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. Author manuscript; available in PMC: 2019 Nov 1.
Published in final edited form as: Hypertension. 2018 Nov;72(5):1236–1242. doi: 10.1161/HYPERTENSIONAHA.118.11550

AGING ALTERS THE RELATIVE CONTRIBUTIONS OF THE SYMPATHETIC AND PARASYMPATHETIC NERVOUS SYSTEMS TO BLOOD PRESSURE CONTROL IN WOMEN

Sarah E Baker 1, Jacqueline K Limberg 1, Gabrielle A Dillon 1, Timothy B Curry 1, Michael J Joyner 1, Wayne T Nicholson 1
PMCID: PMC6211807  NIHMSID: NIHMS1505427  PMID: 30354803

Abstract

Autonomic support of blood pressure (BP) increases with age in humans. Large differences exist in the dose of trimethaphan required for ganglionic blockade in young and older women. We asked if differences in the dose of trimethaphan required to achieve ganglionic blockade are due to differences in the relative contributions of the sympathetic and parasympathetic nervous systems in control of BP with age. Muscle sympathetic nerve activity (MSNA, microneurography, peroneal nerve), heart rate (HR), and blood pressure (BP) were recorded before and during incremental doses of trimethaphan camsylate until ganglionic blockade was achieved (absence of MSNA and <5bpm increase in heart rate during a valsalva maneuver; final trimethaphan dose: 1–7mg/min). Heart rate variability (HRV) was analyzed from the ECG waveform (WinCPRS). The dose of trimethaphan required to achieve ganglionic blockade is positively related to basal heart rate variability (HRV), where women with high HRV require a higher dose of trimethaphan to achieve ganglionic blockade. In contrast, baseline MSNA is inversely related with the dose of trimethaphan required to achieve ganglionic blockade, such that women with high basal MSNA required a lower dose of trimethaphan. As such, the change in HR with ganglionic blockade was positively related, and the change in MAP was inversely related, with the dose of trimethaphan required to achieve ganglionic blockade. These data suggest loss of parasympathetic tone and increased sympathetic tone with aging contribute to the increase in BP with age in women and dictate the dose of trimethaphan that is necessary to achieve ganglionic blockade.

Keywords: Physiology, Aging, Women, Blood Pressure, Autonomic function, sex-specific

INTRODUCTION

It is well established that blood pressure increases with age. In women, this increase in blood pressure with age is largely due to increases in sympathetic nerve activity and transduction of this sympathetic activity into peripheral vasoconstriction1–3. Some of these conclusions are based from results using intravenous infusions of trimethaphan4–6. Trimethaphan blocks autonomic neurotransmission by competing for acetylcholine on the postsynaptic nicotinic (NN-cholinergic) receptors in autonomic ganglia. This ganglionic blockade essentially eliminates the influence of both sympathetic and parasympathetic nervous system activity4–7. Though no longer used clinically, this drug has been used as a research tool to assess autonomic support of blood pressure. Our group and others have observed significant reductions in muscle sympathetic nerve activity (MSNA), circulating norepinephrine, heart rate variability, and arterial blood pressure in healthy young and older individuals with intravenous trimethaphan infusion4–8. As such, individuals will have different blood pressure and heart rate responses to trimethaphan infusion based on their basal level or “ratio” of sympathetic and parasympathetic tone.

As it relates to aging, Seals and colleagues have shown that, in older men, the fall in blood pressure in response to ganglionic blockade is double that of younger men 6. This group went on to show that younger men had greater parasympathetic support of resting blood pressure, whereas the older men had greater sympathetic support of BP 6. Consistent with data from older men, our group has shown that the fall in blood pressure with ganglionic blockade in older women is greater than that of younger women 4; however, we did not assess the relative contributions of the sympathetic and parasympathetic nervous system. This is important as our group and others have shown that blood pressure regulation differs significantly between men and women. This is especially true when examining autonomic control of blood pressure. Some of the first findings in this area were published by our group, where we show that the relationship between sympathetic nervous system activity and blood pressure increases dramatically in women as they age9, 10. Our data also found a loss of β-adrenergic receptor mediated buffering of blood pressure control in older women following menopause11. This is a mechanism uniquely present in women and is not observed in men. The relative contributions of the sympathetic and parasympathetic nervous systems are also important as we know that sympathetic activity has a greater rate of rise with age in women than in men12, and the ability to buffer sympathetically-mediated vasoconstriction through beta-adrenergic mediated vasodilation also decreases in women with age 11, 13. Furthermore, as women age the transduction of sympathetic activity into increases in blood pressure is increased in women, whereas it decreases in men3. Therefore, as women age they have more sympathetic activity that results in larger changes in blood pressure as compared to men.

In previous work, the average dose of trimethaphan necessary to achieve ganglionic blockade in young women was double what was given in older women despite achieving a clear absence of detectable bursts of sympathetic activity by dose 3–4mg/min4. In addition, the average dose necessary to achieve autonomic blockade in older women (~2 mg/min) was substantially lower than previous studies using trimethaphan in young adults (anywhere from 4–8mg/min) 8, 14, 15. Clinically, individual responses to trimethaphan have been shown to be highly variable, with dosing range from 0.3 to 6 mg/min for the treatment of malignant hypertension16–18. The underlying mechanisms behind large differences in dosing of trimethaphan were previously unknown. The differential contribution of the sympathetic versus parasympathetic nervous system in the dose of trimethaphan require to achieve ganglionic blockade has not been examined.

As such, we sought to understand the contribution of the sympathetic and parasympathetic nervous systems to blood pressure control in young and older women. We further investigated whether differences in the dose of trimethaphan necessary to achieve complete autonomic blockade can provide insight into mechanisms of blood pressure regulation with aging. We hypothesized that the dose of trimethaphan necessary to achieve autonomic blockade would differ between young and older women and would be related to basal levels of sympathetic (MSNA) and parasympathetic (heart rate variability) activity. We further hypothesized relative differences in sympathetic vs parasympathetic support of blood pressure between young and older women would underlie observed changes in blood pressure and heart rate following ganglionic blockade, where younger women would have greater parasympathetic support of blood pressure than older women.

METHODS

All procedures were reviewed and approved by the Institutional Review Board at Mayo Clinic (IRB # 09–008584) and conformed to the ethical principles of the Declaration of Helsinki and Title 45, US Code of Federal Regulations, Part 46, Protection of human subjects. All procedures were carried out in accordance with institutional guidelines. All individuals provided written informed consent prior to participation. The data that support the findings of this study are available from the corresponding author upon reasonable request.

Participants:

A total of 42 women (18–76 years of age) participated in the study. Data from 24 of these individuals were published previously4, 19. All participants were healthy, nonsmoking, non-obese (body mass index <28 kg/m2), normotensive, and taking no systemic medications influencing cardiovascular function, with the exception of oral contraceptives (n=19) and menopausal hormonal therapy (n=2). There was an n of 1, 4, 12, and 2 women on generations 1–4 of oral contraceptives, respectively. All women were either on or off of oral contraceptives for greater than 2 months. Women on oral contraceptives were studied on days 2–5 of the placebo phase (greater than >48 hrs from the last active pill). All young women (<35 years of age) were studied during the early follicular phase of the menstrual cycle or the placebo phase of oral contraceptive use. None of the participants had a history of diabetes or pre-diabetes in their Mayo Clinic medical record, had a fasting glucose of >126, or reported diabetes on a screening form. All young women completed a pregnancy test within 48 hours of the study. All older women were ≥50 years of age and were post-menopausal based on self-report (>12 months from last menstruation).

Participant Monitoring:

Studies were performed in the Clinical Research and Trial Unit (CRTU) at the Mayo Clinic where the ambient temperature was controlled between 22°C and 24°C. Participants arrived at the laboratory after an overnight fast and ≥24 hours without caffeine or vigorous exercise. On arrival, participants were asked to rest in a seated position and blood pressure was taken via sphygmomanometer. Subjects then rested in the supine position during instrumentation. After local anesthesia with 2% lidocaine, a 5-cm 20-gauge arterial catheter was placed in the brachial artery of the non-dominant arm, using aseptic technique. Beat-to-beat blood pressure was collected from a pressure transducer connected to the arterial catheter. A 3-lead ECG was used for continuous recordings of heart rate and to allow for assessment of heart rate variability.

Multiunit muscle sympathetic nerve activity (MSNA) was measured from the right peroneal nerve at the fibular head using insulated tungsten microelectrodes. A muscle sympathetic fascicle was identified when taps on the muscle belly or passive muscle stretch evoked mechanoreceptive impulses, and no afferent neural response was evoked by skin stimuli. The recorded signal was amplified 80 000-fold, band-pass filtered (700–2000 Hz), rectified, and integrated (resistance-capacitance integrator circuit, time constant 0.1 s) by a nerve traffic analyzer. The signal was amplified, band-pass filtered, rectified, and integrated (662C-4 Nerve Traffic Analysis System, University of Iowa, Iowa City, IA) and then recorded at 250 Hz (WinDaq, DATAQ Instruments, Akron, OH, n=24) or 10,000 Hz (PowerLab, ADInstruments, Colorado Springs, CO, n=18). Sympathetic bursts in the integrated neurogram were identified in the recorded data by a single investigator (SEB) using a semi-automated analysis program that assigns each sympathetic burst to the appropriate cardiac cycle by compensating for latency 20. In addition to the cardiovascular and neurophysiological criteria included in the automated program, a minimum of a 3:1 signal-to-noise ratio was used for burst confirmation. MSNA is reported as bursts/min (burst frequency [BF]), bursts/100 heartbeats (burst incidence [BI]), and total activity (AU).

Drug Administration:

Ganglionic blockade was achieved using incremental intravenous infusion of trimethaphan camsylate (Cambridge Laboratories, Wallsend, United Kingdom). Infusions started between 0.5 mg/min and 2mg/min and were increased by 0.5–1mg/min at approximately 6-minute intervals up to a maximum of 7 mg/min, or until autonomic blockade was established. Subjects were considered “blocked” if they demonstrated 2 or more of the following criteria: an absence of “bursts” of sympathetic activity, no change in blood pressure in response to increasing trimethaphan dose, and/or <5 bpm increase in heart rate during phase II of the Valsalva maneuver21.

Protocol:

After the placement of arterial and intravenous catheters, subjects rested quietly in the supine position. Participants remained supine during instrumentation for microneurography. When a good quality neurogram was established, 10 minutes of quiet resting baseline data were recorded. After the baseline period, ganglionic blockade was then achieved via infusion of trimethaphan (Total time: range 15 to 45 minutes). Once blockade was determined and a stable heart rate and blood pressure had been reached, data were recorded during quiet rest. After discontinuation of the trimethaphan infusion and de-instrumentation, subjects remained in the CRTU for ≥2 hours for observation. In cases where we were unable to obtain a quality neurogram (n=4) the participant did not receive trimethaphan and the study was terminated. One study was terminated early due to nausea and vomiting during the infusion. These data were excluded as the infusion was discontinued prior to ganglionic blockade.

Data Analysis and Statistics:

Steady-state physiological variables [heart rate, blood pressure, MSNA, and heart rate variability (WinCPRS, Absolute Aliens Oy, Turku, Finland)] were assessed as an average over 5-minutes of baseline and 5-minutes of trimethaphan infusion during ganglionic blockade. Standard short term recordings (5 minutes) were used to assess time-domain indices of heart rate variability22, 23. The root mean square of successive differences between normal heart beats (RMSSD) reflects beat to beat differences in heart rate and is generally believed to reflect parasympathetic activity24. The percentage of adjacent normal to normal intervals that differ by more than 50ms (pNN50) is also believed to be a marker of parasympathetic activity25. As such, these indices were used as our indices of parasympathetic activity. Differences between data collected during baseline and ganglionic blockade were taken as the measure of autonomic support 6. Data were analyzed statistically using commercially available software (Sigma Plot 12, San Jose, CA; IBM SPSS Statistics Version 22, Chicago, IL). Baseline group differences were assessed using independent sample T-tests and data are expressed as mean±SEM. Repeated measures ANOVA was used to assess changes in blood pressure and other hemodynamic parameters with ganglionic blockade by group. To measure whether there was a relationship of trimethaphan dose necessary to achieve ganglionic blockade and hemodynamic variables, regression analysis was performed and Pearson Spearman rho correlation coefficients were calculated. Spearman’s rho was used as trimethaphan dose is a non-continuous variable. Regression analysis was performed on pooled data (young and older women) unless otherwise specified. The α level was set at 0.05.

RESULTS

Baseline differences and effect of ganglionic blockade

A total of 18 older women (59.8 ± 2 years) and 24 younger women (25.8 ± 1 years) participated in this study. Weight and body mass index did not differ between groups, however the younger women were taller than the older women (Table 1, p<0.05). Muscle sympathetic nerve activity (MSNA) was higher in the older women as compared to the younger women (Table 1, p<0.05), while systolic blood pressure (BP), mean BP, diastolic BP, and resting heart rate (HR) were not significantly different between age groups (Table 1). Measures of heart rate variability (HRV; RMSSD, SDNN, pNN50) were lower in the older women compared to the younger women (Table 1, all p<0.05). Similar to our previous work, the average trimethaphan dose necessary to achieve complete ganglionic blockade was greater in younger women (4.3 ± 0.3 mg/min) when compared to older women (1.9 ± 0.2 mg/min, p<0.001). Although the average dose of trimethaphan was lower in the older women, they had a larger reduction in mean arterial pressure, heart rate variability was significantly reduced, and sympathetic nerve activity was eliminated during steady-state infusion. When the Valsalva maneuver was conducted during the final steady-state dose of trimethaphan infusion, there was a significant reduction in MAP (ΔMAP with Valsalva: Young:−21± 9, Older:−18±9mmHg) without a reflex increase in heart rate (ΔHR with Valsalva: Young: 2.4±4.0 Older: 3.5±6bpm), suggesting that we achieved ganglionic blockade. As expected, there was a significant increase in heart rate and decrease in blood pressure in both groups during blockade of the autonomic ganglia. The increase in heart rate during ganglionic blockade was greater in younger women when compared to older women, resulting in a smaller fall in BP during ganglionic blockade in the younger women (p<0.001, Table 1). Measures of HRV decreased significantly in both groups during ganglionic blockade (with the exception of pNN50 in the older women; Table 1, all p<0.05).

Table 1.

Participant demographics

Baseline
Demographics Young (n=24) Older (n=18)
Age (years) 26 ± 1 60 ± 2‡
Height (cm) 168 ± 1 163 ± 2*
Weight (kg) 65 ± 2 62 ± 1
BMI (kg/m2) 23 ± 1 23 ± 1
Taking OCP (n) 19 --
Taking MHT (n) -- 2
Systolic BP (mmHg) 114 ± 2 122 ± 3
Mean BP (mmHg) 83 ± 2 86 ± 2
Diastolic BP (mmHg) 68 ± 2 69 ± 3
Heart Rate 69±2 65±2
MSNA Burst Incidence (bursts/100hb) 22 ± 3 68 ± 4‡
MSNA Frequency (bursts/min) 12 ± 1 40 ± 2‡
MSNA Activity (AU) 19±3 85±13‡
R-R Interval (ms) 1011 ± 42 1062 ± 31
R-R Interval SD (ms) 69 ± 7 45 ± 4†
RMSSD (ms) 71 ± 10 31 ± 3*
pNN50 (%) 35 ± 5 10 ± 2‡
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BMI, Body mass index; OCP, oral contraceptives; MHT, menopausal hormone therapy; BP, blood pressure; MSNA, muscle sympathetic nerve activity; BP, blood pressure, RMSSD, root mean square of the successive Differences in R-R interval; pNN50, % R-R interval differences >50ms. Values are mean±SE. Age group differences:

*

p<0.05,

†

p<0.01,

‡

p<0.001.

Relationship between trimethaphan doses required for autonomic blockade and autonomic indices

The dose of trimethaphan necessary to achieve complete ganglionic blockade was related to baseline Heart Rate Variability (HRV; R-R Interval: rs=0.079, p=0.617; SD R-R Interval: rs =0.581; RMSSD: r=0.453; pNN50: r=0.592; p<0.001 for all but R-R Interval; See Figure 1) where greater variability in resting heart rate was related to a higher dose of TMP necessary to achieve ganglionic blockade. Baseline MSNA (Burst Incidence and Burst Frequency) was negatively correlated to trimethaphan dose when looking at young and older women together; however when considering the age groups separately, there was no relationship in the older women, and a positive relationship between MSNA and trimethaphan dose in the young women (All: Burst incidence: rs = −0.531, p<0.001; Burst Frequency: rs =−0.619, p<0.001; Young: Burst incidence: rs =0.373, p=0.072; Burst Frequency: rs =0.298, p=0.157; Older: Burst incidence: rs =0.015, p=0.952; Burst Frequency: rs =−0.169, p=0.503; See Figure 2).

Figure 1. Heart rate variability as a function of trimethaphan dose required for autonomic blockade in Young and Older Women.

Figure 1.

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The dose of trimethaphan necessary to achieve ganglionic blockade is significantly related to A.) R-R interval (rs=0.079, p=0.62), B.) standard deviation of the R-R interval (rs =0.581, p<0.001), C.) root mean square of the successive differences in R-R interval (RMSSD; rs =0.453, p<0.01), and D.) % R-R interval differences >50ms (pNN50; rs =0.592, p<0.001).

Figure 2. Muscle sympathetic nerve activity (MSNA) as a function of trimethaphan dose.

Figure 2.

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Baseline MSNA (burst incidence, burst frequency and, MSNA activity in panels A-C, respectively) was related to the dose of trimethaphan required to achieve ganglionic blockade in young women (All: Burst incidence: rs =−0.531, p<0.001; Burst Frequency: rs =−0.619, p<0.001; MSNA Activity: r=−0.514, p=0.001; Young: Burst incidence: rs =0.373, p=0.072; Burst Frequency: rs =0.289, p=.157; MSNA Activity: rs =−0.153, p=0.962. Older: Burst incidence: rs =0.015, p=.952; Burst Frequency: rs =−.169, p=0.503; MSNA Activity: rs =.390, p=0.122).

Mechanistic differences in autonomic cardiovascular control between young and older women underlie observed changes in blood pressure and heart rate.

The change in mean arterial pressure with autonomic blockade was significantly related to the dose of trimethaphan, where women requiring the largest dose of trimethaphan had the smallest change in mean arterial pressure (rs =0.787, p<0.001; Figure 3). The change in heart rate with autonomic blockade was related to trimethaphan dose, such that women who required the largest required the largest doses of trimethaphan to achieve ganglionic blockade had the largest changes in heart rate (rs = 0.631, p<0.001; Figure 3).

Figure 3. Change in Mean Arterial Pressure and Heart Rate in Response to Ganglionic Blockade as a Function of Trimethaphan dose required to achieve Ganglionic Blockade in Young and Older Women. Panel A.).

Figure 3.

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The dose of trimethaphan required to achieve ganglionic blockade is significantly related to the change in MAP (rs =0.787, p<0.001). Panel B.) The dose of trimethaphan required to achieve ganglionic blockade is significantly related to the change in heart rate with ganglionic blockade (rs =0.631, p<0.001).

DISCUSSION

The main novel findings from the present study are three-fold: 1) The dose of trimethaphan required to achieve ganglionic blockade in older women was nearly half of that required to achieve ganglionic blockade in young women, 2) Sympathetic support of BP (relationship between MSNA and fall in blood pressure) was most evident in women requiring the lowest dose of trimethaphan (older women), 3) Parasympathetic support of BP (relationship between heart rate variability and rise in heart rate) was most evident in women requiring the highest dose of trimethaphan (younger women).

During trimethaphan infusion, both sympathetic activity and parasympathetic activity are blocked at the autonomic ganglia. The combination of the two will result in a fall in MSNA and total peripheral resistance (sympathetic) as well as a reduction in heart rate variability and an increase in heart rate (parasympathetic). The combination of the two would thus be expected to achieve a relatively small change in systemic arterial pressure, due to the compensation of any fall in total peripheral resistance by the increase in heart rate and cardiac output. However, blood pressure is significantly reduced in both younger and older women (and men6) during trimethaphan infusion. Because trimethaphan in the doses we used eliminates both sympathetic and parasympathetic tone, populations of individuals (e.g. aging) will have different blood pressure responses to trimethaphan infusion based on the basal level or “ratio” of sympathetic to parasympathetic tone. Our data show that the young women studied have a larger parasympathetic contribution (higher heart rate variability) at rest when compared to older women. During trimethaphan infusion, these young women thusly exhibit a greater increase in heart rate and therefore cardiac output compared to the older women. In contrast, older women have greater sympathetic activity (higher MSNA) and lower parasympathetic activity (heart rate variability) at rest. With this, very little change in heart rate is observed in response to trimethaphan despite a significant fall in MSNA and peripheral vascular tone in older women. Our data are in agreement with those seen in men, where older men had lower baseline heart rate variability and the change in heart rate with trimethaphan was positively associated with baseline heart rate variability6. Data from the present investigation also suggest that in the basal state, high sympathetic tone in older women is relatively unopposed by parasympathetic tone and plays a more dominant role in baseline blood pressure.

Blockade of the sympathetic nervous system is achieved early in the dosing scheme for trimethaphan [MSNA and baroreflex function are effectively lost in the early doses (2–3mg/min) – no apparent sympathetic bursts of activity]8, 19, 26 and yet a dose up to 7 mg/min was necessary in some younger women to achieve “blockade” (i.e. a lack of a heart rate response to the Valsalva maneuver). With this observation, we began to speculate whether blocking the parasympathetic nervous system requires a higher dosage of trimethaphan. Consistent with this idea, anatomical placement of the ganglia differs between the sympathetic (paraspinal) and parasympathetic (on the organ) nervous systems. Therefore, perhaps these differences in placement affect the amount of drug (dose) necessary to effectively achieve effective blockade. Consistent with this, we did not observe a relationship between baseline MSNA and trimethaphan dose. Conversely, a strong relationship is observed between heart rate variability and trimethaphan dose was observed, indicating a strong parasympathetic contribution to the trimethaphan dose required to achieve autonomic blockade. A similar dosing strategy to ours was used by Seals and Colleagues 6; however final doses were not included in the published manuscript, so it is unclear whether the age-related dosing differences we saw in women also translate into men. Diedrich and colleagues also used an incremental dosing approach. They were able to differentiate between sympathetic dependent hypertension (multiple system atrophy) and non-sympathetic dependent hypertension (pure autonomic failure) using the relationship between blood pressure and incremental trimethaphan dosing8. Patients with sympathetic dependent hypertension generally had dramatic and immediate drops in blood pressure with low doses of trimethaphan (<2mg/min) whereas the patients with sympathetic independent hypertension were all able to tolerate large doses of trimethaphan (up to 8mg/min). These data further highlight the importance physiology plays in dictating the dose of trimethaphan required to achieve ganglionic blockade.

Considerations:

There are several important limitations to consider. First, large changes in blood pressure, like those experienced during ganglionic blockade, are a trigger for the release of vasopressin. Potential differences in the vasopressin response between young and older women were not investigated in this this study, but could potentially influence the hemodynamic response to ganglionic blockade7. Second, we are unable to address the impact of hormonal contraceptives on the responses in young women as 19/24 of the women were on hormonal contraceptives. However, our group has demonstrated that basal MSNA does not differ between normally cycling women and those using oral hormonal contraceptives, despite an approximately 5mmHg increase in blood pressure in women on oral contraceptives27. Given around 80% of women are exposed to oral contraceptives at some point in their lifetime28, 29 and that the hemodynamic data were qualitatively similar (ΔMAP with trimethaphan= −10±2 vs −9±2mmHg; ΔHR with trimethaphan = 22±3 vs 26±4bpm oral contraceptives vs. naturally cycling), we feel the present group is representative of the current population of young women. It is also important to acknowledge that two older women were on menopausal hormone therapy; however, their data were undistinguishable from the rest of the older women in their baseline measures and response to ganglionic blockade. Although these data suggest our conclusions are not affected by the use of hormonal contraceptives and/or hormone replacement therapy, future work in this area is warranted. Finally, trimethaphan is a rapidly acting NN-cholinergic antagonist that achieves pharmacological ganglionic blockade by inhibiting cholinergic transmission at the nicotinic receptors of the sympathetic ganglia. It was used in the management of hypertensive cardiovascular disease, in addition to emergency control of blood pressure in patients with acute dissecting aortic aneurysm30, 31 and to reduce bleeding during surgery 16, 32. The current therapeutic uses of trimethaphan are limited due to the competition from newer drugs that are more selective in their actions and effects produced. With this, trimethaphan is no longer produced and there are only small quantities exist for physiology research.

Perspectives:

Although trimethaphan is no longer used, these data illustrate the large differences between older and younger individuals in respect to compensatory hemodynamics. Other currently clinically used antihypertensive therapies also reduce sympathetic outflow or tone (e.g. alpha adrenergic blockers, centrally acting agents, etc.) and therefore total peripheral resistance. Though these compounds operate through different mechanisms than trimethaphan they all essentially reduce total peripheral resistance and the reduced parasympathetic tone in this population means that they have a reduced capacity to buffer acute drops in blood pressure and may lead to the higher risk of adverse events seen in this population. Older individuals are more likely to require antihypertensive therapy at lower dosages and their risk of adverse effects is higher in older than in younger individuals (e.g. hypotension, syncope etc.). This may be explained in part by the inability to fully compensate blood pressure changes with parasympathetic withdrawal as in younger individuals. In summary, these data highlight the importance of increased sympathetic tone along with the loss of parasympathetic compensation on the increase in blood pressure with age in women. Furthermore, the inability to fully compensate blood pressure changes with withdrawal of parasympathetic tone in older women has important implications for dosing and risk of adverse events with antihypertensive therapies.

Table 2.

Cardiovascular Measures

Change with Ganglionic
Blockade
Cardiovascular Measures Young (n=24) Older (n=18)
Heart Rate (bpm) 23±2 10±2‡
Systolic BP (mmHg) −19±2 −49±3‡
Diastolic BP (mmHg) −5±1 −18±1‡
Mean Arterial BP (mmHg) −10±1 −29±2‡
R-R Interval (ms) −299±36 −149±27†
R-R Interval SD (ms) −56±6 −22±6‡
RMSSD (ms) −64±10 −21±9†
pNN50 (%) −37±5 −22±5‡
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Change in cardiovascular measures with ganglionic blockade. Values are mean±SE. Age group differences:

*

p<0.05,

†

p<0.01,

‡

p<0.001.

Novelty and Significance.

  1. What is New?
    • The dose of trimethaphan required to achieve ganglionic blockade in older women was half that of young women.
    • Sympathetic tone was most evident in women requiring the lowest dose of trimethaphan.
    • Parasympathetic tone was most evident in women requiring the highest dose of trimethaphan.
  2. What is Relevant?
    • Inability to fully compensate blood pressure changes with parasympathetic withdrawal in older women has important implications for dosing and risk of adverse events with antihypertensive therapies.
  3. Summary
    • Our data highlight the importance of increased sympathetic activity along with the reduced parasympathetic tone on the increase in blood pressure with age in women.

ACKNOWLEDGEMENTS

We would like to acknowledge the contribution of the Human Integrative Physiology Laboratory and the Clinical Research and Trials Unit (CRTU) at the Mayo Clinic. We would like to thank Shelly Roberts, Lauren Newhouse, Zachariah Scruggs, Katherine Russell, Pamela Engrav, Andrew Miller, and Christopher Johnson for their continued assistance throughout the project.

SOURCES OF FUNDING: National Institutes of Health HL83947 (MJJ), HL131151 (SEB), and UL1TR000135 (CRTU).

ABBREVIATIONS

MSNA

Muscle Sympathetic Nerve Activity

BP

Blood Pressure

HRV

Heart Rate Variability

TMP

Trimethaphan

Footnotes

DISCLOSURES

There are no competing interests.

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