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Published in final edited form as: Hypertension. 2011 Jan 24;57(3):484–489. doi: 10.1161/HYPERTENSIONAHA.110.165365

Impact of aging on conduit artery retrograde and oscillatory shear at rest and during exercise: Role of nitric oxide

Jaume Padilla 1, Grant H Simmons 1, Paul J Fadel 2,3, M Harold Laughlin 1,2,3, Michael J Joyner 4, Darren P Casey 4
PMCID: PMC3049300  NIHMSID: NIHMS267067  PMID: 21263118

Abstract

Aging has been recently associated with increased retrograde and oscillatory shear in peripheral conduit arteries; a hemodynamic environment that favors a pro-atherogenic endothelial cell phenotype. We evaluated whether nitric oxide (NO) bioavailability in resistance vessels contributes to age-related differences in shear rate patterns in upstream conduit arteries at rest and during rhythmic muscle contraction. Young (n=11, 26±2 yr) and older (n=11, 61±2 yr) healthy subjects received intra-arterial saline (control) and the NO synthase inhibitor NG-Monomethyl-L-arginine (L-NMMA). Brachial artery diameter and velocities were measured via Doppler ultrasound at rest and during a 5-min bout of rhythmic forearm exercise. At rest, older subjects exhibited greater brachial artery retrograde and oscillatory shear (−13.2±3.0 s−1 and 0.11±.0.02 a.u., respectively) compared to young subjects (−4.8±2.3 s−1 and 0.04±0.02 a.u., respectively; both p<0.05). NO synthase inhibition in the forearm circulation of young, but not older, subjects increased retrograde and oscillatory shear (both p<0.05) such that differences between young and old at rest were abolished (both p>0.05). From rest to steady state exercise, older subjects decreased retrograde and oscillatory shear (both p<0.05) to the extent that no exercise-related differences were found between groups (both p>0.05). Inhibition of NO synthase in the forearm circulation did not affect retrograde and oscillatory shear during exercise in either group (all p>0.05). These data demonstrate for the first time that reduced NO bioavailability in the resistance vessels contributes, in part, to the age-related discrepancies in resting shear patterns, thus identifying a potential mechanism for increased risk of atherosclerotic disease in conduit arteries.

Keywords: Age, Retrograde shear stress, Oscillatory shear stress, Nitric oxide bioavailability, Vascular conductance

INTRODUCTION

The non-uniform distribution of atherosclerosis throughout the arterial tree suggests that localized factors such as hemodynamic forces can modulate the susceptibility of the endothelium to dysfunction. Atherosclerotic lesions are indeed preferentially developed in regions distinguished by oscillatory (bidirectional blood flow) and low-time average shear stress; whereas areas subjected to unidirectional and high shear (within a physiological range) exhibit an atheroresistant endothelial phenotype.1–5 The remarkable capacity of endothelial cells to discern between different shear signals has been extensively demonstrated by in-vitro cell/organ culture6–15 and in-vivo animal studies16–20 as well as, more recently, in healthy humans.21,22 Indeed, human data indicate that an acute increase in retrograde and oscillatory shear in peripheral conduit arteries is associated with a reduction in endothelium-dependent dilation,21 while the opposite is also true. That is, transient removal of retrograde and oscillatory shear, in conjunction with increased forward shear, augments endothelial function.22

With the recognition that flow profiles can impact endothelial health, current research is exploring whether certain risk factors for vascular disease are linked to detrimental shear profiles in peripheral conduit arteries. In this regard, two recent reports indicate that aging is associated with greater presence of retrograde and oscillatory shear in both the brachial23 and femoral24 arteries; however, the mechanisms underlying such age-related differences in flow profiles have not been investigated. Given that conduit artery blood flow profiles are markedly affected by downstream vascular resistance,25,26 it is likely that biological pathways that both alter vascular tone and are influenced by aging (e.g. endothelial-derived nitric oxide27,28) contribute to the shear pattern differences between young and older populations. However, to date, this has not been tested. Furthermore, despite the plethora of data on blood flow responses to exercise in young and older subjects, no studies have examined the impact of aging on conduit artery shear rate patterns during exercise.

With this information as background, we evaluated the extent to which nitric oxide (NO) bioavailability in the resistance vessels may explain the age-associated discrepancies in resting shear rate patterns in the upstream conduit arteries. In addition, we determined whether the age-related differences in shear patterns that are present at rest are also manifested during skeletal muscle contraction where flow magnitude and profiles are markedly altered; in part, as a result of activation of additional non-NO vasoactive mechanisms and external forces (i.e. muscle compression).29 Primarily, we hypothesized that under resting conditions, NO synthase inhibition in the forearm circulation would increase brachial artery retrograde and oscillatory shear in young, but not older, subjects. We further hypothesized that during rhythmic forearm exercise, the age-related differences in brachial artery retrograde and oscillatory shear would be abolished and that inhibition of NO synthase in the forearm circulation would not have an impact.

METHODS

Subjects

Eleven young (26±2 yr; 6 men, 5 women) and eleven older (61±2 yr; 5 men, 6 women) healthy subjects were recruited for voluntary participation in this study. All subjects were free of any recognized cardiovascular, pulmonary, metabolic, or neurological disease, and were non-hypertensive (resting blood pressure < 140/90 mmHg), non-obese, and non-smokers. Subjects were not taking prescribed medications (except for oral contraceptives in some young women). Fasting blood chemistry screening in older subjects indicated that triglycerides (94.9±9.3) and low density lipoprotein cholesterol (116.8±12.1) were within the normal range for healthy adults. On the experimental day, subjects were instructed to report to the laboratory after an overnight fast and refraining from exercise and caffeine for at least 24 h. Young female subjects were studied during the early follicular phase of the menstrual cycle or the placebo phase of oral contraceptives. All older female subjects were postmenopausal and were not taking any form of hormone replacement therapy. Each subject received a verbal and written explanation of the study objectives, measurement techniques, the risks and benefits associated with the investigation, and provided written informed consent prior to participation. All procedures were approved by the Institutional Review Board and experiments were conducted at the Mayo Clinic (Rochester, MN).

Experimental Procedures

Arterial catheterization

A 20 gauge, 5 cm (Model RA-04020, Arrow International, Reading, PA, USA) catheter was placed in the brachial artery of the non-dominant arm under aseptic conditions after local anaesthesia (2% lidocaine) for administration of study drugs. The catheter was connected to a three-port connector in series, as previously described in detail.30 One port was linked to a pressure transducer positioned at heart level (Model PX600F, Edwards Lifescience, Irvine, CA, USA) to allow measurement of arterial blood pressure. The remaining two ports allowed arterial drug administration.

Brachial artery imaging

After placement of the catheter, subjects were positioned supine in a dark, climate-controlled (22–23°C) quiet room with both arms extended laterally. Brachial artery blood velocity and diameter were determined with a 12-MHz linear-array Doppler transducer (Model M12L, Vivid 7, General Electric, Milwaukee, WI, USA) placed proximal to the arterial catheter. Doppler velocity signals were corrected at an insonation angle of 60° and measurements were performed with a large sample volume to encompass the vessel lumen without extending outside of it. Brachial artery diameter measurements were obtained at end diastole during rest and steady-state exercise.

Drug infusions

NG-Monomethyl-L-arginine (L-NMMA; NO synthase inhibitor; Bachem, Switzerland) was infused at a loading dose of 5 mg min−1 for 5 min and then at a maintenance dose of 1 mg min−1 for the remainder of the study. In addition, intra-arterial infusions of acetylcholine (ACh; 2–8 μg/dl forearm volume/min) were used to estimate resistance vessel NO-dependent endothelial function in young and older subjects.31,32

Rhythmic forearm exercise

Subjects performed rhythmic forearm exercise with a handgrip device by the non-dominant arm at 10% of each subject's maximal voluntary contraction determined at the beginning of each experiment. The weight was lifted 4–5 cm over a pulley at a duty cycle of 1 s contraction and 2 s relaxation (20 contractions per minute) using a metronome to ensure correct timing.

Experimental protocol

Measurements were collected at rest and during a 5-min bout of rhythmic forearm exercise under a saline (control) infusion, followed by an L-NMMA infusion. Due to the long half-life of L-NMMA, saline was always administered first. A rest period of at least 20 min was allowed between both conditions to ensure re-establishment of baseline hemodynamic variables.

Data Analysis

Doppler shifts measured across the lumen of the vessel were demodulated so that a continuous (200 Hz) analog signal of mean blood velocity could be obtained. This signal, along with the electrocardiogram and arterial pressure tracing, were digitized and stored on a computer until off-line analysis using signal processing software (WinDaq, DATAQ Instruments, Akron, OH, USA). Time-average mean blood velocity, antegrade mean velocity and retrograde mean velocity were calculated. Diameter and velocity measures were used to estimate brachial artery shear rates. Mean shear rate (s−1) was defined as 4·Vm / D, where Vm is mean blood velocity (cm s−1) and D is arterial diameter (cm).33,34 For calculations of antegrade and retrograde shear rate, antegrade and retrograde mean blood velocities were used, respectively. Oscillatory shear index is a dimensionless parameter that can be used as an indicator of the magnitude of oscillation and can be defined as: |Retrograde shear| / (|Antegrade shear| + |Retrograde shear|).34–36 Note that the values for oscillatory shear range from 0 to 0.5, where a value of 0 corresponds to a unidirectional shear rate throughout the cardiac cycle, whereas a value of 0.5 represents pure oscillation with a time-average shear equal to zero. Forearm vascular conductance was calculated as the ratio between forearm blood flow (Vm·Π·D2/4·60) and mean arterial pressure and expressed as ml min−1 (100 mmHg)−1. All measurements at rest and during rhythmic forearm exercise were averaged over the last minute of data collection. During muscle contractions, the quality of the Doppler signal in two subjects (one from each group) was not optimal and therefore they were excluded from the analysis.

Statistical Analysis

Descriptive statistics were used to characterize the young and older groups of subjects. A 2 × 3 (group × ACh dose) mixed design repeated measures ANOVA was used to evaluate the aging effect on ACh-induced vasodilation and 2 × 2 (group × treatment) mixed design repeated measures ANOVA were employed to test the effects of age and NO synthase inhibition on all dependent variables under resting and exercise conditions. In addition, 2 × 2 (group × condition) ANOVA were used to test the effects of rhythmic forearm exercise in both groups under saline and L-NMMA infusions. Simple main effects were used to evaluate within-group (saline vs. LNMMA; rest vs. exercise) and between-group (young vs older) comparisons. All data are presented as mean ± standard error (SE). For all statistical tests, the alpha level was set at 0.05. Statistical analyses were performed with PASW Statistics 18 (SPSS, Inc. Chicago, IL, USA).

RESULTS

Subject characteristics are summarized in Table 1. Young and older subjects were of similar height, weight, body mass index, and exhibited a similar maximal voluntary contraction in the forearm (all p>0.05). As illustrated in Figure 1, older subjects had a blunted ACh-induced forearm vasodilation when compared to young subjects; however, this difference did not reach statistical significance.

Table 1.

Young and older subject characteristics

Variable Young Older
n 11 11
Gender (Men/Women) 6/5 5/6
Age (years) 26±2 61±2*
Height (cm) 173.1±0.03 171.0±0.03
Weight (kg) 70.8±3.2 73.4±3.9
Body mass index (kg m−2) 23.5±0.7 25.0±0.9
Systolic blood pressure (mmHg) 114±3 125±3*
Diastolic blood pressure (mmHg) 69±2 72±3
Maximal voluntary contraction (kg) 39.7±2.9 34.1±3.2
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Values are means ± SE.

*

Significantly different from Young; p<0.05

Figure 1.

Figure 1

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Change (Δ) in forearm vascular conductance during brachial artery infusion of acetylcholine (ACh; 2–8 μg/dl forearm volume/min) in young and older subjects.

For all outcome variables assessed, men and women from both groups (young and older) responded similarly to L-NMMA and rhythmic forearm exercise (all p>0.05); thus data were pooled across sexes. As depicted in Figure 2, older subjects demonstrated greater retrograde and oscillatory shear at rest (−13.2±3.0 s−1 and 0.11±.0.02 a.u., respectively) compared to young subjects (−4.8±2.3 s−1 and 0.04±0.02 a.u., respectively; both p<0.05). At rest, L-NMMA infusion in young, but not older, subjects increased retrograde (from −4.8±2.3 to −10.8±2.8 s−1; p<0.05) and oscillatory (from 0.04±0.02 to 0.10±0.03 a.u.; p<0.05) shear such that differences between young and old were abolished (both p>0.05).

Figure 2.

Figure 2

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Brachial artery retrograde shear rate and oscillatory shear index at rest and during rhythmic forearm exercise under saline and L-NMMA infusions in young and old subjects. Values are means ± SE. *Significantly different from Young; †Significantly different from Saline; ‡Significantly different from Rest; p<0.05

From rest to steady-state exercise, older subjects decreased retrograde (from −13.2±3.0 to −5.3±1.3 s−1; p<0.05) and oscillatory shear (from 0.11±0.02 to 0.02±0.01 a.u.; p<0.05) to the extent that no differences were found between young and old (both p>0.05). During exercise, L-NMMA infusion did not affect retrograde and oscillatory shear in either young or older subjects (all p>0.05). The effects of aging, inhibition of NO synthase, and rhythmic forearm exercise on all hemodynamic variables are summarized in Table 2.

Table 2.

Systemic and forearm hemodynamics at rest and during exercise under saline and L-NMMA infusions in young and older subjects

Rest Rhythmic Forearm Exercise
Young (n=11) Older (n=11) Young (n=10) Older (n=10)
Variable Saline L-NMMA Saline L-NMMA Saline L-NMMA Saline L-NMMA
Heart rate (beats min−1) 62±3 62±3 66±4 66±4 66±4‡ 65±3‡ 70±4‡ 69±4‡
Mean arterial pressure (mmHg) 88.7±2.2 91.3±2.0 102.1±4.4* 104.9±4.7*† 91.4±2.3‡ 93.3±2.2 107.7±4.7*‡ 108.7±5.1*‡
Forearm blood flow (ml min−1) 69.8±8.4 46.3±6.7† 61.5±6.4 53.4±7.4 214.4±24.1‡ 183.3±24.0‡ 217.3±25.5‡ 183.3±22.6‡
Forearm vascular conductance (ml min−1 100 mmHg−1) 78.9±9.5 51.3±7.5† 60.0±5.6 50.7±6.0 234.0±24.3‡ 196.1±24.2†‡ 199.6±20.2‡ 170.1±20.5‡
Brachial artery diameter (cm) 0.36±0.02 0.36±0.02 0.41±0.03 0.41±0.03 0.37±0.02‡ 0.37±0.02‡ 0.42±0.03 0.42±0.03
Mean velocity (cm s−1) 11.3±1.1 7.7±0.9† 8.1±0.8* 6.8±0.6 33.0±2.2‡ 29.4±3.3‡ 26.9±3.0‡ 21.7±1.6*‡
Mean shear rate (s−1) 129.1±16.0 88.9±11.8† 86.2±12.0* 70.4±7.5 367.8±33.9‡ 334.7±45.1‡ 273.1±41.6‡ 214.4±21.1*‡
Antegrade velocity (cm s−1) 11.7±1.1 8.6±0.8† 9.4±0.8 7.9±0.7 33.4±2.2‡ 29.8±3.2‡ 27.4±3.1‡ 22.1±1.6*‡
Antegrade shear rate (s−1) 133.9±15.0 99.7±11.1† 99.3±13.0 81.8±8.8 371.3±33.7‡ 338.9±44.8‡ 278.4±42.1‡ 218.3±21.3*‡
Retrograde velocity (cm s−1) −0.4±0.2 −1.0±0.3† −1.2±0.3* −1.1±0.2 −0.3±0.1 −0.4±0.1‡ −0.6±0.1‡ −0.4±0.1†‡
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Values are means ± SE.

*

Significantly different from Young

†

Significantly different from Saline

‡

Significantly different from Rest; p<0.05

DISCUSSION

The primary novel findings of the present study are as follows: 1) NO synthase inhibition in the forearm circulation of young subjects increased retrograde and oscillatory shear such that values were similar to those observed in older subjects at rest; 2) during steady-state forearm rhythmic exercise, older subjects decreased retrograde and oscillatory shear to the extent that the age-related differences observed under resting conditions were eliminated; and 3) NO synthase inhibition did not affect retrograde and oscillatory shear during exercise in either young or older subjects. Collectively, these data indicate that a reduction of NO in the forearm circulation of young subjects recapitulates the aging effect on resting upstream conduit artery shear rate profiles. Furthermore, rhythmic muscle contraction markedly reduced conduit artery retrograde and oscillatory shear of older subjects; thus identifying a favorable impact of acute exercise on age-related changes in shear patterns.

The clinical significance of these findings is noteworthy. The present study is the first to suggest that an age-related reduction in basal NO bioavailability in the resistance vessels contributes, in part, to the greater presence of retrograde and oscillatory shear in the upstream conduit artery. This is supported by the fact that NO synthase inhibition in the forearm circulation results in an increase in brachial artery retrograde and oscillatory shear in young, but not older, subjects. In fact, the increases in retrograde and oscillatory shear with inhibition of NO synthase in young subjects is such that they reach the levels exhibited by older subjects; therefore, it is suggested that a large portion of age-related differences in shear profiles may be mediated by discrepancies in NO bioavailability in the microcirculation. However, contributions of downstream arteries in the forearm (e.g. radial artery) cannot be completely discounted.

In the current study, we also observed that stimulated NO release (i.e. response to ACh) can reduce brachial artery retrograde and oscillatory shear in both young and older subjects (p<0.05; data not shown). However, it should be noted that the lack of an effect of L-NMMA in the older subjects does not necessarily indicate reduced basal NO bioavailability as the sole cause for age-related alterations in shear profiles. It is possible that the age-related increase in retrograde and oscillatory shear may be explained by other factors such as vascular smooth muscle impairment or increased sympathetic nerve activity.23,36 In fact, the finding that resistance vessel NO-dependent endothelial function was not markedly impaired in our older subjects (Figure 1) supports the idea that disruption of the NO pathway may not be the sole contributor to the discrepancies in upstream shear profiles at rest. Therefore, at this time, the age-related reduction in NO remains as a potential and likely mechanism by which aging is associated with altered retrograde and oscillatory shear; however, further research is required to confirm this hypothesis.

Collectively, these data support a potential path by which microvascular endothelial dysfunction may evolve into macrovascular dysfunction. As such, we propose that, with advancing age, a reduction in NO bioavailability in the resistance vessels among other factors provokes a chronic exposure of conduit arteries to increased retrograde and oscillatory shear which ultimately may lead to enhanced endothelial vulnerability and risk for atherosclerotic disease in conduit arteries.

Equally important is the remarkable impact of skeletal muscle contraction on the magnitude and profile of conduit artery shear. Indeed, during muscle contractions, additional non-NO vasoactive mechanisms and external forces (i.e. muscle compression) are activated29 which together result in complex flow waveforms.37–40 It is commonly accepted that repeated episodes of elevated and altered shear stress profiles represent the primary physiological signal for beneficial endothelial adaptations to exercise training.41 Despite the wealth of information on blood flow responses to exercise in young versus old, little data is currently available evaluating the influence of aging on shear rate responses to exercise.38,42 In this regard, our study indicates that during rhythmic muscle contraction, the age-related differences in conduit artery retrograde and oscillatory shear observed at rest are abolished. Indeed, vasodilation within the active muscle beds leads to an overall increase in vascular conductance which favors the reduction of retrograde flow in the upstream conduit arteries.

The concept that vascular conductance influences flow profiles is well exemplified by studies of reactive hyperemia; a period during which retrograde flow is completely eliminated.43 In this context, our group44 and others22 have observed that brachial artery retrograde flow is reduced as a result of decreases in downstream resistance; reciprocally, conditions that elevate vascular resistance provoke an increase in retrograde flow.21,25,36,44 For example, in the present study we found significant correlations between L-NMMA-induced reduction in forearm vascular conductance and changes in retrograde (R2=0.31, R=0.56, p=0.007) and oscillatory (R2=0.57, R=0.75, p<0.0001) shear (all subjects combined). That is, the greater the reduction in conductance, the larger the increase in retrograde and oscillatory shear. In fact, the group discrepancies in shear patterns are explained by the fact that young subjects exhibited a robust reduction (−55%, P<0.05) in conductance in response to L-NMMA infusion while the older subjects only experienced a mild decrease (−17%, P>0.05). The observation that the (non-significant) 17% reduction in forearm vascular conductance did not result in a trend for a change in upstream brachial artery shear patterns in older subjects is interesting. It is plausible that a minimal change in conductance (i.e. threshold) may be necessary to trigger an alteration in upstream shear profiles. Indeed, there are likely a number of factors that interact to influence shear profiles. In this regard, we recently demonstrated that acute elevations in muscle sympathetic nerve activity are associated with an increase in conduit artery retrograde and oscillatory shear, an effect that is counteracted by concurrent increases in arterial blood pressure.36

In contrast to the apparent role of NO in regulating shear profiles at rest, during skeletal muscle contraction NO did not appear to contribute to the modulation of retrograde and oscillatory shear in either young or older subjects. This observation is consistent with previous data also indicating that intra-brachial infusion of L-NMMA does not impact flow profiles (including the magnitude of retrograde flow) during handgrip exercise;39 hence further supporting the notion that NO release is not required for skeletal muscle hyperemia during normoxic exercise.31 Of interest, our results suggest that transitioning from rest to exercise is an effective strategy for exposing the endothelium of conduit arteries to favorable (“younger looking”) hemodynamic signals even in the presence of reduced NO bioavailability in the resistance vasculature.

Perspectives

While the impact of aging on conduit artery endothelial health is well established,45–49 the mechanisms underlying the age-related decline in vascular function have not yet been fully elucidated. In this regard, our data and those from others23,24 demonstrating that aging is associated with greater presence of retrograde and oscillatory shear in peripheral conduit arteries stimulate the possibility that endothelial dysfunction with aging may be attributable, at least in part, to disturbed shear profiles. Indeed, a causal link between disturbed flow patterns and a pro-atherogenic endothelial cell phenotype has been extensively demonstrated by in-vitro studies using cell culture and isolated perfused arteries6–12,15 as well as by in-vivo animal16–20 and human21 data. The current study suggests that a reduction in basal NO bioavailability in downstream arteries (i.e. radial artery) and resistance vessels of the forearm contributes, in part, to the age-related discrepancies in shear rate patterns in upstream conduit vessels (i.e. brachial artery); proposing a potential path by which microvascular dysfunction and macrovascular disease may be connected. Furthermore, rhythmic muscle contraction markedly reduced conduit artery retrograde and oscillatory shear of older subjects; thus identifying a favorable impact of acute exercise on age-related changes in shear patterns.

ACKNOWLEDGMENTS

The authors thank all the subjects for their time, effort, and willingness to participate in the study.

SOURCE OF FUNDING: This study was supported by the following grants from NIH: AR-55819 (DPC), HL-46493 (MJJ), CTSA RR-024150, HL-093167 (PJF), and T32-AR048523 (JP and GHS). The Caywood Professorship via the Mayo Foundation also supported this research (MJJ).

Footnotes

CONFLICT OF INTEREST/DISCLOSURE: None

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