Chronic endurance exercise training offsets the age-related attenuation in contraction-induced rapid vasodilation

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1 J ppl Physiol 12: , 216. First published March 31, 216; doi:1.1152/japplphysiol Chronic endurance exercise training offsets the age-related attenuation in contraction-induced rapid vasodilation William E. Hughes, 1 Kenichi Ueda, 4 and Darren P. Casey 1,2,3 1 Department of Physical Therapy and Rehabilitation Science; 2 bboud Cardiovascular Research Center; 3 Fraternal Order of Eagles Diabetes Research; and 4 Department of nesthesia, Carver College of Medicine, University of Iowa, Iowa City, Iowa Submitted 19 January 216; accepted in final form 25 March 216 Hughes WE, Ueda K, Casey DP. Chronic endurance exercise training offsets the age-related attenuation in contraction-induced rapid vasodilation. J ppl Physiol 12: , 216. First published March 31, 216; doi:1.1152/japplphysiol ging is associated with attenuated contraction-induced rapid onset vasodilation (ROV). We sought to examine whether chronic exercise training would improve ROV in older adults. dditionally, we examined whether a relationship between cardiorespiratory fitness and ROV exists in young and older adults. Chronically exercisetrained older adults (n 16; 66 2 yr, mean SE) performed single muscle contractions in the forearm and leg at various intensities. rachial and femoral artery diameter and blood velocity were measured using Doppler ultrasound. Vascular conductance (VC) was calculated as the quotient of blood flow (ml/min) and mean arterial pressure (mmhg). These data were compared with our previously published work from an identical protocol in 16 older untrained (66 1 yr, mean SE) and 14 young (23 1 yr) adults. Peak ( VC peak ) and total vasodilator (VC total ) responses were greater in trained compared with untrained older adults across leg exercise intensities (P.5). There were no differences in responses between trained older and young adults in the arm or leg at any exercise intensity (P.5). Comparison of VC peak in a subset of subjects at an absolute workload in the leg revealed that trained older adults exhibited augmented responses relative to untrained older adults. Exercise capacity (V O 2 peak ) was associated with VC peak and VC total across arm (r.59.64) and leg exercise intensities (r.55.68, P.5) in older adults. Our data demonstrate that 1) chronic exercise training improves ROV in the arm and leg of trained older adults, such that age-related differences in ROV are abolished, and 2) VO 2 peak is associated with VC peak responses in both limbs of older adults. aging; vasodilation; hyperemia; exercise training NEW & NOTEWORTHY ging is associated with attenuated exercise hyperemia and vasodilation. Chronic endurance exercise training augments exercise hyperemia and vasodilation during steady-state exercise in older adults. In the current study, we found that chronic exercise improves contraction-induced rapid vasodilation in both the arm and leg of older adults. Furthermore, our current results suggest that exercise capacity is associated with peak dilator responses in both the arm and leg of older adults. GING IS SSOCITED with impairments in vascular function and the regulation of skeletal muscle blood flow, as well as reductions in aerobic exercise capacity (1, 17, 24, 5). These age-related impairments in the regulation of skeletal muscle ddress for reprint requests and other correspondence: D. P. Casey, Dept. of Physical Therapy and Rehabilitation Science, Carver College of Medicine, Univ. of Iowa, Iowa City, I ( darren-casey@uiowa.edu). blood flow, particularly during exercise, are apparent after a single skeletal muscle contraction (6, 7, 9, 19, 21) and persist under steady-state conditions (8, 23, 33, 34, 36). lunted skeletal muscle blood flow responses in older adults have been attributed to alterations in local vasodilatory mechanisms, elevations in sympathetic vasoconstrictive activity, or an impaired ability to modulate sympathetic vasoconstriction during exercise (13, 17, 22, 26, 42). Collectively, these adverse changes in the vasculature and decreased limb blood flow can potentially lead to an inadequate matching of oxygen delivery to the metabolic demand of the contracting muscle (1, 23, 4). Rapid onset vasodilation (ROV) describes the immediate increase in blood flow and vasodilation elicited with a single muscle contraction (1, 41, 48, 49) and is thought to serve a critical role in modulating the blood flow response during steady-state exercise conditions (41, 44). The influence of age on ROV is well characterized in the human forearm (6, 7, 9, 21) and, more recently, in the leg (19). Collectively, these studies indicate that older adults exhibit attenuated peak and total hyperemic and vasodilator responses following a single muscle contraction (6, 7, 9, 21), which appears to be independent of limb (19). t least in the forearm, these age-related decrements in contraction-induced rapid vasodilation are thought to be due in part to diminished nitric oxide (NO) bioavailability or signaling and enhanced -adrenergic vasoconstrictor tone (7, 9). However, to date, all studies examining ROV in both young and older adults have exclusively examined the hyperemic and vasodilator responses in sedentary or recreationally active individuals. Chronic exercise training has been shown to ameliorate many age-associated changes in vascular function (26, 28, 43), while physical inactivity is a risk factor for the development of chronic diseases (5, 32). Indeed, there is a strong inverse relationship between cardiorespiratory fitness (e.g., maximal oxygen consumption) and overall mortality (4, 15), highlighting the benefits of lifelong exercise and high levels of physical activity. However, it is unclear whether the attenuated ROV in contracting muscle of older adults is due to aging per se or the reduction of physical activity and functional fitness that often accompanies the aging process (14, 24). Moreover, it is unknown whether long-term exercise training can prevent the blunting of ROV that occurs in untrained older adults. With this information as background, we tested the hypothesis that chronic endurance exercise training in older adults would ameliorate the age-related impairments in contraction-induced rapid vasodilation. dditionally, we sought to examine whether a relationship between cardiorespiratory fitness and ROV exists in young and older adults /16 Copyright 216 the merican Physiological Society 1335

2 1336 Exercise Training and Rapid Vasodilation Hughes WE et al. METHODS Subjects Sixteen older endurance exercise-trained (9 men, 7 women, age yr) subjects volunteered to participate in this study. To address our primary aim, data from our previous study, which included 16 older and 14 young sedentary to recreationally active adults (19), were used for comparison with the present group of older exercise-trained adults (see Table 1 for complete demographics). ll subjects completed a general health history screening and written informed consent and were generally healthy, free of any diagnosed cardiovascular or metabolic complications, nonobese (body mass index 3 kg/m 2 ), nonsmokers, and not taking any vasoactive medications. Exercisetrained older adults self-reported chronic endurance exercise training 4 days per week, 1 h per session per day, and for at least the past year. On average, subjects reported meeting these training requirements for the past 19 4 yr, and several of them were still actively competing in races (both running and cycling). Trained status was confirmed with a graded, maximal exercise stress test. Studies were performed after an overnight fast, and subjects refrained from exercise, alcohol, and caffeine for 24 h before reporting to the laboratory. female subjects were studied during the early follicular phase of their menstrual cycle or the placebo phase of oral contraceptives to control for the potential influence of sex hormones on primary outcome variables (25). ll older female subjects were postmenopausal and were not taking any form of hormone replacement therapy. ll study protocols were approved by the Institutional Review oard at the University of Iowa. Pre-Study Day Measurements ody composition, forearm, and leg tissue mass. ody composition was determined by dual-energy X-ray absorptiometry (DEX; Hologic software version PEX 4.). Total mass and fat-free mass of the left forearm and right leg were determined from regional analysis from the whole-body DEX scan using bony landmarks for normalization of blood flow and vascular conductance responses. ody mass index was calculated as body weight (kg) divided by height (m) squared. Measurement of exercise capacity. Peak exercise oxygen consumption (V O 2 peak; ml kg 1 min 1 ) was determined in all subjects using respiratory gas analysis (Parvo Medics TrueOne 2, Sandy, UT) during incremental treadmill exercise using a ruce protocol performed to exhaustion as previously described (16). Table 1. Subject characteristics Variable dults (n 14) Untrained Older dults (n 16) Trained Older dults (n 16) ge, yr Men/women 9/5 1/6 9/7 Height, cm Weight, kg ody mass index, kg/m Percent body fat Forearm muscle mass, kg Thigh muscle mass, kg V O 2peak, ml kg 1 min MVC, kg WR max, W Systolic pressure, mmhg Diastolic pressure, mmhg Mean arterial pressure, mmhg Values are means SE. V O 2peak, peak exercise oxygen consumption; MVC, maximal voluntary contraction; WR max, work rate maximum. P.5 vs. young adults. P.5 vs. untrained older adults. Determination of work rate maximum. Work rate maximum (WR max) was determined from a single leg knee extensor incremental maximal exercise test completed during a familiarization session prior to the study day as previously described (19). riefly, subjects were seated in a semirecumbent position on a modified adjustable bucket seat that accommodated variable body and leg lengths allowing each subject s lower leg to move through a 9 18 range of motion during the knee extension exercise. Resistance was developed by a custom-made computer-controlled leg ergometer. riefly, resistance (torque) was developed by an alternating current motor turning at a constant rpm that was transferred to the leg shaft, against which subjects contracted. The computer monitored the elapsed time and the angle of the leg and controlled the actual torque presented to the leg during contraction. In this way, the subject was required to develop enough power to extend the leg through a full range of motion. WR max testing consisted of an initial workload of 5 W that incrementally increased every minute by 3 W and 5 W in female and male subjects, respectively. Subjects kicked dynamically through a full range of motion at a cadence of 4 kicks per minute. The single leg knee extensor incremental maximal test continued until the subject could not maintain a full range of motion or a cadence of 4 contractions per minute. The final workload completed was recorded as maximal kicking load, from which relative workloads were calculated. Study Day Measurements Heart rate and systemic blood pressure. Heart rate was recorded via continuous three-lead electrocardiogram, and systemic blood pressure was assessed (beat-to-beat) via finger plethysmography (Nexfin; Edwards Lifesciences, Irvine, C) on the nonexercising hand. rachial artery pressure was measured in duplicate using an automated cuff (Cardiocap/5, Datex-Ohmeda, Louisville, CO) prior to beginning exercise trials while the subjects were in a supine position following 15 min of rest. Single muscle contractions. Subjects performed dynamic single contractions in both the arm and leg as previously described (19). riefly, single forearm contractions were performed with a handgrip device at 1%, 2%, and 4% of the subject s maximal voluntary contraction (MVC), determined (using a handgrip dynamometer) as the average of three maximal squeezes performed on the pre-study measurement day. Single knee extension contractions were performed at 2%, 4%, and 6% WR max. Subjects were instructed to contract and relax on a verbal command from laboratory personnel. WR max and MVC intensities were randomized prior to the experimental protocol, and each contraction intensity was performed in duplicate to calculate the average response for each subject for a given condition. Each contraction (leg and arm) was visually observed by the laboratory personnel to ensure proper timing of contraction. Two minutes of relaxation were given between each contraction to allow continuous measures of limb hemodynamics postcontraction. ll single muscle contractions (knee extensions and forearm contractions) were performed on the same day. Measurement of blood flow. rachial and common femoral ( 2 3 cm proximal to bifurcation) artery diameter and blood velocity were determined with a 12-MHz linear array Doppler probe (model M12L; Vivid 7, General Electric, Milwaukee, WI). lood velocity was measured with a probe insonation angle previously calibrated to 6. Measured velocity waveforms were synchronized to a data acquisition system (WinDaq; DTQ Instruments, kron, OH) via a Doppler audio transformer (18). rtery diameter measurements were obtained at end diastole at rest (before contraction) and 1-min postcontraction. Limb blood flow (F) was calculated as the product of mean blood velocity (cm/s) and artery cross-sectional area (cm 2 ) and expressed as milliliters per minute (ml/min). Data analysis and statistics. Data were collected at 25 Hz and analyzed offline with signal-processing software (WinDaq; DTQ Instruments). eat-to-beat mean arterial pressure (MP) was derived

3 from the Nexfin pressure waveform and was recorded simultaneously with beat-to-beat blood velocity measurements. Heart rate was determined from the electrocardiogram. aseline F and MP represent an average of the last 3 s of the resting time period before each muscle contraction and were used to quantify the hyperemic response. Vascular conductance (VC) was calculated as F/MP (and expressed as ml min 1 mmhg 1 ). Rapid hyperemic and vasodilator responses are expressed as the change in ( ) F and VC from baseline, respectively. Of particular interest are the peak ( VC peak) and total (VC total) dilator responses postcontraction. Total F (ml) and VC (ml/ mmhg) were defined as the area under the curve over 3 postcontraction cardiac cycles after respective baseline values were subtracted for a given flow or conductance curve. To account for the possible influence of muscle mass, F and VC responses were also examined after normalizing for muscle mass (kg). ll values are expressed as mean SE. nalysis of variance (NOV) was used to analyze demographic variables between groups. To address the primary question of whether chronic exercise training offsets the age-related impairment in contraction-induced ROV, comparisons were made between the older trained adults and our previously published data on young and older untrained adults (19). Independent, one-way NOVs were used to compare groups across exercise intensities in both the arm (1%, 2%, and 4%) and leg (2%, 4%, and 6%). When significance was detected, Tukey s post hoc analysis was used to identify differences between groups. Pearson s correlation coefficients were calculated to assess the relationship between exercise capacity (V O 2 peak) and ROV (peak and total VC). ll statistical analyses were completed using SigmaPlot software version 11. (Systat Software, San Jose, C). Statistical difference was set a priori at P.5. RESULTS Subject characteristics are shown in Table 1., untrained older, and trained older subjects were of similar height, weight, body mass, and percent body fat (P.5). rachial blood pressures, forearm and leg muscle masses, and forearm MVC were also similar between groups (P.5 for all). There were no differences in WR max between trained and Exercise Training and Rapid Vasodilation Hughes WE et al untrained older adults. Compared with young adults, untrained older adults had a lower WR max (P.5), but there were no differences between trained older adults and young adults. Lastly, and important to the current study, exercise-trained older adults had higher V O 2 peak compared with their untrained counterparts (P.5). Rapid Hyperemic and Vasodilator Responses to Single Muscle Contractions in Trained Older, Untrained Older, and dults. Figure 1 illustrates the temporal rapid hyperemic and vasodilator responses at the highest arm (Fig. 1, and C; 4% MVC) and leg (Fig. 1, and D; 6% WR max ) exercise intensities in the three groups of subjects (exercise-trained older adults, untrained older adults, and young adults). The responses in the young and untrained older adults have been previously published (19) and are included to highlight the effect of chronic exercise training on the temporal vasodilator response following a single muscle contraction in the arm and leg. The peak responses for the arm and leg tended to occur in the first 3 5 cardiac cycles, and this timing of peak responses was similar between groups. The peak hyperemic and vasodilator responses in the arm were greater in trained older adults at moderate exercise intensities (2 4% MVC) compared with their older untrained counterparts (P.5; Fig. 2, and ). There were no differences between trained and untrained older adults for total F at any exercise intensity (Fig. 2, C and D). dditionally, there were no differences across contraction intensities for the peak and total hyperemic and vasodilator responses in the arm between trained older adults and young adults (P.5). Peak and total hyperemic (Fig. 3, and C) and vasodilator (Fig. 3, and D) responses were greater in the older trained adults across leg exercise intensities compared with older untrained adults (P.5) while there were no differences between trained older and young adults (P.5). ΔF arm 5 ΔF leg 1 C Cardiac Cycle (Post-contraction) Cardiac Cycle (Post-contraction) D 1 Fig. 1. Hyperemic [change ( ) in blood flow (F); and ] and vasodilator [ vascular conductance (VC); C and D] responses over 3 cardiac cycles following single muscle contractions at the highest arm ( and C; 4% MVC) and leg ( and D; 6% WR max) exercise intensities. ΔVC arm (ml min -1 mmhg -1 ) 5 ΔVC leg (ml min -1 mmhg -1 ) Cardiac Cycle (Post-contraction) Cardiac Cycle (Post-contraction)

4 1338 Exercise Training and Rapid Vasodilation Hughes WE et al. Fig. 2. Peak ( and ) and total (C and D) hyperemic and vasodilator responses in the arm for young, untrained older, and trained older adults. Peak hyperemic and vasodilator responses (2% and 4% MVC) were greater in trained compared with untrained older adults. There were no differences in hyperemic and vasodilator responses between trained older adults and young adults. P.5 vs. untrained older adults. F arm (ml) ΔF arm C % 2% 4% 1% 2% 4% 1% 2% 4% 1% 2% 4% VC arm (ml min -1 mmhg -1 ) ΔVC arm (ml min -1 mmhg -1 ) D Normalizing responses to muscle mass elicited similar results, in that peak arm hyperemic and vasodilator responses were greater in trained older adults at moderate exercise intensities compared with untrained counterparts (data not shown P.5). dditionally, peak and total hyperemic and vasodilator responses were greater in trained older adults across leg exercise intensities compared with untrained older adults, with no differences between trained older and young adults (data not shown, P.5). Relationship etween Exercise Capacity and ROV Within the rm and Leg Figure 4 illustrates the relationship between V O 2 peak and peak vasodilator responses at the highest exercise intensities in the arm (Fig. 4) and leg (Fig. 4). V O 2 peak was moderately associated with arm peak and total VC across exercise intensities (r.31.61, P.5 for all) in the group as a whole. When separated by age, V O 2 peak was associated with peak (r Fig. 3. Peak ( and ) and total (C and D) hyperemic and vasodilator responses in the leg for young and untrained and trained older adults. ll parameters of the ROV response (peak and total) were greater in trained older adults compared with untrained older adults across leg exercise intensities. There were no differences between trained older adult responses and young adults. P.5 vs. untrained older adults. F leg (ml) ΔF leg C 1 1 2% 4% 6% 2% 4% 6% 2% 4% 6% 2% 4% 6% VC leg (ml mmhg -1 ) ΔVC leg (ml min -1 mmhg -1 ) D 1 1

5 ΔVC arm (ml min -1 mmhg -1 ) r =.61 P <.5 VO 2 peak (ml kg -1 min-1 ) Exercise Training and Rapid Vasodilation Hughes WE et al. 4% MVC 6% WR max ΔVC leg (ml min -1 mmhg -1 ) r =.65 P < VO 2 peak (ml kg -1 min-1 ) 1339 Fig. 4. Relationship between exercise capacity (V O 2 peak) and peak vasodilator responses ( VC peak) in the arm () and leg () of young and older adults , P.5) and total (r.39.52, P.5) arm VC across exercise intensities in older adults, but only at 4% in young adults (r.53, P.5). Within the leg, V O 2 peak was associated with peak (r.55.65, P.5) and total (r.39.5, P.5) VC across exercise intensities in the entire group. When separated by age, V O 2 peak was moderately associated with peak leg vasodilator responses across exercise intensities in older adults (r.55.68, P.1 for all), and at 4 6% WR max in young adults (r.6 and.65, respectively, P.5 for both). When separated by training status (trained older vs. untrained adults) there were no associations between V O 2 peak or total VC in the arm or leg of untrained older adults (P.5). Conversely, trained older adults exhibited associations between V O 2 peak and peak VC across arm exercise intensities (r.68.7, P.5 for all) and at 4% and 6% WR max in the leg (r.62.7, P.5). ROV, ge, and Physical Fitness: Influence of Workload s untrained older adults had a lower leg WR max it could be argued that because of the tight relationship between blood flow and metabolic rate, any age- or physical fitness-related differences may be due to differences in the absolute work performed between groups. To address this issue, we compared the peak and total responses normalized for work rate (e.g., flow and/or conductance per watt) between groups. Normalizing the data in this way revealed results similar to those presented above for the absolute hyperemic and vasodilator responses. Trained older adults still demonstrated higher peak hyperemic (98 8 vs. 68 8, 56 4 vs. 41 4, and 44 3 vs ml min 1 W 1 ) and vasodilator responses (15 1 vs. 73 9, 59 5 vs. 43 5, and 46 4 vs ml min 1 mmhg 1 W 1 ) across exercise intensities (2 6% WR max ) compared with untrained older adults (P.5 for all). dditionally, the total hyperemic response normalized for work rate was higher at 2% (98 12 vs ) and 6% ( vs ) WR max in trained vs. untrained older adults (P.5 for both). To further address the potential confound of work rate between groups, we compared the peak and total hyperemic and vasodilator responses in a subset of subjects from each of the three groups that performed similar absolute workloads (mean 1 11 W for each group). The mean SE workloads for the subset of trained older (n 1), untrained older (n 11), and young (n 11) adults were 1.6.4, 1.5.3, and W, respectively. s illustrated in Fig. 5, peak hyperemic (Fig. 5) and vasodilator responses (Fig. 5) were greater in trained older adults compared with untrained older adults (P.5 for both) when matched for workload, while peak VC was lower in untrained older adults compared with young adults (P.5). Total hyperemic (Fig. 5C) and vasodilator (Fig. 5D) responses were not different between groups (P.7 for both). When the responses were normalized for muscle mass in the subset of subjects matched for workload, there were no differences between groups (P.9.17) for peak and total F and VC. In the same subset of subjects, V O 2 peak was associated with VC peak in the group as a whole (r.48, P.1), but not when separated by training status (r.8.44, P.5 for all). Total VC and V O 2 peak were not associated in any group, regardless of how responses were expressed (r , P.5 for all). There were no significant associations between V O 2 peak and VC peak (normalized for muscle mass), in the group as a whole (r.15, P.5) or when separated by training status (trained, untrained older adults, and young; r.43.48, P.5 for all). DISCUSSION We and others have previously shown that contractioninduced rapid hyperemic and vasodilator responses are attenuated in untrained or sedentary older adults (6, 7, 9, 19, 21) and that this attenuation appears to be similar between the arm and leg (19). In the present cross-sectional study, we demonstrate for the first time that 1) older adults with a history of chronic endurance exercise training demonstrate greater contractioninduced rapid hyperemic and vasodilator responses within both the arm and leg compared with their age-matched counterparts and 2) vasodilator responsiveness to single muscle contractions is moderately associated with exercise capacity (V O 2 peak ). These conclusions are supported by the fact that chronically trained older adults demonstrated a substantially greater peak ROV in the arm (Fig. 2) as well as an approximately twofold greater peak and total ROV response in the leg (Fig. 3) compared with untrained older adults across a range of relative (percent) workloads. Moreover, the group differences between the older trained and untrained adults still persist when 1) the ROV responses are normalized to the absolute work rate performed and 2) the groups are matched for a similar absolute workload (Fig. 5). Finally, our findings also demonstrate that exercise capacity is positively related to the peak ROV response, regardless of whether the peak ROV responses are expressed at the same relative exercise intensity or matched for

6 134 Exercise Training and Rapid Vasodilation Hughes WE et al. Fig. 5. Peak ( and ) and total (C and D) hyperemic and vasodilator responses in the leg at an absolute workload of 11 W for young adults and untrained and trained older adults. oth parameters of peak ROV responses were greater in trained older adults compared with untrained older adults at an absolute workload. P.5 vs. untrained older adults. F leg (ml) ΔF leg C (n=1) bsolute Workload (~11 Watts) VC leg (ml mmhg -1 ) ΔVC leg (ml min -1 mmhg -1 ) D (n=1) bsolute Workload (~11 Watts) (n=1) bsolute Workload (~11 Watts) (n=1) bsolute Workload (~11 Watts) workload. Taken together, these results suggest that chronic endurance exercise offsets the age-related attenuation in ROV in both the arm and leg of older adults. enefits of Exercise Training on lood Flow in Older dults During submaximal dynamic exercise there is a general decline in steady-state blood flow and vasodilation with age (23, 33 39), which may be offset with exercise training (1, 31). The decline in exercise blood flow with aging is presumably due to an imbalance between local vasodilator and vasoconstrictor signaling, elevated sympathetic vasoconstrictive tone, as well as an impaired ability to blunt sympathetic vasoconstriction within the contracting muscle (12, 13, 2 22, 42). Conversely, lifelong physical activity (27) as well as exercise interventions (26) appear to preserve the ability to blunt sympathetic vasoconstrictive tone (functional sympatholysis) in the leg of older adults and maintain sufficient oxygen delivery in older adults (38, 5). However, it should be noted that the documented benefits of lifelong physical activity or chronic exercise training on the regulation of muscle blood flow during exercise may be sex specific. That is, exercise-trained older women do not appear to exhibit the same preservation of exercise hyperemia and vasodilation that trained older men do (31, 34, 35). In the present study, chronic exercise training appears to offset the age-related attenuation of peak and total hyperemic and vasodilator responses following a single muscle contraction in the leg of both older men and women. However, this study was not adequately powered to detect sex by exercise-training interactions, and therefore we cannot make any conclusions on whether chronic exercise training is less effective in improving ROV in older women compared with men. Training enefits eyond ctive Tissue Exercise-training adaptations to vascular structure and function are not solely restricted to the active limb (e.g., metabolically active limb) and may be conferred to the vasculature perfusing nonexercising tissue (e.g., inactive skeletal muscle) (2, 3). In the context of the present study, the majority of exercise-trained older adults reported participation primarily in activities involving the lower limbs, and as illustrated in Figs. 2 and 3, this chronic exercise training offsets age-related impairment of ROV responses in both limbs. long these lines, lower-body exercise training not only results in an increase in femoral artery diameter but also preserves endothelial function in the brachial artery (e.g., inactive limb), such that agerelated differences in both conduit and resistance arteries are abolished (11, 52). These favorable vascular adaptations in conduit arteries to exercise training in inactive skeletal muscle are hypothesized to be mainly due to repeated bouts of elevated shear stress, with endothelial adaptations evident even after a single bout of acute exercise (47). Taken together, these data confirm and highlight the systemic benefits of chronic exercise training on the vasculature in older adults. Possible Mechanisms This study provides insight into how chronic endurance exercise training offsets age-related attenuations in contraction-induced ROV; however, it is important to emphasize that discerning the underlying mechanisms modulating this response was not the purpose of the present investigation. Instead, this study was designed to highlight and characterize the relationship between chronic exercise training, exercise capac-

7 ity, and age-related attenuations in contraction-induced ROV. Therefore we will only briefly highlight plausible mechanisms by which exercise training may offset age-related attenuation of the ROV response to single muscle contractions. Previous evidence from our laboratory demonstrates that age-related impairments in contraction-induced ROV in the arm are in part due to a reduction in NO bioavailability or signaling, as well as an increase in sympathetic vasoconstriction (7, 9). In this context, evidence from habitually exercising older adults indicates that lifelong exercise training preserves both NO signaling (28, 46) as well as functional sympatholysis within the leg vasculature in older individuals (27). Therefore it is plausible that the mechanisms by which chronic exercise training offsets age-related attenuation of ROV in older adults are similar to those observed under steady-state conditions during submaximal dynamic exercise. Experimental Considerations It should be noted that our current study design does not allow us to examine whether endurance exercise-trained older adults exhibit similar ROV responses relative to trained young adults. Evidence suggests that young, highly trained adults exhibit augmented exercise blood flow responses at submaximal and maximal workloads relative to young sedentary counterparts in both the arm and leg (51). Therefore it can be assumed that young trained adults might exhibit augmented ROV responses; however, this has yet to be confirmed. Given that the aim of the study was to examine how chronic exercise training influences characteristics of ROV in a cross-sectional manner, we could not control which specific type of chronic exercise subjects participated in. Furthermore, as we present a large range of chronic exercise-trained older adults, we were unable to control the number of years the group as a whole participated in. long these lines, improvements to vascular function are apparent even with short-term exercising training interventions, particularly in populations with established vascular dysfunction (11, 26, 29, 45, 52). dditionally, while the older trained and untrained groups were well matched for many characteristics besides exercise training and V O 2, there was a trend (P.11) for a higher percent body fat in the untrained compared with exercise-trained older adults. Since contractioninduced rapid onset vasodilatation has been shown to be blunted with obesity (3), differences in body composition could in part contribute to the augmented ROV responses observed in the exercise-trained group. However, we believe these limitations should not detract from the present study; instead, it should be viewed in a larger picture, in that older adults with a history of performing habitual endurance exercise demonstrate an augmented contraction-induced rapid vasodilation compared with their sedentary older peers. Conclusion To our knowledge, this is the first study to demonstrate that chronic exercise training or physical activity offsets the agerelated attenuation in contraction-induced rapid vasodilation in both the arm and leg. dditionally, exercise capacity is associated with contraction-induced rapid hyperemic and vasodilator responses in older adults. These findings extend upon previous studies demonstrating the ability of chronic aerobic exercise to offset age-related impairments of endothelial Exercise Training and Rapid Vasodilation Hughes WE et al. function as well as steady-state exercise hyperemia and vasodilation, further highlighting the benefits of lifelong exercise training. CKNOWLEDGMENTS The authors are grateful to the study volunteers for their participation. We thank David Treichler, Charles Ganger IV, aron Schneider, Samuel Norton, and Cynthia Pauley for their technical assistance. GRNTS This research was supported by National Heart, Lung, and lood Institute Research Grant HL (to D. P. Casey) and NIH CTS U54TR1356. DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the author(s). 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