Sex-related differences in rapid-onset vasodilation: impact of aging

Abstract

Rapid-onset vasodilation (ROV) in response to a single muscle contraction is attenuated with aging. Moreover, sex-related differences in muscle blood flow and vasodilation during dynamic exercise have been observed in young and older adults. The purpose of the present study was to explore if sex-related differences in ROV exist in young (n = 36, 25 ± 1 yr) and older (n = 32, 66 ± 1 yr) adults. Subjects performed single forearm contractions at 10%, 20%, and 40% maximal voluntary contraction. Brachial artery blood velocity and diameter were measured with Doppler ultrasound, and forearm vascular conductance (mL·min⁻¹·100 mmHg⁻¹) was calculated from blood flow (mL·min⁻¹) and mean arterial pressure (mmHg) and used as a measure of ROV. Peak ROV was attenuated in women across all relative intensities in the younger and older groups (P < 0.05). In a subset of subjects with similar absolute workloads (∼5 kg and ∼11 kg), age-related differences in ROV were observed among both women and men (P < 0.05). However, only older women demonstrated an attenuated peak ROV compared with men (91 ± 6 vs. 121 ± 11 mL·min⁻¹·100 mmHg⁻¹, P < 0.05), a difference not observed in the young group (134 ± 8 vs. 154 ± 11 mL·min⁻¹·100 mmHg⁻¹, P = 0.15). Additionally, examining the slope of peak ROV across contraction intensities indicated a blunted response in older women compared with their younger counterparts (P < 0.05), with no differences observed between older and young men (P = 0.38). Our data suggest that sex-related differences in the rapid vasodilatory response to single muscle contractions exist in older but not young adults, such that older women have a blunted response compared with older men.

NEW & NOTEWORTHY While rapid-onset vasodilation (ROV) has been shown to decrease in older individuals, it is unclear if sex contributes to the decline with aging. We sought to identify if sex-related differences exist in the ROV response to single forearm contractions in young and older adults. Our data suggest sex-related differences are present among older but not young individuals, with women having an attenuated response. These data indicate sex plays a role in decreased vasodilation with aging.

INTRODUCTION

The complex mechanisms of vasodilation have long been studied to understand increases in skeletal muscle blood flow during exercise (1). At the onset of exercise, there is an immediate increase in blood flow and vasodilation, which is thought to serve an essential role in modulating exercise hyperemia in the contracting tissue during steady-state conditions (2, 3). This immediate increase in blood flow and vasodilation occurs within the first 1–2 s after the completion of a single muscle contraction, is proportional to contraction intensity (4, 5), and is commonly referred to as rapid-onset vasodilation (ROV) (6, 7). Importantly, and in contrast to dynamic steady-state exercise, examining the blood flow and vasodilator response to a single muscle contraction allows assessment of the local mechanisms underlying exercise hyperemia without the confounding effects of local or systemic hemodynamic changes that occur with subsequent contractions (8). The release of vasodilators from active skeletal muscle and the vascular endothelium (9–11), mechanical factors (6, 12), as well as sympathetic neural regulation (13) have been identified as potential mechanisms underlying ROV.

Numerous studies have demonstrated the rapid vasodilatory response to a single muscle contraction is attenuated with aging (10, 13–17). Although age-related reductions in ROV do not appear to be attributable to mechanical factors (18), our previous findings suggest changes in nitric oxide (NO) bioavailability and/or signaling may contribute (10). Indeed, the hyperemic and vasodilatory responses to single forearm contractions are attenuated under nitric oxide synthase (NOS) inhibition via N^G-monomethyl-l-arginine in young and older adults (10). However, the magnitude of reduction in the contraction-induced hyperemia and vasodilation with NOS inhibition are significantly greater in young compared with older adults. Taken together, these findings indicate that the age-related decline in ROV is partially due to reduced NO bioavailability or signaling. In addition to alterations in endothelial function and blunted NO signaling contributing to the attenuated ROV observed with aging, enhanced α-adrenergic vasoconstrictor tone may also be a contributing factor (13, 16).

While age-related differences in ROV are apparent, little is known about sex-related differences, or more specifically if these differences are altered with aging. Along these lines, there are indications of sex-related differences in the hyperemic and vasodilatory responses during steady-state dynamic exercise. That is, young women typically show greater hyperemic and vasodilatory responses to dynamic forearm (19–21) and leg (22) exercise compared with young men. Conversely, this greater vasodilatory response seen in women has been shown to be lost with aging. Parker et al. (23) found that hyperemia and vasodilation during submaximal knee extension exercise was attenuated in older women but not men when compared with young adults. These findings, supported by other studies (24, 25), indicate that during steady-state exercise, aging may lead to sex-specific decrements in vasodilation such that women have a sharper decline than men, although evidence is limited. It is not known, however, if these differences can be generalized to the immediate contraction-induced vasodilatory response (i.e., ROV). Although a number of previous ROV studies have included a mix of men and women (2, 9, 10, 14, 17, 18), none were designed to directly investigate potential differences between sexes. Therefore, the purpose of this study is to evaluate possible sex-related differences in forearm ROV that may be present in young and older adults. We hypothesized that there would be a significant influence of age on sex-related differences in ROV, with older women exhibiting greater reductions in forearm hyperemia and vasodilation compared with older men.

METHODS

Subjects

All data used in this study were retrospectively pooled and analyzed from previous trials and published reports by our group (10, 13, 15). All data used for the analyses in the current study were derived from the control trials of the previous studies (10, 13, 15). All control trials from these studies were performed prior to any drug infusions (10, 13) or use of lower body negative pressure (13). Therefore, the other experiments or perturbations used in the previously conducted studies did not influence the data used in the present analyses. The data from a total of 36 young (21 men and 15 women, age: 18–32 yr) and 32 older (19 men and 13 women, age: 58–81 yr) subjects were used for the retrospective analysis. Subjects completed written informed consent and a standard screening. Subjects were healthy, nonobese, nonsmoking, sedentary or moderately active, and free from taking medications that would affect their hemodynamic response to exercise. All studies were completed after an overnight fast (≥8 h), with subjects refraining from exercise, caffeine, or alcohol for at least 24 h before the experimental visit. Young women completed the study during the early follicular phase of the menstrual cycle or the placebo phase of oral contraceptives. Older women were all postmenopausal, and no subjects were taking any form of hormone therapy. All study protocols were approved by the Institutional Review Board at either the Mayo Clinic or the University of Iowa and performed in accordance with the Declaration of Helsinki.

Experimental Protocol

Subjects completed a single study visit consisting of single forearm handgrip contractions. Forearm contractions were performed on a custom-made handgrip device with the subjects lying supine and the left arm held perpendicular to the body (∼80°). Before experimental trials, maximal voluntary contraction (MVC) was determined using an isometric handgrip dynamometer (Stoelting, Chicago, IL). Experimental trials consisted of contractions at 10%, 20%, and 40% MVC. Each forearm contraction involved lifting a weight 4–5 cm over a pulley for a single, 1-s muscle contraction. Verbal command for subjects to contract and relax was given by laboratory personnel. All contractions were observed to ensure proper timing of contraction. Workload intensities were randomized, and each contraction intensity was completed in duplicate to calculate the average response for each subject. Thus, each subject performed six single forearm contractions (two at each intensity). Each trial consisted of 2 min of rest followed by a single forearm contraction. Brachial artery velocity and hemodynamics were measured during the 2-min rest period and for 45 s following contraction.

Forearm Blood Flow Measurements

Brachial artery mean blood velocity and brachial artery diameter were determined with a 12-Hz linear-array Doppler probe (model M12L, Vivid 7, General Electric, Milwaukee, WI). Brachial artery blood velocity was measured throughout each condition with the probe insonation angle previously calibrated to 60°. Brachial artery diameter measurements were obtained at end diastole at rest (before contraction) and 45 s postcontraction. Forearm blood flow (FBF) was calculated as the product of mean blood velocity (cm·s⁻¹) and brachial artery cross-sectional area (cm²) and expressed as milliliters per minute (mL·min⁻¹).

Data Analysis and Statistics

Data were collected at 250 Hz and analyzed offline with signal processing software (WinDaq, DATAQ Instruments, Akron, OH). Mean arterial pressure (MAP) was derived from a finger plethysmography waveform (Nexfin, Edwards Lifesciences, Irvine, CA) or intraarterial pressures of the brachial artery, and heart rate was determined from a continuous three-lead electrocardiogram. Baseline FBF and MAP represent an average of the last 30 s of the resting period before each muscle contraction and were used to quantify the vasodilatory response. Forearm vascular conductance (FVC) was calculated as FBF/MAP × 100 (and expressed as mL·min⁻¹·100 mmHg⁻¹). Rapid hyperemic and vasodilator responses are expressed as the change from baseline in (Δ) FBF and FVC, respectively. All postcontraction FVC data were based on beat-to-beat FBF divided by the corresponding beat-to-beat MAP. Of interest are peak and total dilator responses postcontraction. Total FBF (mL) and FVC (mL·100 mmHg⁻¹) were defined as the area under the curve after baseline values were subtracted for a given curve. To account for differences in MVC, and weight used at each relative intensity, a subset of subjects with two similar absolute workloads (ranging between 4–6 and 10–12 kg) were also compared. Additionally, the magnitude of the change in the peak ΔFBF and ΔFVC across increasing intensities (i.e., the slope of a linear regression line) was calculated and compared between groups.

All values are displayed as means ± standard deviation. All subject characteristic data were analyzed via one-way analysis of variance (ANOVA). A two-way ANOVA was used to analyze differences in variables of interest between sex and age-groups during relative and absolute workloads. When a significant main effect of age or sex was detected, a Tukey’s post hoc analysis was used to identify any significant differences. To determine differences in the magnitude of change in peak ΔFBF and ΔFVC with increasing workloads, the slopes of the linear regression lines were compared via two-way ANOVA. All statistical analyses were performed using SigmaPlot software version 11.0 (Systat Software Inc., San Jose, CA), with statistical significance set a priori at P < 0.05.

RESULTS

Subject characteristics are shown in Table 1. Collectively, older subjects had greater body mass index (BMI) than their young counterparts (P < 0.05) but did exhibit similar MVC (P = 0.28). Young and older men had greater weight, BMI, and MVC compared with women (P < 0.05). Baseline systolic and diastolic blood pressures were not significantly different between any subject group (P = 0.07 and 0.22, respectively). Men in both the young and older groups exhibited greater brachial artery diameter compared with women (P < 0.05). Additionally, brachial artery diameter was greater in older compared with young men (P < 0.05).

Table 1.

Subject characteristics

	Young		Older
Variable	Men (n = 21)	Women (n = 15)	Men (n = 19)	Women (n = 13)
Age, yr	25 ± 6.6	25 ± 3.2	66 ± 4.4†	66 ± 5.3†
Weight, kg	83 ± 10	65 ± 9.2*	84 ± 7.4	64 ± 7.7*
BMI, kg/m2	25.3 ± 2.3	23.4 ± 2.9*	27.2 ± 2.1†	24.4 ± 3.0*
Brachial SBP, mmHg	126 ± 6	122 ± 9	130 ± 9	128 ± 10
Brachial DBP, mmHg	76 ± 4	76 ± 9	79 ± 7	74 ± 6
Brachial artery diameter, cm	0.42 ± 0.03	0.32 ± 0.03*	0.45 ± 0.04†	0.34 ± 0.04*
MVC, kg	49 ± 8.9	32 ± 7.5*	47 ± 5.4	28 ± 4.5*
Relative workload utilized
10% MVC, kg	4.9 ± 0.9	3.2 ± 0.8*	4.7 ± 0.5	2.7 ± 0.4*
20% MVC, kg	9.8 ± 1.8	6.4 ± 1.5*	9.4 ± 1.1	5.6 ± 0.8*
40% MVC, kg	19.6 ± 3.5	12.8 ± 2.9*	18.8 ± 2.1	11.2 ± 1.7*

Values are means ± SD. BMI, body mass index; DBP, diastolic blood pressure; MVC, maximal voluntary contraction; SBP, systolic blood pressure. *P < 0.05 vs. male within age-group. †P < 0.05 vs. young within sex group.

Hyperemic and Vasodilatory Responses to Single Forearm Contraction

Hyperemic responses to single handgrip contractions across workloads are displayed in Table 2. Peak and total FBF were attenuated in young women at all relative intensities compared with young men (P < 0.05). Older women had an attenuated peak ΔFBF compared with older men at all relative intensities (P < 0.05), whereas total FBF was attenuated at 20% and 40% (P < 0.05) but not at 10% MVC (P = 0.45). Older men had a decreased peak ΔFBF compared with young men at all relative intensities (P < 0.05) and a lower total FBF at 10% and 40% (P < 0.05) but not at 20% MVC (P = 0.16). Older women had an attenuated peak ΔFBF compared with young women at 20% (P < 0.05); however, no difference was observed among women at 10% or 40% MVC (P = 0.35 and 0.06, respectively). No significant difference in total FBF was detected among young and older women at any intensity (P = 0.06–0.45).

Table 2.

Peak and total hyperemic response to a single handgrip contraction at relative workloads

	Young		Older
Variable	Men (n = 21)	Women (n = 15)	Men (n = 19)	Women (n = 13)
Peak ΔFBF, mL·min−1
10% MVC	106 ± 42	57 ± 13*	76 ± 37†	46 ± 16*
20% MVC	147 ± 39	88 ± 20*	118 ± 39†	60 ± 14*†
40% MVC	214 ± 75	138 ± 53*	166 ± 66†	94 ± 18*
Total FBF, mL
10% MVC	18 ± 11	9 ± 3*	10 ± 7†	7 ± 3
20% MVC	24 ± 9	16 ± 5*	20 ± 11	10 ± 4*
40% MVC	47 ± 24	32 ± 15*	35 ± 15†	21 ± 6*

Values are means ± SD. FBF, forearm blood flow; MVC, maximal voluntary contraction. *P < 0.05 vs. male within age-group. †P < 0.05 vs. young within sex group.

Peak and total vasodilatory (FVC) responses to a single forearm contraction were attenuated young women at all relative intensities compared with young men (P < 0.05; Fig. 1). Peak ΔFVC responses were attenuated in older women compared with older men at all relative intensities (P < 0.05; Fig. 1A), whereas total FVC responses were attenuated in older women at 20% and 40% (P < 0.05) but not at 10% MVC (P = 0.38; Fig. 1B). Older men had lower peak and total FVC compared with young men at all relative intensities (P < 0.05; Fig. 1, A and B). Among women, older women had lower peak and total FVC responses compared with young women at 20% and 40% (P < 0.05) but not at 10% MVC (P = 0.30 for peak, P = 0.52 for total; Fig. 1, A and B).

Figure 1.

Peak (A) and total (B) vasodilatory (forearm vascular conductance, FVC) responses to a single handgrip contraction at relative workloads of 10%, 20%, and 40% maximal voluntary contraction (MVC) in young (n = 21 men, 15 women) and older (n = 19 men, 13 women) adults. The effects of age and sex on FVC were evaluated by two-way analysis of variance (ANOVA) and Tukey’s post hoc test. Data presented as means ± SD. *P < 0.05 vs. men within age-group, †P < 0.05 vs. young within sex group.

Rapid-Onset Vasodilation in Response to Absolute Workloads

To account for differences in MVC between men and women in both the young and older groups (Table 1), hyperemic and ROV responses to two absolute weights were assessed in a subset of subjects. This was accomplished by comparing vasodilatory responses in subjects who completed single muscle contractions at a weight of ∼5 kg (range, 4–6 kg) and ∼11 kg (range, 10–12 kg). In total, data from 12 young men (5.3 ± 0.5 and 10.6 ± 0.9 kg), 10 young women (5.5 ± 0.6 and 11.0 ± 1.1 kg), 11 older men (5.1 ± 0.3 and 10.2 ± 0.7 kg), and 11 older women (5.6 ± 0.5 and 11.2 ± 1.1 kg) were used for the two “absolute” workload subanalysis. The actual weight did not differ between groups for the ∼5 kg (P = 0.11) or ∼11 kg (P = 0.13) analyses. As shown in Table 3, peak ΔFBF did not differ between young men and women at the ∼5 kg and ∼11 kg workloads (P = 0.07 and 0.06, respectively); however, older women had a lower response compared with older men at the ∼11 kg workload (P < 0.05). No age-related difference in peak ΔFBF was seen among men at either workload (P = 0.06–0.12); however, older women had an attenuated response compared with their young counterparts at ∼11 kg (P < 0.05) but not at ∼5 kg (P = 0.09). Utilizing the absolute workload comparisons, older men and women demonstrated an attenuated peak ΔFVC compared with their young counterparts at both workloads (P < 0.05; Fig. 2A). Furthermore, peak ΔFVC was decreased in older women compared with older men at ∼11 kg (P < 0.05; Fig. 2A). However, no difference was observed in peak ΔFVC between young men and women at either workload (P = 0.08–0.15; Fig. 2A). Total hyperemic and vasodilatory responses were not different between and within age-groups (P > 0.05 for all), with the exception of a lower total FVC in older compared with young men at the ∼5 kg workload (P < 0.05; Table 3 and Fig. 2B).

Table 3.

Peak and total hyperemic response to a single handgrip contraction at absolute workloads in subset of subjects

	Young		Older
Variable	Men (n = 12)	Women (n = 10)	Men (n = 11)	Women (n = 11)
Peak ΔFBF, mL·min−1
∼5 kg	115 ± 46	85 ± 14	84 ± 45	60 ± 15
∼11 kg	154 ± 41	125 ± 28	132 ± 42	92 ± 19*†
Total FBF, mL
∼5 kg	19 ± 11	15 ± 5	12 ± 8†	10 ± 3
∼11 kg	25 ± 9	26 ± 11	24 ± 12	22 ± 6

Values are means ± SD. FBF, forearm blood flow. *P < 0.05 vs. male within age-group. †P < 0.05 vs. young within sex group.

Fig. 2.

Peak (A) and total (B) vasodilatory (forearm vascular conductance, FVC) responses to a single handgrip contraction at absolute workloads of ∼5 kg and ∼11 kg in young (n = 12 men, 10 women) and older (n = 11 men, 11 women) adults. The effects of age and sex on FVC were evaluated by two-way analysis of variance (ANOVA) and Tukey’s post hoc test. Data presented as means ± SD. *P < 0.05 vs. men within age-group. †P < 0.05 vs. young within sex group.

Hyperemic and Vasodilator Responsiveness to Increasing Workload

Analysis of peak hyperemic and vasodilatory responses across intensities revealed a main effect of age (P < 0.05 for both), with older subjects having a blunted slope. Of interest, the vasodilator slope of the older women was smaller than that of their young counterparts (P < 0.05; Fig. 3, A and B). Differences in the vasodilator slope were not observed in older compared with in young men (P = 0.38 Fig. 3, A and B). No sex-related difference in the vasodilator slope was observed in young adults (P = 0.43) or in older adults (P = 0.23). Similarly, the hyperemic slope was smaller in older compared to young women (5.8 ± 2.1 vs. 8.6 ± 3.7 mL·min⁻¹·intensity). The hyperemic slope did not differ between older and young men (6.7 ± 2.1 vs. 7.6 ± 4.7 mL·min⁻¹·intensity), and no sex-related difference was observed in young (P = 0.39) or in older adults (P = 0.51).

Fig. 3.

Graphical representation (A) and the calculated slope (B) of the magnitude of change in peak vasodilatory (forearm vascular conductance, FVC) response to single handgrip contraction across 10%, 20%, and 40% maximal voluntary contraction (MVC) workloads in young (n = 21 men, 15 women) and older (n = 19 men, 13 women) adults. The slope of a linear regression line was calculated from the peak FVC at each relative workload, and differences between groups were evaluated by two-way analysis of variance (ANOVA) and Tukey’s post hoc test. Data presented as means ± SD. *P < 0.05 vs. young women.

DISCUSSION

The present study explored sex-related differences in the rapid vasodilatory response following a single voluntary forearm contraction with aging. To the best of our knowledge, this is the first study to specifically investigate sex-related differences in ROV. We hypothesized that age would have a significant influence on sex-related differences in ROV, with a greater impact on women. In concordance with previous studies (10, 13–17, 26), our data clearly demonstrate that ROV is blunted with aging. The novel findings of the present study suggest that 1) independent of age, women have a lower peak and total ROV compared with men at relative intensities; 2) when comparing peak ROV at absolute workloads, sex-related differences are only observed among older adults; and 3) the slope of the peak vasodilatory response across increasing workloads is blunted in older compared with in young women, a difference not seen with aging in men.

Across all relative intensities in both young and older subjects, peak ROV was attenuated in women compared with men. As a close relationship exists between contraction intensity and rapid vasodilation (i.e., greater workload produces greater vasodilation) (5), the attenuated responses observed in women at each relative intensity (10%, 20%, and 40% MVC) may be simply related to an overall lower absolute workload performed. That is, men had a greater MVC and subsequently contracted at higher absolute workloads for each of the relative exercise intensities than women (Table 1). To help circumvent this issue, ROV responses were assessed in a subset of the subjects at relatively common absolute weights (∼5 kg and ∼11 kg). Utilizing this approach revealed that the sex-related difference in peak ROV remained within the older group, whereas the difference was abolished in the young adults. Conversely, the total vasodilatory response (total FVC) to relative workloads of 20% and 40% MVC observed between older men and women (Fig. 1B) was not apparent at the absolute workloads (Fig. 2B). It is unclear why sex-related differences in older adults at absolute workloads are specific to the peak response, but not the total, especially considering each response appears to share similar mechanisms (10, 11, 13).

Our findings demonstrating a sex-specific influence with aging on rapid vasodilation following a single contraction are consistent with data during dynamic steady-state exercise (23–25). As the rapid vasodilatory response following a single muscle contraction is thought of as a feedforward mechanism, a blunted response in older women may influence the modulation of exercise hyperemia from rest to steady-state exercise. Proctor et al. (24) found that in response to submaximal dynamic leg cycling exercise, older women had an impaired vascular response relative to young women, a difference that was not observed in men (25). Furthermore, older women have a decreased vasodilator responsiveness during graded knee extension exercise in comparison with young women, whereas these responses in older men were relatively preserved (23). Although the findings from these studies are specific to dynamic leg exercise, they somewhat parallel the observed findings of the present study which found that the age-related reductions in the peak hyperemic and vasodilatory responses to single forearm contractions are more pronounced in older women compared with men. Further supporting this notion is the blunted slope in the hyperemic and vasodilatory responses to increasing contraction intensity (10%–40% MVC) in older women (Fig. 3). Analyzing it from this perspective suggests the age-related blunting of peak ROV in women becomes more magnified with increasing contraction intensity.

While the present study was observational in nature and not designed to explore specific mechanisms, there are a few potential explanations for the sex-related differences in peak ROV that should be considered. There is evidence that NO contributes to the vasodilator response following a single muscle contraction (9, 11), and previous data from our group (10) indicate that impaired NO bioavailability or signaling contribute to the age-related reduction in ROV. Although similar NO-mediated vasodilation has been reported among young men and women during steady-state exercise (20), to our knowledge, there is no clear evidence to suggest that NO bioavailability is necessarily different between older men and women. However, some studies involving measures of brachial artery flow-mediated dilation (FMD), a response that is partially NO mediated (27), demonstrate preserved FMD in aging men (28), whereas there is a significant decline in aging women (28, 29). These sex-related differences in FMD with aging parallel the aforementioned hyperemic and vasodilator responses observed between older men and women during dynamic exercise (23–25). Therefore, the attenuated peak ROV in older women could be due to NO-bioavailability or signaling differences, although direct evidence for this is lacking.

We have previously reported (13) that enhanced α-adrenergic vasoconstrictor tone can partially explain the age-related reductions in contraction-induced ROV. Specifically, we demonstrated α-adrenergic receptor blockade via phentolamine reversed the age-related decline in ROV. Moreover, when sympathetic activity was stimulated via lower body negative pressure, vasodilation in response to a single muscle contraction was blunted in young adults, whereas older adults were unaffected. These data indicate that an increase in sympathetic tone contributes to age-related reductions in ROV following a single muscle contraction. Therefore, the sex-related difference in peak ROV observed in the present study may be related to potential differences in sympathetic activity. In young adults, men typically express greater muscle sympathetic nerve activity (MSNA) and neurovascular transduction than women (30, 31), whereas in older adults, women have demonstrated elevated MSNA at rest compared with that of men (32), although evidence is conflicting (33). Additionally, aging appears to influence sympathetic neurovascular transduction differently between sexes, with a decrease in older men and an increase in older women relative to their young counterparts (30). Thus, the lower peak ROV response in older women could potentially be attributed to elevated sympathetic activity and/or neurovascular transduction. However, our previous findings in a small group of older adults (13) suggest the influence of sympathetic restraint on ROV may not be greater in women, as they did not demonstrate a greater change in the ROV response during phentolamine. It should be noted that the aforementioned study (13) was not directly designed or adequately powered to detect sex-related differences. Conversely, Jackson et al. (16) reported aging impacts α-adrenergic restraint of ROV across a range of exercise intensities to a greater degree in male compared with female mice. Aside from possible species differences, the reason for these discrepancies is unclear.

In addition to possible differences in basal α-adrenergic vasoconstrictor tone explaining the sex-related differences in the older adults of the present study, the decreased ability to blunt sympathetic vasoconstriction (i.e., functional sympatholysis) in the vascular beds of contracting muscle should also be considered (34–37). The blunting of sympathetic vasoconstriction in contracting muscle occurs early in exercise (38) and can contribute to the rapid vasodilator response following a single contraction (39). Although evidence indicates young men and women express a similar degree of functional sympatholysis during steady-state exercise (40), sex-related differences in older adults have not been directly assessed. However, our previous data in a small group of older adults (seven men and six women) suggest that the ability to inhibit sympathetic vasoconstriction at the onset of exercise was similar between older men and women (13). Interestingly, the reported sympatholysis following a single muscle contraction appears to be intensity dependent and only occurs at a workload ≥ 30% MVC (39). In the present study, the comparison for a given absolute workload (∼11 kg) represents ∼20% MVC in older men and ∼40% MVC in older women. Assuming the 30% MVC threshold observed in young adults is needed for rapid sympatholysis (i.e., following a single muscle contraction) (39), it is possible only the older women in the present study had a stimulus great enough to lyse sympathetic vasoconstriction. Despite this possibility, older women still present a significantly lower peak ROV than older men, thus any potential impairment in functional sympatholysis does not fully explain the sex-related differences in peak ROV of older adults observed in the current study. Additionally, non-adrenergic neurovascular control of blood flow, such as adenosine triphosphate (ATP) and neuropeptide Y (NPY), may also play a role in sex differences related to sympathetic-mediated vascular tone during exercise (41). ATP seems to have a similar effect on vasodilation among young and older adults (36); however, little is known on how sex may impact vasodilation via ATP as well as on NPY. Likewise, it is unknown if a single forearm contraction can produce a great enough stimulus for a similar release of ATP and NPY as during dynamic exercise, or if there is a sex-related difference in the concentration or signaling of these substances.

While the present study provides new information related to potential sex-related differences in contraction-induced ROV, some experimental considerations are worth noting. First, the studies (10, 13, 15) used for this retrospective analysis were designed to measure hemodynamic responses at three relative intensities and a precise absolute workload was not performed by all subjects. Instead, we used small workload ranges (4–6 and 10–12 kg) to gain insight on whether the ROV response to “absolute” workloads of ∼5 kg and ∼11 kg differed between sexes. This range allowed for the greatest number of subjects with similar workloads to be compared between groups. Importantly, and as noted earlier, this approach resulted in the average workloads being very similar between each of the four groups.

As a second consideration, due to the retrospective nature of this study, multiple methods to assess continuous blood pressure (BP) postcontraction were utilized. That is, the BP waveforms were measured with finger plethysmography in some subjects (15), whereas intraarterial brachial pressures were utilized in others (10, 13). It could be argued that the discrepancies in the way BP was measured may have influenced the calculated MAP values and subsequent FVC data and ultimately the overall findings of the present study. However, previous studies have shown that noninvasive BP measurement with the Nexfin device is comparable with intraarterial catheter-measured BP over a wide range of pressure changes (42, 43). Likewise, it is important to note that for all contraction intensities, there were no significant changes in MAP (from baseline to postcontraction) in any of the groups regardless of method used for BP measurement (finger plethysmography or intraarterial). Furthermore, comparing the change in MAP from baseline to postcontraction revealed that the two methods were not significantly different at 10% (P = 0.27), 20% (P = 0.72), or 40% (P = 0.66) MVC. Lastly, the proportion of subjects who had intraarterial BP measurements did not differ between age groups (χ² = 0.44, P = 0.51) or between sexes (χ² = 0.92, P = 0.34). Therefore, it is unlikely that the two different methods used to assess continuous BP significantly influenced our current findings.

Conclusions

The novelty of the findings from the present study revolves around the effect aging has on sex-related differences in the rapid vasodilatory response to a single muscle contraction. Our findings demonstrate that sex influences contraction-induced rapid vasodilation in older adults, such that older women have blunted peak ROV compared with older men. As previous studies have clearly illustrated an age-related decline in ROV, our current data suggest older women may be driving the age-related differences in peak ROV to a greater extent than men.

GRANTS

This research was supported and funded by National Heart, Lung, and Blood Institute Research Grants HL-105467 (to D. P. Casey), HL-46493 and HL-139854 (to M.J. Joyner), RR-024150, and by Clinical and Translational Science Awards UL1 TR000135, and U54TR001013. The Caywood Professorship via the Mayo Foundation also supported this research.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

M.J.J. and D.P.C. conceived and designed research; M.J.J. and D.P.C. performed experiments; B.E.H. and D.P.C. analyzed data; B.E.H. and D.P.C. interpreted results; B.E.H. prepared figures; B.E.H. drafted manuscript; B.E.H., M.J.J., and D.P.C. edited and revised manuscript; B.E.H., M.J.J., and D.P.C. approved final version of manuscript.