Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2021 Aug 1.
Published in final edited form as: J Physiol. 2020 Jun 16;598(16):3331–3341. doi: 10.1113/JP279877

Broader adaptive range of sympathetic burst size in response to blood pressure change in older women with greater arterial stiffness

Yoshiyuki Okada 1,2,3, M Melyn Galbreath 1,2, Sara S Jarvis 1,2,4, Shigeki Shibata 1,2, Wanpen Vongpatanasin 2, Benjamin D Levine 1,2, Qi Fu 1,2
PMCID: PMC7429302  NIHMSID: NIHMS1614247  PMID: 32449522

Abstract

There are sex differences in arterial stiffness and neural control of blood pressure (BP) among older adults. We examined whether the sympathetic response to BP is greater in older women than men in burst size but not burst occurrence. Burst occurrence and size were assessed with burst interval and area of muscle sympathetic nerve activity, respectively, and the distributions of these indices were evaluated by range during supine rest in 61 healthy older subjects [30 men (69±6years) and 31 women (68±6years); means±SD]. Also, we analyzed sympathetic baroreflex sensitivity (BRS) with burst occurrence and area simultaneously. Carotid β-stiffness was measured with B-mode ultrasonic image and carotid BP. The range of burst interval was smaller in older women than men (P=0.002), while there was no difference in the range of burst area. Carotid β-stiffness was greater in older women than men (6.7±2.7 vs. 5.1±2.7, P =0.027). Sympathetic BRS assessed with burst incidence was lower in older women than men (−2.3±1.4 vs. −3.3±1.4 bursts·100beats−1·mmHg−1, P=0.007), while this sex difference was observed when assessed with burst area after adjusting for carotid β-stiffness (−116.1±135.0 vs. −185.9±148.2 a.u.·burst−1·mmHg−1, P=0.040), but not before. Sympathetic BRS assessed with burst area was negatively (more sensitive) correlated with carotid β-stiffness in older women (r=−0.53, P=0.002) but not men. These data suggest that the response of burst size within each burst is augmented for the baroreflex BP control despite the impaired response of burst occurrence in older women with greater carotid stiffness.

Keywords: baroreceptors, muscle sympathetic nerve activity, β-stiffness, aging, sexes

Introduction

The occurrence of sympathetic outflow to the skeletal muscle is higher (Ng et al., 1993; Matsukawa et al., 1998b), while the integrative blood pressure (BP) buffering capacity is lower in older people compared to the young (Jones et al., 2003). These physiological alterations in the old have been identified as risk factors for hypertension and cardiovascular diseases (Cohn et al., 1984; Fisher & Paton, 2012). Thus, it is clinically and physiologically important to ascertain the underlying mechanism(s) of these age-related changes in neural-vascular control of BP.

The magnitude of the sympathetic nervous response to a given change in BP, measured by sympathetic baroreflex sensitivity (BRS), is known as the beat-by-beat BP buffering capacity through the vasculature. It was generally reported that the response of muscle sympathetic nerve activity (MSNA) was similar across all ages when assessed with total activity or the summation of burst area/amplitude per min during the neck chamber method (Ebert et al., 1992), phase IV of the Valsalva maneuver (Matsukawa et al., 1998a), and stepwise infusion of phenylephrine for baroreceptor loading by BP elevation (Davy et al., 1998). On the other hand, the age-related reduction in the response of sympathetic outflow was shown when assessed with total MSNA or summation of burst area/amplitude per unit beat during BP reduction by bolus injection of nitroprusside (Studinger et al., 2009) and during phase II of the Valsalva maneuver (Matsukawa et al., 1998a). These discrepancies between different studies suggest that baroreflex mediated sympathetic response may be modulated differently, some of which are blunted and the others seem to be maintained or even increased with age.

We previously demonstrated a positive (less sensitive) correlation between carotid stiffness and sympathetic BRS assessed with burst incidence (the number of bursts per 100 heart beats) in older adults with no difference in the slope of the regression line relating stiffness and BRS between men and women (Okada et al., 2011). Based on the evidence of an age-related increase in arterial stiffness (Tanaka et al., 2000), this lower response in sympathetic occurrence to a given change of BP in older people seems to be caused by increased stiffness of the barosensory arteries and the effects appear to be comparable between sexes. We also showed less responsiveness of burst occurrence in older women with greater carotid stiffness than men, which may be attributed to the impaired mechanical component of the sympathetic baroreflex. However, the integrated sympathetic BRS was reported to be similar between older men and women (Studinger et al., 2009), suggesting that the impaired oscillation system of MSNA burst occurrence in women could have been compensated by other module(s) of the neural component (Malpas, 1995; Kienbaum et al., 2001), such as control over the number of activated neurons for the strength of each burst. Because MSNA burst area reflects the number of the efferent fibers firing in each burst, the burst area regulation may remain intact and be a predominant BP buffering system in older women with increased arterial stiffness.

Accordingly, we hypothesized that the relative changes of burst area versus burst occurrence in response to BP changes would be greater in older women than men and sympathetic BRS calculated with burst area would be correlated with carotid artery stiffness, which may be opposite to the relationship between sympathetic BRS calculated with burst incidence and the stiffness. To test these hypotheses, we measured variabilities from distributions of burst occurrence and burst area and calculated the ratio between them to evaluate contributions of both MSNA factors to control BP in older men and women, separately. Moreover, we evaluated sympathetic BRS with burst area and its relationship with the carotid artery stiffness in older men and women.

Methods

Ethical Approval

All subjects gave their written informed consent to a protocol approved by the Institutional Review Boards of the University of Texas Southwestern Medical Center and Texas Health Presbyterian Hospital Dallas (STU 102010–072). The study conformed to the standards set by the Declaration of Helsinki, except for registration in a database.

Subjects

Sixty-one older volunteers (30 men, 31 women) participated in this study. They were non-smokers and had no overt history of cardiovascular, neuromuscular, diabetes mellitus, renal diseases, or sleep apnea. They were excluded if they regularly exercised at moderate-to-high intensity levels for >30 min/day for >3 times/week, or their body mass index was >35 kg·m−2. Women taking hormone replacement therapy were excluded. Subjects’ physical characteristics are presented in Table 1.

Table 1.

Physical characteristics

Men Women P-value
Age, years 69 ± 6 68 ± 6 0.382
Height, cm 176 ± 5 162 ± 6 <0.001
Weight, kg 83 ± 9 71 ± 10 <0.001
Body surface area, m2 2.01 ± 0.13 1.78 ± 0.15 <0.001
Body mass index, kg m−2 26.7 ± 2.5 26.7 ± 3.4 0.963
Open in a new tab

Values are means ± SD. Each variable of physical characteristics was compared between men (n=30) and women (n=31) using unpaired t-tests.

Measurements

Muscle sympathetic nerve activity

MSNA signals were obtained with the microneurography (Sundlof & Wallin, 1978; Vallbo et al., 1979). In brief, a recording electrode was placed in the peroneal nerve at the popliteal fossa, and a reference electrode was placed subcutaneously 2–3 cm apart from the recording electrode. The nerve signals were amplified (70 000 to 160 000-fold), band-pass filtered (700 to 2000 Hz), full-wave rectified and integrated with a resistance-capacitance circuit (time constant 0.1 sec). Criteria for adequate MSNA recording include: pulse synchrony, facilitation during the hypotension phase of the Valsalva maneuver, increase in response to breath-holding, and insensitivity to loud noise (Vallbo et al., 1979).

Hemodynamics

Heart rate (HR) was determined from lead II of the electrocardiogram (ECG; model 78532B, Hewlett-Packard, Andover, MA) and beat-by-beat BP was derived by finger photoplethysmography (Nexfin, BMEYE, Amsterdam, the Netherlands). Arm cuff BP was measured by electrosphygmomanometry (model 4240, SunTech Medical Instrument Inc., Raleigh, NC) with Korotkoff sounds detected by a microphone from the brachial artery. Beat-by-beat carotid pressure was obtained with a pencil-sized tonometer containing a high-fidelity strain gauge transducer (SphygmoCor, AtCor Medical Inc, Itasca, IL). Since the absolute levels of these arterial pressures were subjected to hold-down force, the pressure signals obtained by tonometry were calibrated by equating their DBP and mean BP (MBP) to those obtained at the brachial artery as previously reported (Tanaka et al., 2000). Cardiac output (CO) was measured with the modified acetylene rebreathing technique (Jarvis et al., 2007). Stroke volume (SV) was calculated from CO divided by HR and total peripheral resistance (TPR) was calculated as the quotient of MBP (DBP + [systolic BP (SBP) – DBP] / 3) from arm cuff and CO, multiplied by 80 (expressed as dyne•s·cm−5), where all variables were measured during rebreathing. CO, SV, and TPR were normalized to body surface area as cardiac, stroke, and TPR indices.

Carotid artery images

Cross-sectional images of the right common carotid artery were obtained using a phase-locked echo tracking system coupled to a B-mode ultrasonic imager (iE33 Ultrasound System, Philips Ultrasound, Bothell, WA). This allows sequential capture of the arterial vessel wall movement non-invasively through a high-resolution transducer (7.5 MHz) positioned at 2 cm proximal to the carotid bifurcation with simultaneous ECG recordings (Izumi et al., 2006).

Protocol

The experiment was performed in the morning ≥2 h after the breakfast, ≥72 h after the last caffeinated or alcoholic beverage, and ≥24 h after strenuous physical activity in a quiet, environmentally controlled laboratory with an ambient temperature of ~25°C. Subjects were asked to rest in the supine position. At least 10 min after a satisfactory site for MSNA measurement had been located, baseline data were recorded for 6 min with the subjects resting quietly and breathing spontaneously. Baseline hemodynamics were obtained in all subjects in the supine position on the next day in the morning. Subsequently, duplicate carotid and brachial arterial pressures were measured using tonometry and arm cuff, followed by ultrasonography on the common carotid artery. Throughout these experimental procedures, beat-by-beat BP and HR were recorded continuously.

Data Analysis

Data were sampled at 625 Hz and stored on personal computer with a commercial data acquisition system (AcqKnowledge, Biopac System, Santa Barbara, CA). Off-line data analyses were performed using signal-processing software (LabView, National Instrument, Austin, TX). Beat-by-beat SBP and DBP were obtained from the arterial-pressure waveform and beat-by-beat MBP was calculated as the time integral over the pressure pulse. Sympathetic bursts were identified by a computer program (Cui et al., 2002), and then confirmed by an experienced microneurographer. The integrated neurogram was normalized by assigning a value of 100 to the largest amplitude of sympathetic burst during the 6-min baseline (Halliwill, 2000). Burst area was measured as the area under the curve of each sympathetic burst of the normalized integrated neurogram on a beat-by-beat basis. The number of bursts per minute (burst frequency), the number of bursts per 100 heart beats (burst incidence), mean area per burst (mean burst area), and the burst area per minute and that per 100 beats (total activity and total MSNA) were used as quantitative indices.

Distribution rate of burst size and burst occurrence

Figure 1 illustrates the relation of burst occurrence and burst size, and how these variables were analyzed. Burst occurrence was assessed with burst interval as a time between peaks of a given burst and next burst, and burst size was assessed with burst area as mentioned above (Figure 1C). Each pair of the data for a burst was plotted in the X-Y plane (Figure 1B). Distributions of burst interval and area were then evaluated separately with the probability of the variables in each bin (Figure 1A and D). Variabilities of burst interval and area, as well as those of beat-by-beat SBP and DBP were assessed by range, SD, and the coefficient of variance (CV). We calculated the “variation ratio” using burst area variability divided by burst interval variability to evaluate the contribution of burst size versus burst occurrence to neural control of BP during spontaneous breathing.

Figure 1:

Figure 1:

Open in a new tab

Representative data of the relationship between burst peak-to-peak interval indicating burst occurrence rate and burst area (B) and the probabilities of these variables (A & D) for a subject. Right-upper panel (C) demonstrates how to analyze peak-to-peak interval and area of a given burst.

Sympathetic baroreflex sensitivity

Baroreflex control of MSNA was assessed by using the slope of the linear correlation between MSNA and DBP (Ichinose et al., 2008; Fu et al., 2009) because changes in MSNA correlate closely with changes in DBP but not SBP (Sundlof & Wallin, 1978). To perform a linear regression, value for burst incidence, burst area, and total MSNA were averaged over a 2-mmHg DBP bin increment covering the lowest to highest DBP, respectively (Rudas et al., 1999; Halliwill, 2000; Ichinose et al., 2008). This pooling procedure reduces the statistical impact of inherent beat-by-beat variability in nerve activity due to non-baroreflex influences (e.g. respiration) (Vallbo et al., 1979). Moreover, a statistical weighting was adopted to minimize the effect of minor variation of bin width and bin position on the slope with respect to the number of cardiac cycles in the bins (Kienbaum et al., 2001).

Carotid arterial stiffness

Stiffness of the carotid artery was determined using a combination of ultrasound images and carotid arterial pressures. The operator traced the vessel wall boundary corresponding to the interface between the lumen and intima to detect luminal area at minimal diastolic relaxation and at maximal systolic expansion with image-analysis software (QLAB, Philips Ultrasound, Bothell, WA). The β-stiffness index was then calculated as an arterial stiffness adjusted for distending pressure as previously reported (Hirai et al., 1989).

Statistical Analysis

Values are expressed as means±SD. Data between men and women were compared using unpaired t-tests. If normality tests and equal variance tests failed, we compared the sex differences using Mann-Whitney rank sum tests. Linear regression analysis was used to evaluate the correlation between carotid artery stiffness and sympathetic BRSs and the parallel line analysis was performed to compare the slope of the regression line between men and women. Furthermore, we evaluated sex differences in sympathetic BRSs using ANCOVA with carotid artery stiffness as a covariate. A P value of <0.05 was considered statistically significant.

Results

Hemodynamics and MSNA Variables

Table 2 showed supine resting hemodynamics and MSNA variables in older men and women. There was no difference between sexes in arm cuff SBP and MBP. Women had lower arm cuff DBP, CO, and SV, but higher HR compared with men (all, P<0.05). Cardiac index showed no sex difference (P=0.392) while stroke index was significantly smaller in older women than men (P<0.001). Absolute TPR trended to be higher in older women than men (P=0.099), but TPR index did not differ between sexes (P=0.458). Although MSNA burst frequency tended to be higher in older women (P=0.096), there were no significant sex differences in burst incidence, total activity, or total MSNA.

Table 2.

Resting hemodynamics and MSNA variables

Men Women P-value
Cuff SBP, mmHg 124 ± 15 122 ± 15 0.656
Cuff DBP, mmHg 73 ± 10 68 ± 9 0.028
Cuff MBP, mmHg 90 ± 10 86 ± 10 0.113
HR, beats min−1 60 ± 9 65 ± 7 0.046
CO, l min−1 4.2 ± 0.5 3.6 ± 0.7 <0.001
Cardiac index, l min−1 m−2 2.1 ± 0.3 2.0 ± 0.3 0.392
SV, ml 68 ± 12 52 ± 8 <0.001
Stroke index, ml m−2 34 ± 6 29 ± 4 <0.001
TPR, dyne.s.cm−5 1618 ± 293 1753 ± 332 0.099
TPR index, dyne.s.cm−5 m2 3269 ± 689 3096 ± 527 0.458
MSNA
 Burst frequency, bursts min−1 39 ± 9 42 ± 8 0.096
 Burst incidence, bursts 100beats−1 64 ± 12 66 ± 11 0.664
 Total activity, a.u. min−1 565 ± 152 586 ± 173 0.617
 Total MSNA, a.u. 100beats−1 953 ± 268 907 ± 233 0.479
Open in a new tab

SBP indicates systolic blood pressure; DBP, diastolic blood pressure; MBP, mean blood pressure; HR, heart rate; CO, cardiac output; SV, stroke volume; TPR, total peripheral resistance; MSNA, muscle sympathetic nerve activity; a.u., arbitrary unit. Values are means ± SD. Each variable of hemodynamics and MSNA indices was compared between men (n=30) and women (n=31) using unpaired t-tests.

Blood Pressure and MSNA Variability

Beat-by-beat SBP and DBP, and burst area showed no significant differences between older men and women (Table 3). There were no sex differences in range, SD, or CV of beat-by-beat SBP or DBP (all P>0.05). MSNA burst interval and its range and SD were smaller in older women than men (P=0.047, 0.002, and 0.050), while those of burst area showed no differences between sexes (all P>0.05). The variation ratio assessed with the range of burst area to that of burst interval was significantly larger and the ratio assessed with the CV of burst area to that of burst interval tended to be larger in older women than men, respectively (P=0.021 and 0.098).

Table 3.

BP and MSNA variability

Men Women
Beat-by-beat SBP, mmHg 126.5 ± 19.5 117.1 ± 20.7
 Range, mmHg 33.4 ± 9.6 31.8 ± 16.1
 SD, mmHg 6.2 ± 2.0 6.7 ± 4.8
 CV, % 5.0 ± 1.7 5.8 ± 4.1
Beat-by-beat DBP, mmHg 67.6 ± 12.5 62.8 ± 12.7
 Rangea, mmHg 18.2 ± 6.2 15.8 ± 4.3
 SD, mmHg 3.2 ± 1.0 2.9 ± 0.9
 CV, % 4.9 ± 1.6 5.1 ± 2.9
Burst interval, ms 1649.4 ± 396.5 1469.9 ± 287.8 *
 Range, ms 7047.5 ± 2514.8 5247.2 ± 1857.9 *
 SD, ms 1136.8 ± 434.9 933.8 ± 358.4 *
 CV, % 67.2 ± 14.2 61.8 ± 12.6
Burst area, a.u. 14.6 ± 2.4 13.8 ± 2.7
 Range, a.u. 26.7 ± 4.3 25.2 ± 6.5
 SD, a.u. 4.7 ± 0.6 4.6 ± 0.9
 CV, % 33.0 ± 5.1 34.0 ± 5.9
Variation ratio
 Rangeburst area/Rangeburst interval, a.u. s−1 4.2 ± 1.4 5.3 ± 2.2 *
 SDburst area/SDburst interval, a.u. s−1 4.8 ± 1.9 5.6 ± 2.4
 CVburst area/CVburst interval × 102 51.0 ± 12.3 57.4 ± 17.3
Open in a new tab

SD indicates standard deviation; CV, coefficient of variance. Values are means ± SD. Each variable of BP variabilities and MSNA variabilities was compared between men (n=30) and women (n=31) using unpaired t-tests or Mann-Whitney rank sum tests. a, the Mann-Whitney rank sum test.

*

, P < 0.05 vs. Men.

Responses in Sympathetic Outflow and Arterial Stiffness

Table 4 depicts sympathetic BRSs assessed with MSNA indices as the response of sympathetic outflow to BP. Sympathetic BRSs assessed with burst incidence and total MSNA were significantly lower in older women than men (P=0.007 and 0.002), while the sex difference of sympathetic BRS was weakened when assessed with burst area even in the same subjects (P=0.059). The carotid artery stiffness is also shown in Table 4. Older women had greater β-stiffness in the carotid artery than older men (P=0.027). Lower sympathetic BRSs assessed with burst incidence and total MSNA in older women were still observed after adjusting for β-stiffness of the carotid artery (ANCOVA P=0.025 and 0.010; Table 4), while the P values became greater compared to pre-adjusted values. In contrast, sympathetic BRS assessed with burst area in older women became significantly lower than men after adjusting for the β-stiffness (ANCOVA P=0.040). Figure 2 shows the relationship between carotid artery stiffness and sympathetic BRS assessed with burst area. The slope of the regression line was significantly different between older men and women (P<0.001), which was negatively (more sensitive) correlated with each other in older women but not older men. These results were different from those reported in a previous study showing that sympathetic BRS assessed with bust incidence was positively (less sensitive) correlated with carotid stiffness in both older men and women (Okada et al., 2011).

Table 4.

Sympathetic BRS and carotid artery stiffness

Men Women P-value (t-tests) P-value (ANCOVA)
Sympathetic BRS
 bursts 100beats−1 mmHg−1 −3.3 ± 1.4 −2.3 ± 1.4 0.007 0.025
 a.u. 100beats−1 mmHg−1 −63.9 ± 29.1 −42.8 ± 22.3 0.002 0.010
 a.u. burst−1 mmHg−1 −185.9 ± 148.2 −116.1 ± 135.0 0.059 0.040
β-stiffness of carotid artery 5.1 ± 2.7 6.7 ± 2.7 0.027 -
Open in a new tab

BRS indicates baroreflex sensitivity. Values are means ± SD. Each variable of sympathetic BRS and carotid artery stiffness was compared between men (n=30) and women (n=31) using unpaired t-tests. In addition, sex difference of each sympathetic BRS was also compared using ANCOVA with carotid artery stiffness as a covariate.

Figure 2:

Figure 2:

Open in a new tab

Linear regression analysis of the inter-individual relationships between β-stiffness of the carotid artery and sympathetic BRS assessed with burst area in older men (○; n=30) and women (●; n=31). Bivariate correlations were examined using the Pearson correlation coefficient and the slopes of the regression line were compared between older men and women using the parallel line analysis.

Discussion

Our major findings were: (1) the variation ratio of MSNA burst size (burst area) to burst occurrence (burst interval) was higher in older women than men; (2) sympathetic BRSs were smaller in older women than men, while the sex difference was relatively weak when assessed with burst area; (3) however, sympathetic BRS assessed with burst area was also significantly smaller in older women after adjusting for arterial stiffness; and (4) sympathetic BRS assessed with burst area was negatively correlated with carotid artery stiffness; it was hence more sensitive as the carotid artery was stiffer in older women. Thus, the broader distribution of burst area and its higher response to a given change in BP may compensate for the impaired response of baroreflex mediated burst occurrence in older women with greater carotid artery stiffness.

Burst Occurrence and Burst Size

MSNA is composed of burst occurrence and size, both of which play an important role in maintaining BP around the operating point of the baroreflex curve. In the current study, we did not observe any sex differences in range, SD, or CV of spontaneous BP changes, while variabilities of MSNA burst interval were smaller in older women than men. Interestingly, the variation ratios calculated from the range and CV of burst area divided by those of burst interval were larger in older women. Collectively, these results suggest that BP in older women is regulated similarly to older men through a broader capacity of the response in MSNA burst size rather than burst occurrence. Thus, burst size regulation may be the predominant mechanism in sympathetic control of BP in older women.

Malpas (Malpas, 1995) proposed, in the rabbit model, that separate MSNA discharge processes of the neural component exist. It was proposed that the oscillation system—that is, the burst occurrence stems from the higher site and the recruiting system—that is, the number of firing neurons stems from the lower site. Keinbaum et al. (Kienbaum et al., 2001) have supported this proposal in the human model. Relative changes in burst size indicating the number of firing neurons within each MSNA burst can be used for intra-individual comparisons during a recording session, but not for inter-individual comparisons for technical reasons (Vallbo et al., 1979; Wallin & Elma, 1997). However, recent cross-sectional studies demonstrated that burst size distribution was inter-individually larger in patients with congestive heart failure than healthy controls and reduced to the normal level after heart transplantation along with a decrease in burst occurrence (Sverrisdottir et al., 2000). Moreover, Shoemaker et al. (Shoemaker et al., 2001) reported a higher increase in MSNA during both progressive head-up tilt and the cold pressor test in young men than women, which was caused by a greater response of burst size but not burst frequency or incidence in men. It becomes impossible to evaluate sympathetic activation by counting bursts when baseline MSNA burst occurrence reaches almost maximum, in which a burst is observed with nearly every heart beat and the number of bursts could not increase any more—a ceiling effect, and the burst size would be an only index for MSNA to increase in this condition. Indeed, sympathetic BRS assessed with burst incidence was reported to be impaired in older women who have greater arterial stiffness and a higher baseline MSNA burst occurrence, especially during baroreflex unloading evoking sympathetic activation. Conversely, sympathetic BRS was reported to be sustained when assessed during baroreflex loading that induced a reduction in MSNA (Davy et al., 1998) because the reduction in the number of firing neurons can also decrease burst occurrence from its maximum rate. Thus, BP buffering capacity by sympathetic burst can be verified only with burst size but not with burst occurrence, when basal burst frequency was very high and the sympatho-excitatory reservoir of burst occurrence was very small especially during baroreceptor unloading. Therefore, it looks as if the sympathetic response in burst size was sustained, but the response of sympathetic burst occurrence was impaired in older women.

Contribution of Each Neural Site to Sympathetic BRS

It has been well established that the occurrence of MSNA bursts assessed with burst incidence or burst frequency, as well as total activity which includes the factor of burst occurrence, is closely regulated by the baroreflex (Barman & Gebber, 1980; Ebert et al., 1992; Fu et al., 2009), while there is little information on the regulation of the burst size assessed with area of each burst in older adults. As shown in Figure 1B, differences of burst interval had less impact on burst area, suggesting that the timing of baroreceptor input may affect the probability of burst occurrence but not burst size. In other words, the strength of input depending on the accumulation levels of baroreceptor loading appeared to predominantly affect burst area in older adults. Sundlof and Wallin (Sundlof & Wallin, 1978) showed that a 10 mmHg variation in DBP caused a twofold change in burst amplitude and a fivefold change in burst frequency of MSNA. These data suggested that the number of firing neurons within a burst was regulated with the intensity of baroreceptor input, while the input contributed more on burst frequency than burst area in young and middle-aged subjects. Matsukawa et al. (Matsukawa et al., 1998a) assessed sympathetic BRS with burst area response to a given change in beat-by-beat MBP during the Valsalva maneuver and showed lower sensitivity in older men than young men. Since the age-related change was reported to be greater in burst frequency compared with burst amplitude (Sverrisdottir et al., 2000), aging might have a different impact on burst incidence versus burst area, and hence, their balance of contribution to baroreflex control in the older group may differ from the young and middle-aged groups. The response in burst occurrence to progressive head-up tilt as a value of sympathetic baroreflex function in young women was the same as men (100% of response in men) (Shoemaker et al., 2001), while sympathetic BRS assessed with burst incidence was lower in older women than older men. On the other hand, the response in burst size to head-up tilt in young women was much lower than young men (Shoemaker et al., 2001), which seemed to be consistent with the data showing lower sympathetic BRS assessed with burst area in older women than older men after adjusting for arterial stiffness, while sympathetic BRS assessed with burst area including the effect of arterial stiffness in older women was not significantly lower compared to men in the current study. These results suggested that distribution of burst size as sympathetic BRS might be altered with advancing age accompanied by the progression of arterial stiffness, which may be different from that of burst occurrence and also between men and women. Thus, the contribution of burst area to sympathetic BRS in older women became greater in contrast to that of burst incidence and was higher compared to young individuals and older men. It is possible that the stiffer barosensory artery in older women increases baseline MSNA burst occurrence and decreases its responsiveness during changes in BP. It is also possible that peripheral vascular transduction per sympathetic burst is decreased in older women. Indeed, the magnitude of the increase in BP after an MSNA burst occurrence was reported to be attenuated in older compared with young subjects and the attenuation was greater in older women compared with older men (Vianna et al., 2012). As a result, the effects of burst area in each burst may be relatively enhanced in older women compared to young women and older men. The complicated interactions between age, sex, and control sites along with various methods used to evaluate sympathetic BRS may be responsible for the inconsistent findings of age-related changes in baroreflex function in previous studies (Ebert et al., 1992; Matsukawa et al., 1998a; Studinger et al., 2009).

Carotid Stiffness and Baroreflex Response of MSNA

We demonstrated the same slope of the regression line relating carotid artery stiffness and sympathetic BRS assessed with burst incidence in older men and women in our previous study (Okada et al., 2011), suggesting that the effect of the carotid artery stiffness on sympathetic BRS was the same in older men and women. Since this reported sensitivity was controlled by the oscillation system of MSNA burst occurrence in the higher site of the neural component (Malpas, 1995), the deteriorated sensitivity in older women can be originated from impaired function of the higher site of the neural component of baroreflex and additive deficiency of the mechanical component (baroreceptor segment) because of greater carotid stiffness than men. Indeed, the lower sensitivity of burst occurrence in older women became weaker but still significant after adjusting for carotid artery stiffness, supporting this concept. On the other hand, as in Figure 2, the regression line between carotid stiffness and sympathetic BRS assessed with burst area showed a negative slope (i.e. more sensitive as the carotid artery was stiffer) in older women but not in men, suggesting that the effect of the carotid artery stiffness on this sensitivity was different between sexes and between the control sites of burst occurrence and burst size. Since the sensitivity in burst area was controlled by the recruiting system of the number of firing neurons in the lower site of the neural component (Malpas, 1995), the carotid artery stiffness influenced the lower site of the neural component of the baroreflex in opposition to the higher site in older women. In addition, sympathetic BRS assessed with burst area in older women became smaller than men with statistical significance after adjusting with carotid artery stiffness, suggesting that carotid artery stiffness may act to maintain or increase the response of burst size in contrary to that of burst occurrence. Therefore, the reduction of response in burst occurrence/incidence to a given change in BP seemed to be compensated by the increased response in burst area due to greater carotid stiffness in older women, although the effect of burst area on sympathetic BRS was still lower than that of burst occurrence because sympathetic BRS assessed by total MSNA which includes both factors of burst incidence and area was lower in older women than men.

What Augments the Response in Burst Area?

The question arises, then, as to the mechanisms responsible for the detection of impaired BRS of burst incidence to compensate for the impairment with the response of burst area. Numerous animal studies have examined the chronic effect of denervation of the arterial baroreceptors and have indicated that the larger standard deviation of BP is chronically sustained while subsequent hypertension returned to the pre-denervation level in a few weeks (Saito et al., 1986; Persson et al., 1988; Irigoyen et al., 1995). Carotid resection in human patients was also shown to cause a marked rise in MSNA accompanied by hypertension, which had gradually declined to normal levels with persistent decreased sympathetic BRS or increased variability of BP (Robertson et al., 1993; De Toma et al., 2000; Timmers et al., 2003). This normalization of BP without restoration of sympathetic BRS suggested that other mechanisms(s) rather than the arterial baroreflex are involved. It is possible that unknown factors/receptors may detect the gap between changes in BP and MSNA burst occurrence to directly/indirectly enhance the response in the numbers of the firing neurons within each burst, resulting in higher responses in burst area in older women.

Limitations

First, sympathetic BRS was evaluated during spontaneous breathing and, therefore, the entire baroreflex stimulus-response curve cannot be determined as described in our previous studies (Fu et al., 2009; Okada et al., 2011). However, we used the binning method to reduce the impact of non-baroreflex influence and the statistical weighting to reduce the influence of the different number of pairs of MSNA burst and DBP among bins (Kienbaum et al., 2001). Moreover, our focus was the difference of physiological modulation of BP by sympathetic burst incidence and burst area in older men and women. Therefore, we could compare these sympathetic controls around the prevailing and operating points between sexes. Second, we recognize the effect of the aortic stiffness on sympathetic BRS is necessary to assess. However, our previous data showed no significant correlation between sympathetic BRS and aortic stiffness (Okada et al., 2011). Even if the baroreceptor in the aorta functions differently for burst incidence and/or burst area in older men and women, it should not be opposite to the receptor in the carotid artery.

Perspectives

We showed sympathetic BRS assessed with burst incidence and cardiovagal BRS were lower in older women than men (Okada et al., 2011). Thus, baroreflex function in older women seems to be so labile that it is difficult to maintain BP. Women in this study, however, showed the same fluctuations of BP, as well as the same level of average BP as men. This suggests that there might be some compensatory mechanisms for the lower response of MSNA burst occurrence to maintain BP in older women. Based on our data, increases in the response of burst area to given changes in BP appear to play an important role in maintaining BP in women with greater stiffness of barosensory arteries. On the other hand, some epidemiological studies have concluded that lower BRS is one of the predictors of hypertension (Gribbin et al., 1971; Lage et al., 1993) and increased risk of cardiac mortality (Billman et al., 1982; La Rovere et al., 2001) and, in fact, older women show a higher prevalence of hypertension (Burt et al., 1995). To better understand sex and/or age differences in sympathetic neural mechanisms underlying hypertension and cardiovascular disease in humans, it is important to evaluate both the size and occurrence of MSNA burst.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Supplementary Material

supp info

Key Point Summary.

  • In this study, we focused on MSNA burst size and occurrence separately as subcomponents of the sympathetic baroreflex in older adults, and we found that the distribution (variation) of burst size against burst occurrence was greater in women than men.

  • Older women had greater carotid artery stiffness compared with older men, while blood pressure (BP) distribution (variation) was comparable between sexes.

  • Sympathetic baroreflex sensitivity assessed with bust incidence was less sensitive as the carotid artery became stiffer in older men and women, while that assessed with burst area was more sensitive as the carotid artery became stiffer in older women but not in older men.

  • These results help us understand the mechanisms underlying the compensation for the impaired response of MSNA burst occurrence in older women with greater carotid artery stiffness to regulate BP similarly to that in older men.

Acknowledgments

We are especially grateful for the subjects that volunteered to be a part of this study. We thank Jeffrey L. Hastings, M. Dean Palmer, Peggy Fowler, Murugappan Ramanathan, Cyrus Oufi, and Wade Wang for their valuable laboratory assistance.

Funding

This study was supported by the National Institutes of Health grant; NIH R01 grant (HL091078).

Footnotes

Competing interests

The authors declare that they have no competing interests.

References

  1. Barman SM & Gebber GL. (1980). Sympathetic nerve rhythm of brain stem origin. Am J Physiol 239, R42–47. [DOI] [PubMed] [Google Scholar]
  2. Billman GE, Schwartz PJ & Stone HL. (1982). Baroreceptor reflex control of heart rate: a predictor of sudden cardiac death. Circulation 66, 874–880. [DOI] [PubMed] [Google Scholar]
  3. Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, Horan MJ & Labarthe D. (1995). Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988–1991. Hypertension 25, 305–313. [DOI] [PubMed] [Google Scholar]
  4. Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB & Rector T. (1984). Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 311, 819–823. [DOI] [PubMed] [Google Scholar]
  5. Cui J, Wilson TE & Crandall CG. (2002). Baroreflex modulation of muscle sympathetic nerve activity during cold pressor test in humans. Am J Physiol Heart Circ Physiol 282, H1717–1723. [DOI] [PubMed] [Google Scholar]
  6. Davy KP, Tanaka H, Andros EA, Gerber JG & Seals DR. (1998). Influence of age on arterial baroreflex inhibition of sympathetic nerve activity in healthy adult humans. Am J Physiol 275, H1768–1772. [DOI] [PubMed] [Google Scholar]
  7. De Toma G, Nicolanti V, Plocco M, Cavallaro G, Letizia C, Piccirillo G & Cavallaro A. (2000). Baroreflex failure syndrome after bilateral excision of carotid body tumors: an underestimated problem. J AVasc Surg 31, 806–810. [DOI] [PubMed] [Google Scholar]
  8. Ebert TJ, Morgan BJ, Barney JA, Denahan T & Smith JJ. (1992). Effects of aging on baroreflex regulation of sympathetic activity in humans. Am J Physiol 263, H798–803. [DOI] [PubMed] [Google Scholar]
  9. Fisher JP & Paton JF. (2012). The sympathetic nervous system and blood pressure in humans: implications for hypertension. J Hum Hypertens 26, 463–475. [DOI] [PubMed] [Google Scholar]
  10. Fu Q, Okazaki K, Shibata S, Shook RP, VanGunday TB, Galbreath MM, Reelick MF & Levine BD. (2009). Menstrual cycle effects on sympathetic neural responses to upright tilt. J Physiol 587, 2019–2031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gribbin B, Pickering TG, Sleight P & Peto R. (1971). Effect of age and high blood pressure on baroreflex sensitivity in man. Circ Res 29, 424–431. [DOI] [PubMed] [Google Scholar]
  12. Halliwill JR. (2000). Segregated signal averaging of sympathetic baroreflex responses in humans. J Appl Physiol 88, 767–773. [DOI] [PubMed] [Google Scholar]
  13. Hirai T, Sasayama S, Kawasaki T & Yagi S. (1989). Stiffness of systemic arteries in patients with myocardial infarction. A noninvasive method to predict severity of coronary atherosclerosis. Circulation 80, 78–86. [DOI] [PubMed] [Google Scholar]
  14. Ichinose M, Saito M, Fujii N, Ogawa T, Hayashi K, Kondo N & Nishiyasu T. (2008). Modulation of the control of muscle sympathetic nerve activity during incremental leg cycling. J Physiol 586, 2753–2766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Irigoyen MC, Moreira ED, Ida F, Pires M, Cestari IA & Krieger EM. (1995). Changes of renal sympathetic activity in acute and chronic conscious sinoaortic denervated rats. Hypertension 26, 1111–1116. [DOI] [PubMed] [Google Scholar]
  16. Izumi S, Muano T, Mori A, Kika G & Okuwaki S. (2006). Common carotid artery stiffness, cardiovascular function and lipid metabolism after menopause. Life Sci 78, 1696–1701. [DOI] [PubMed] [Google Scholar]
  17. Jarvis SS, Levine BD, Prisk GK, Shykoff BE, Elliott AR, Rosow E, Blomqvist CG & Pawelczyk JA. (2007). Simultaneous determination of the accuracy and precision of closed-circuit cardiac output rebreathing techniques. J Appl Physiol 103, 867–874. [DOI] [PubMed] [Google Scholar]
  18. Jones PP, Christou DD, Jordan J & Seals DR. (2003). Baroreflex buffering is reduced with age in healthy men. Circulation 107, 1770–1774. [DOI] [PubMed] [Google Scholar]
  19. Kienbaum P, Karlssonn T, Sverrisdottir YB, Elam M & Wallin BG. (2001). Two sites for modulation of human sympathetic activity by arterial baroreceptors? J Physiol 531, 861–869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. La Rovere MT, Pinna GD, Hohnloser SH, Marcus FI, Mortara A, Nohara R, Bigger JT Jr., Camm AJ & Schwartz PJ (2001). Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials. Circulation 103, 2072–2077. [DOI] [PubMed] [Google Scholar]
  21. Lage SG, Polak JF, O’Leary DH & Creager MA. (1993). Relationship of arterial compliance to baroreflex function in hypertensive patients. Am J Physiol 265, H232–237. [DOI] [PubMed] [Google Scholar]
  22. Malpas SC. (1995). A new model for the generation of sympathetic nerve activity. Clin Exp Pharmacol Physiol 22, 11–15. [DOI] [PubMed] [Google Scholar]
  23. Matsukawa T, Sugiyama Y, Watanabe T, Kobayashi F & Mano T. (1998a). Baroreflex control of muscle sympathetic nerve activity is attenuated in the elderly. J Auton Nerv Syst 73, 182–185. [DOI] [PubMed] [Google Scholar]
  24. Matsukawa T, Sugiyama Y, Watanabe T, Kobayashi F & Mano T. (1998b). Gender difference in age-related changes in muscle sympathetic nerve activity in healthy subjects. Am J Physiol 275, R1600–1604. [DOI] [PubMed] [Google Scholar]
  25. Ng AV, Callister R, Johnson DG & Seals DR. (1993). Age and gender influence muscle sympathetic nerve activity at rest in healthy humans. Hypertension 21, 498–503. [DOI] [PubMed] [Google Scholar]
  26. Okada Y, Galbreath MM, Shibata S, Jarvis SS, VanGundy TB, Meier RL, Vongpatanasin W, Levine BD & Fu Q. (2011). Relationship between sympathetic baroreflex sensitivity and arterial stiffness in elderly men and women. Hypertension 59, 98–104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Persson P, Ehmke H, Kirchheim H & Seller H. (1988). Effect of sino-aortic denervation in comparison to cardiopulmonary deafferentiation on long-term blood pressure in conscious dogs. Pflugers Arch 411, 160–166. [DOI] [PubMed] [Google Scholar]
  28. Robertson D, Hollister AS, Biaggioni I, Netterville JL, Mosqueda-Garcia R & Robertson RM. (1993). The diagnosis and treatment of baroreflex failure. N Engl J Med 329, 1449–1455. [DOI] [PubMed] [Google Scholar]
  29. Rudas L, Crossman AA, Morillo CA, Halliwill JR, Tahvanainen KU, Kuusela TA & Eckberg DL. (1999). Human sympathetic and vagal baroreflex responses to sequential nitroprusside and phenylephrine. Am J Physiol 276, H1691–1698. [DOI] [PubMed] [Google Scholar]
  30. Saito M, Terui N, Numao Y & Kumada M. (1986). Absence of sustained hypertension in sinoaortic-denervated rabbits. Am J Physiol 251, H742–747. [DOI] [PubMed] [Google Scholar]
  31. Shoemaker JK, Hogeman CS, Khan M, Kimmerly DS & Sinoway LI. (2001). Gender affects sympathetic and hemodynamic response to postural stress. Am J Physiol Heart Circ Physiol 281, H2028–2035. [DOI] [PubMed] [Google Scholar]
  32. Studinger P, Goldstein R & Taylor JA. (2009). Age- and fitness-related alterations in vascular sympathetic control. J Physiol 587, 2049–2057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sundlof G & Wallin BG. (1978). Human muscle nerve sympathetic activity at rest. Relationship to blood pressure and age. J Physiol 274, 621–637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sverrisdottir YB, Rundqvist B, Johannsson G & Elam M. (2000). Sympathetic neural burst amplitude distribution: A more specific indicator of sympathoexcitation in human heart failure. Circulation 102, 2076–2081. [DOI] [PubMed] [Google Scholar]
  35. Tanaka H, Dinenno FA, Monahan KD, Clevenger CM, DeSouza CA & Seals DR. (2000). Aging, habitual exercise, and dynamic arterial compliance. Circulation 102, 1270–1275. [DOI] [PubMed] [Google Scholar]
  36. Timmers HJ, Karemaker JM, Wieling W, Marres HA & Lenders JW. (2003). Baroreflex control of muscle sympathetic nerve activity after carotid body tumor resection. Hypertension 42, 143–149. [DOI] [PubMed] [Google Scholar]
  37. Vallbo AB, Hagbarth KE, Torebjork HE & Wallin BG. (1979). Somatosensory, proprioceptive, and sympathetic activity in human peripheral nerves. Physiol Rev 59, 919–957. [DOI] [PubMed] [Google Scholar]
  38. Vianna LC, Hart EC, Fairfax ST, Charkoudian N, Joyner MJ & Fadel PJ (2012). Influence of age and sex on the pressor response following a spontaneous burst of muscle sympathetic nerve activity. Am J Physiol Heart Circ Physiol 302, H2419–2427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Wallin BG & Elma M. (1997). Micronuerography and autonomic dysfunction In: Low, PA ed Clinical Autonomic Disorders: Evaluation and Management. Lippincott-Raven Publishers, Philadelphia, Pa. [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

supp info
NIHMS1614247-supplement-supp_info.docx (104.5KB, docx)

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

RESOURCES