals. Moreover, physical activity appears to augment the vasodilator potency of NO during low intensity muscle contraction.

Hyperbaric hyperoxia reduces exercising forearm blood flow in humans

Hypoxia during exercise augments blood flow in active muscles to maintain the delivery of O(2) at normoxic levels. However, the impact of hyperoxia on skeletal muscle blood flow during exercise is not completely understood. Therefore, we tested the hypothesis that the hyperemic response to forearm exercise during hyperbaric hyperoxia would be blunted compared with exercise during normoxia. Seven subjects (6 men/1 woman; 25 ± 1 yr) performed forearm exercise (20% of maximum) under normoxic and hyperoxic conditions. Forearm blood flow (FBF; in ml/min) was measured using Doppler ultrasound. Forearm vascular conductance (FVC; in ml·min(-1)·100 mmHg(-1)) was calculated from FBF and blood pressure (in mmHg; brachial arterial catheter). Studies were performed in a hyperbaric chamber with the subjects supine at 1 atmospheres absolute (ATA) (sea level) while breathing normoxic gas [21% O(2), 1 ATA; inspired Po(2) (Pi(O(2))) ≈ 150 mmHg] and at 2.82 ATA while breathing hyperbaric normoxic (7.4% O(2), 2.82 ATA, Pi(O(2)) ≈ 150 mmHg) and hyperoxic (100% O(2), 2.82 ATA, Pi(O(2)) ≈ 2,100 mmHg) gas. Resting FBF and FVC were less during hyperbaric hyperoxia compared with hyperbaric normoxia (P < 0.05). The change in FBF and FVC (Δ from rest) during exercise under normoxia (204 ± 29 ml/min and 229 ± 37 ml·min(-1)·100 mmHg(-1), respectively) and hyperbaric normoxia (203 ± 28 ml/min and 217 ± 35 ml·min(-1)·100 mmHg(-1), respectively) did not differ (P = 0.66-0.99). However, the ΔFBF (166 ± 21 ml/min) and ΔFVC (163 ± 23 ml·min(-1)·100 mmHg(-1)) during hyperbaric hyperoxia were substantially attenuated compared with other conditions (P < 0.01). Our data suggest that exercise hyperemia in skeletal muscle is highly dependent on oxygen availability during hyperoxia.

Protection against skeletal muscle hypoperfusion by adenosine and nitric oxide: together alone?

regulation of vasomotor tone in the microcirculation is essential to ensure adequate tissue oxygenation, particularly when oxygen demand is high, i.e., in skeletal or cardiac muscle during exercise and/or when supply is compromised, i.e., during hypoxia or in the presence of a flow-limiting stenosis

Age-induced endothelial dysfunction: is it time to redefine the “reactivity” of reactive oxygen species?

endothelium-dependent signaling through nitric oxide (NO) is a critical contributor to exercise hyperemia in skeletal muscle. The results of numerous studies indicate that age impairs NO-dependent vasodilation in skeletal muscle ([5][1], [8][2], [9][3], [13][4], [14][5]). The bioavailability of NO

Exercise training increases inwardly rectifying K+ current and augments K+-mediated vasodilatation in deep femoral artery of rats

A moderate increase in extracellular [K(+)] ([K(+)](e)) induces relaxation of small arteries by activating inwardly rectifying K(+) current (I(Kir)). The K(+)-induced vasodilatation is an important mechanism for exercise-induced hyperaemia in skeletal muscle. We investigated whether I(Kir) and K(+)-induced vasodilatation are enhanced in deep femoral arteries (DFAs) from exercise-trained rats (ET rats; treadmill running for 20 min at 20 m/min, 3 days/week for 2 weeks). The effects of exercise training on K(+)-induced vasodilatation and I(Kir) were also investigated in cerebral (CA) and mesenteric arteries. The K(+)-induced vasodilatation of DFAs and the density of I(Kir) and voltage-gated K(+) current (I(Kv)) were increased in DFA myocytes of ET rats. The myogenic tone of the DFA was unchanged by exercise. Although similar functional up-regulations of I(Kir) and I(Kv) were observed in CA myocytes, the K(+)-induced vasodilatation was not increased in the CA of ET rats. Interestingly, concomitant to the increases in I(Kir) and I(Kv), background Na(+) conductance was also increased in the CA myocytes. However, such an effect was not observed in DFA myocytes from ET rats. Neither I(Kir) nor K(+)-induced vasodilatation was observed in mesenteric arteries of ET rats. The present study provides evidence that regular exercise up-regulates I(Kir) in DFA and CA myocytes. Although the increase in I(Kir) was observed in two types of arteries, augmentation of K(+)-induced relaxation was observed only in the DFA of ET rats, possibly due to the increased Na(+) conductance in CA myocytes. The increases in I(Kir) and K(+)-induced vasodilatation of the arteries of skeletal muscle suggest novel mechanisms of improved exercise hyperaemia with physical training.

Hemodynamic responses to heat stress in the resting and exercising human leg: insight into the effect of temperature on skeletal muscle blood flow.

Heat stress increases limb blood flow and cardiac output (Q) in humans, presumably in sole response to an augmented thermoregulatory demand of the skin circulation. Here we tested the hypothesis that local hyperthermia also increases skeletal muscle blood flow at rest and during exercise. Hemodynamics, blood and tissue oxygenation, and muscle, skin, and core temperatures were measured at rest and during exercise in 11 males across four conditions of progressive whole body heat stress and at rest during isolated leg heat stress. During whole body heat stress, leg blood flow (LBF), Q, and leg (LVC) and systemic vascular conductance increased gradually with elevations in muscle temperature both at rest and during exercise (r(2) = 0.86-0.99; P < 0.05). Enhanced LBF and LVC were accompanied by reductions in leg arteriovenous oxygen (a-vO(2)) difference and increases in deep femoral venous O(2) content and quadriceps tissue oxygenation, reflecting elevations in muscle and skin perfusion. The increase in LVC occurred despite an augmented plasma norepinephrine (P < 0.05) and was associated with elevations in muscle temperature (r(2) = 0.85; P = 0.001) and arterial plasma ATP (r(2) = 0.87; P < 0.001). Isolated leg heat stress accounted for one-half of the increase in LBF with severe whole body heat stress. Our findings suggest that local hyperthermia also induces vasodilatation of the skeletal muscle microvasculature, thereby contributing to heat stress and exercise hyperemia. The increased limb muscle vasodilatation in these conditions of elevated muscle sympathetic vasoconstrictor activity is closely related to the rise in arterial plasma ATP and local tissue temperature.

Nitric oxide, but not vasodilating prostaglandins, contributes to the improvement of exercise hyperemia via ascorbic acid in healthy older adults

Acute ascorbic acid (AA) administration increases muscle blood flow during dynamic exercise in older adults, and this is associated with improved endothelium-dependent vasodilation. We directly tested the hypothesis that increase in muscle blood flow during AA administration is mediated via endothelium-derived vasodilators nitric oxide (NO) and prostaglandins (PGs). In 14 healthy older adults (64 ± 3 yr), we measured forearm blood flow (FBF; Doppler ultrasound) during rhythmic handgrip exercise at 10% maximum voluntary contraction. After 5-min steady-state exercise with saline, AA was infused via brachial artery catheter for 10 min during continued exercise, and this increased FBF ∼25% from 132 ± 16 to 165 ± 20 ml/min (P < 0.05). AA was infused for the remainder of the study. Next, subjects performed a 15-min exercise bout in which AA + saline was infused for 5 min, followed by 5 min of the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-l-arginine (l-NMMA) and then 5 min of the cyclooxygenase inhibitor ketorolac (group 1). The order of inhibition was reversed in eight subjects (group 2). In group 1, independent NOS inhibition reduced steady-state FBF by ∼20% (P < 0.05), and subsequent PG inhibition had no impact on FBF (Δ 3 ± 5%). Similarly, in group 2, independent PG inhibition had little effect on FBF (Δ -4 ± 4%), whereas subsequent NO inhibition significantly decreased FBF by ∼20% (P < 0.05). In a subgroup of five subjects, we inhibited NO and PG synthesis before AA administration. In these subjects, there was a minimal nonsignificant improvement in FBF with AA infusion (Δ 7 ± 3%; P = nonsignificant vs. zero). Together, our data indicate that the increase in muscle blood flow during dynamic exercise with acute AA administration in older adults is mediated primarily via an increase in the bioavailability of NO derived from the NOS pathway.

Hocus pocus hypoxia – NO and augmented vasodilatation in the systemic vasculature during hypoxic exercise

Evidence clearly points to an enhanced vasodilatation in systemic vessels during hypoxic exercise that serves to defend oxygen delivery to active musculature in the face of a reduced inspired fraction of O2 (Wilkins et al. 2008). Exercise-induced hyperaemia is a complex process with redundant mechanisms that can be called upon when required. During hypoxic exercise there is an additional dilator response in human skeletal muscle attributable to the reduction in arterial oxygen content rather than arterial O2 tension per se. Importantly, prevailing vascular tone results from both neural and metabolic factors acting on the vascular smooth muscle and endothelium. At the vascular endothelium adrenergic and non-adrenergic vasoactive pathways play a regulatory role in normal vascular function. The overall effect on haemodynamics and arterial pressure will be determined by how these various pathways and mechanisms integrate at the level of the vascular smooth muscle cell. Over recent years various research groups, including ours (Bailey et al. 2009), have combined a number of invasive experimental protocols across isolated vascular beds in conjunction with pharmacological blockade of vasoactive metabolite receptors or the actual metabolite itself to elucidate any potential contribution to exercise and/or hypoxic vasodilatation. One of the most intensely studied candidates for both exercise hyperaemia and hypoxic vasodilatation is nitric oxide (NO•). Increases in blood flow, cyclic wall stress due to pulsatile blood flow and catecholamines produce an up-regulation and release of NO• from the vascular endothelium (Busse & Fleming, 2006) via the enzyme endothelial nitric oxide synthase (eNOS). Hypoxia has been associated with additional sources of NO• release from deoxyhaemoglobin, β-adrenergic and adensosine receptor stimulation (Stamler et al. 1997; Bryan & Marshall, 1999; Wilkins et al. 2008). The NO• released toward the vascular lumen is a powerful vasodilator responsible for mediating basal vascular tone (Stamler et al. 1997). However, not all vascular beds respond in a similar manner with the pulmonary vasculature demonstrating a strong hypoxia-induced vasoconstriction whereas the cerebral vasculature responds in a similar fashion to the systemic vessels with a vasodilatation (Bailey et al. 2009). Metabolism of NO• within the vasculature to the more biochemically stable moiety nitrite serves as a means to determine circulating bioavailability of NO•. It appears that whilst this metabolic pathway of NO• was initially considered unidirectional, exogenous nitrite can induce sustained vasodilatation especially when the local vascular environment is hypoxic or ischaemic (Maher et al. 2008). It is within this environment that deoxygenated haemoglobin appears to convert nitrite to NO• (Stamler et al. 1997). Our laboratory, in collaboration with others, recently reported a reduced pulmonary vasoconstriction with systemic infusion of sodium nitrite (Ingram et al. 2010) while others have also reported augmented systemic arterial hypoxic vasodilatation with the same agent (Maher et al. 2008). Thus, with this background it is evident that during hypoxic exercise there is a compensatory vasodilatation that is sustained during increased exercise intensity and a clear contender for mediating the response is NO• either from enhanced endothelial release and/or circulating deoxyhaemoglobin. Casey et al. (2010), in a recent article in the The Journal of Physiology, sought to address this issue by examining the effects of hypoxic forearm exercise whilst simultaneously infusing the NOS inhibitor NG-monomethyl-l-arginine (l-NMMA) to investigate the influence of endothelial-derived NO•. In a parallel branch of the investigation, the authors also attempted to glean further information regarding hypoxic-induced NO• release via adenosine receptor stimulation by exogenous administration of combined l-NMMA and aminophylline, an adenosine receptor antagonist (Casey et al. 2010). Efficacy of eNOS blockade was established via intra-arterial acetylcholine infusion. Casey and colleagues (2010) utilised the isolated forearm exercise model with 22 healthy young adults. Subjects performed rhythmic forearm exercise in the non-dominant arm at 10% and 20% of individual maximal voluntary contraction. Twelve subjects completed protocol 1 (saline or l-NMMA infusion) and ten subjects completed protocol 2 (saline or l-NMMA–aminophylline infusion). Due to the long half-life of l-NMMA, study drugs were administered in the same order. Exercise was performed in normoxia and normocapnic hypoxia. Hypoxic inspiration rendered systemic arterial O2 saturations at ∼80%. Arterial pressure responses were monitored with an indwelling pressure transducer in the brachial artery whilst forearm blood flow was determined in the brachial artery via ultrasound. Forearm vascular conductance was calculated by the quotient of forearm blood flow and arterial pressure (Casey et al. 2010). The paper highlights three key findings of importance regarding the role of NO• in hypoxic vasodilatation.

Low-volume strength and endurance training prevent the decrease in exercise hyperemia induced by non-dominant forearm immobilization

We examined the effect of 3-week upper limb immobilization on conduit artery cross-sectional area and peak hyperemia (BF(peak)) after exhaustive dynamic handgrip exercise (Ex(dyn)), and that of low-volume strength and endurance training during immobilization. Healthy volunteers (n = 21; mean age, 22 years) were divided into 3 groups: immobilization only (IMM; n = 7), immobilization with training (STR + END; n = 7), and control (no immobilization or training, CNT; n = 7). Endurance training comprised Ex(dyn) at 30% maximum voluntary contraction (MVC) (duration of each session, ~60 s; twice weekly). Strength training involved intermittent isometric handgrip exercise at 70% MVC (duration of each session, 40 s; twice weekly), repeated 10 times. We used ultrasound methods to measure the brachial artery cross-sectional area and the BF(peak) after Ex(dyn) for 5 min pre- and post-immobilization. We found a significant group by time interaction in BF(peak) (p < 0.05). A significant decrease was found in BF(peak) in the IMM (p < 0.05) between pre- and post-immobilization and a protective effect in the STR + END. The 3-week upper limb immobilization did not influence the baseline artery cross-sectional area. In conclusion, BF(peak) decreased after 3-week upper limb immobilization and a combination of strength training and endurance training preserved the blunted BF(peak).

Control of muscle blood flow during exercise: local factors and integrative mechanisms

Understanding the control mechanisms of blood flow within the vasculature of skeletal muscle is clearly fascinating from a theoretical point of view due to the extremely tight coupling of tissue oxygen demands and blood flow. It also has practical implications as impairment of muscle blood flow and its prevention/reversal by exercise training has a major impact on widespread diseases such as hypertension and diabetes. Here we analyse the role of mediators generated by skeletal muscle activity on smooth muscle relaxation in resistance vessels in vitro and in vivo. We summarize their cellular mechanisms of action and their relative roles in exercise hyperaemia with regard to early and late responses. We also discuss the consequences of interactions among mediators with regard to identifying their functional significance. We focus on (potential) mechanisms integrating the action of the mediators and their effects among the cells of the intact arteriolar wall. This integration occurs both locally, partly due to myoendothelial communication, and axially along the vascular tree, thus enabling the local responses to be manifest along an entire functional vessel path. Though the concept of signal integration is intriguing, its specific role on the control of exercise hyperaemia and the consequences of its modulation under physiological and pathophysiological conditions still await additional analysis.

Is the Response Capacity of Rapid Vasodilation Mechanism(s) at Exercise Onset Sensitive to Exercise Training?

Resistance vessels in skeletal muscle dilate with the first contraction of exercise. This dilation is proportional to contraction intensity. Whether the mechanism(s) responsible for this immediate, rapid vasodilation can be modified with exercise training is unknown. PURPOSE: We tested the hypothesis that the immediate and peak forearm vasodilatory response to a single, brief forearm contraction would be higher in arm + leg trained athletes vs. leg trained athletes. METHODS: 8 male distance runners and 9 male rowers were recruited from the Queen's University varsity teams. Varsity runners served as a control for whole body training status. Subjects lay supine with the arm extended laterally at heart level and performed single, 1 s isometric handgrip contractions at each of 5 kg, 15 kg, 25 kg and 35 kg contraction force. 3 trials per contraction force were averaged for each subject. Order of contraction force was counterbalanced across subjects. Beat by beat measures of brachial artery forearm blood flow (FBF; Doppler and Echo ultrasound) mean arterial blood pressure (MAP; finger photoplethysmography) and heart rate (HR; ECG) were made at baseline and for 1 min following each contraction. RESULTS: Data are mean ±SE. MAP was not different between groups. Therefore, increases in FBF (DFBF) from rest were representative of the vasodilatory response to contractions. DFBF (ml/min) in the first cardiac cycle post-contraction was not different between groups at 5 kg (P=0.275) or 35 kg (P=0.332), but was significantly elevated in rowers at 15 kg (118 ±19 vs. 84 ±9, P=0.013) and 25 kg (176 ±17 vs. 130 ±13, P=0.038). Peak DFBF (∼3rd - 4th cardiac cycle following contraction) was not different at 5 kg (P=0.967). It was elevated in rowers at 15 kg (183 ±18 vs. 112 ±11, P=0.015), 25 kg (266 ±23 vs. 193 ±21, P=0.005) and 35 kg (333 ±32 vs. 256 ±27, P<0.001). The slope of the peak FBF response vs. contraction force was significantly steeper in rowers than runners (8.6 ±0.9 vs. 5.5 ±0.8 ml/min/kg, P=0.02) CONCLUSIONS: These data support the hypothesis that rapid vasodilatory mechanisms responsible for the onset of exercise hyperemia can be improved with exercise training. This effect can be achieved in young, healthy males and is independent of whole body training status. The stimulus for this adaptation appears to be local to the trained muscle.

Age and Attenuated Exercise Hyperemia: Partitioning the Contributors

The influence of age on the central and peripheral contributors to exercise induced hyperemia is unclear. PURPOSE: Utilizing a reductionist approach, we compared the peripheral and central responses to passive limb movement (exercise without an increase in metabolism) in 11 old (68±7 years of age) and 10 young (25±3 years of age) healthy subjects. METHODS: Cardiac output (CO), heart rate (HR), stroke volume (SV), mean arterial pressure (MAP), and femoral blood flow of the passively moved leg were evaluated second by second during 3 min of passive knee extension at a rate of 1 Hz. RESULTS: In the older subjects CO, SV, HR, and femoral blood flow increased by 15%, 7%, 8% and 97% respectively. The young subjects displayed similar increases in CO, SV, and HR (15%, 6%, and 12% respectively). However, the young subjects displayed a greater increase in femoral blood flow (136%) compared to the older subjects. The difference with age in the hyperemic response to the passive leg movement with age can be explained by a greater increase in antegrade blood flow (103%) and smaller increase in retrograde blood flow (165%) in the young compared to the old subjects (74% and 204% respectively). CONCLUSIONS: Thus, in agreement with previous reports of attenuated exercise induced hyperemia with age, it appears that the difference is unrelated to central responses to limb movement, is peripheral in nature, and is not dependent upon metabolism. Funding: NIH PO1 HL-091830