Sympathetic nerve hyperactivity of essential hypertension is lower in postmenopausal women than men

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Abstract

Sympathetic activation has been associated with the development and complications of hypertension. While the prevalence of hypertension and its cardiovascular risks in women are found to be less than in men and tend to become similar to men after the menopause, there have been no data on the level of sympathetic activation in postmenopausal women relative to men. Therefore, we planned to find out whether muscle sympathetic nerve hyperactivity of essential hypertension (EHT) in postmenopausal women is different from that in matched men. We quantified muscle sympathetic nerve activity (MSNA) as mean frequency of single units (s-MSNA) and multiunit bursts (b-MSNA) in 21 postmenopausal women with EHT (W-EHT) relative to 21 matched men with EHT (M-EHT), in comparison to two control groups of 21 normal women (W-NC) and 21 men (M-NC), respectively. The EHT groups had greater MSNA indices than NC groups. W-EHT had lower (P<0.05) s-MSNA (63±22.7 impulses per 100 cardiac beats) than M-EHT (78±11.2 impulses per 100 cardiac beats). W-NC had lower (P<0.05) s-MSNA (53±12.4 impulses per 100 cardiac beats) than M-NC (65±16.3 impulses per 100 cardiac beats). Similar results were obtained for b-MSNA. Postmenopausal women with EHT had lower level of central sympathetic hyperactivity than men. Similarly, normal postmenopausal women had lower MSNA than men. These findings suggest that postmenopausal women continue to have a lower sympathetic nerve activity than men even after the development of EHT, and that this could have implications for gender-specific management of hypertension.

Introduction

Several studies have shown that the prevalence of hypertension and raised arterial pressure is lower in women than in men,1, 2, 3, 4, 5, 6, 7, 8 and that such a difference tends to disappear in older women and men.1, 2, 3, 4, 5 Also, hypertension has been associated with increased incidence of cardiovascular events,4, 9, 10, 11, 12 which are lower in women than in men4, 12 though these events become similar to men in postmenopausal women.4, 8, 13

There has also been evidence that sympathetic hyperactivity is associated with essential hypertension (EHT) and both have been implicated in its pathogenesis and ensuing cardiovascular risks.14, 15, 16, 17, 18, 19 Using microneurography to directly quantify the resting mean frequency of muscle sympathetic nerve activity (MSNA), we recently found that EHT in a group comprising premenopausal and postmenopausal women was associated with a lower level of central sympathetic hyperactivity than in a group of matched men.20 Also, reports on the level of MSNA in older and postmenopausal women without hypertension have been inconsistent in that they were found to have a lower21 or similar22, 23 level of resting MSNA relative to older men. Despite these data, there have been no reported data regarding the level of central sympathetic neural activation in postmenopausal hypertensive women compared to matched hypertensive men. This issue is important because there have been reports indicating, in general, that women have a lower level of resting MSNA relative to men,21, 22, 23, 24, 25, 26, 27 raising the hypothesis that women may be protected against sympathetic activation.27, 28

The present investigation was therefore planned, in untreated patients with uncomplicated EHT, to find out whether or not the level of resting mean frequency of MSNA in postmenopausal women (W-EHT) is different from that in matched men (M-EHT). For this purpose, we used peroneal microneurography to directly measure the mean frequency of single units (s-MSNA) and the overall activity (b-MSNA) of efferent sympathetic output. We examined two matched groups of women and men with untreated and uncomplicated EHT in comparison to two matched normal control groups of women (W-NC) and men (M-NC).

Materials and methods

Subjects

We examined a total of 84 Caucasian subjects. They comprised two groups (each of 21 middle-aged or older patients) of W-EHT and M-EHT with untreated and uncomplicated EHT, and another two normal control groups (each of 21 middle-aged or older individuals) of W-NC and M-NC. All had similar sedentary occupational status and dietary habits, including a sodium intake of ≈400 mmol d−1, and none was engaged in exercise training. All the women were postmenopausal and none was on hormonal therapy. Patients were screened by history, physical and laboratory examination. None had evidence of secondary hypertension, left ventricular hypertrophy, peripheral vascular disease, arrhythmia, neuropathy or chronic disease that may influence the autonomic nervous system. Five women and six men with hypertension have been included in a previously reported study.20 Arterial blood pressure was defined on the basis of the average of at least three brachial sphygmomanometer readings, taken on separate occasions, using a standard measurement technique; the presence of hypertension was accepted when patients had systolic 140 mm Hg or diastolic 90 mm Hg arterial pressure. Patients in the two EHT groups had established hypertension for no longer than 6 months and none were receiving drug therapy prior to the study. Subjects in the four groups were matched during recruitment according to gender, age, body mass index and heart rate. In addition, subjects in each of the two EHT and the two NC groups were matched for arterial blood pressure levels. Waist circumference was measured as the minimal circumference at the navel and used as a marker of abdominal fat. The investigation was carried out with the approval of Leeds (East) Research Ethics Committee and all subjects provided informed written consent.

General protocol

Microneurographic and hemodynamic measurements were obtained in an identical manner for all subjects during each session, as has previously been reported in detail.17, 20, 27, 29 All investigations were performed under similar conditions between the hours of 0900 and 1200. Patients were asked to have had a light breakfast and to empty their bladder before commencing the study. They were instructed to avoid nicotine and caffeine products for 12 h, as well as alcohol and strenuous exercise for 24 h prior to investigation. During each session, the subjects were studied in the semi-supine position when data attained a steady state for at least 30 min. Measurements were made in a darkened laboratory in which the temperature was constant between 22 and 24 °C. Resting arterial blood pressure was measured from the arm, using a mercury sphygmomanometer. Changes in heart rate and arterial blood pressure were monitored and recorded, using a standard electrocardiogram and a Finometer device (FMS, TPD Biomedical Instruments, Arnhem, The Netherlands).

Microneurography

Postganglionic muscle sympathetic nerve activity was recorded from the right peroneal nerve, simultaneously with the other data as described previously.17, 20, 27, 29 The neural signal was amplified (× 50 000) and it was either filtered (bandwidth of 700–2000 Hz) and integrated (time constant 0.1 s) for the purpose of generating bursts representing multiunit discharge or left intact to examine raw action potentials. The output of action potentials and bursts from this assembly was passed to a PC-based data-acquisition system (LabView, National Instruments Corp., Austin, TX, United States), which digitized the acquired data at 12 000 samples s−1 (16 bits).

Muscle sympathetic nerve activity was differentiated from skin sympathetic activity and afferent activity, as described previously.17, 20, 27, 29 single units (s-MSNA) in the raw action potential neurogram were obtained by adjusting the electrode position, while using fast monitor sweep and online storage oscilloscope, to confirm the presence of consistent action potential morphology, as described previously.17, 20, 27, 29, 30 Only vasoconstrictor units were accepted and examined; the criteria of acceptance being appropriate response to spontaneous changes in arterial blood pressure during verification by preliminary Valsalva maneuver and isometric handgrip exercise. During the Valsalva maneuver, sympathetic activity increased during the latter part of phase-II and/or phase-III and decreased during phase-IV (corresponding to the decrease and increase of arterial blood pressure). During the isometric handgrip exercise at about 30% of maximal voluntary effort, performed using a dynamometer (MIE Medical Research Ltd., Leeds, UK), a delayed increase of sympathetic nerve activity and calf vascular resistance was observed.

Analysis was performed independently offline, using dedicated software based on the LabView system. This allowed spikes in the raw action potential to be scrutinized and electronically superimposed to establish the same morphology to use as single units (s-MSNA). An electronic discriminator window was then used to objectively count the s-MSNA spikes with consistent morphology and a threshold discriminator was used to count the R-waves of the electrocardiogram. The mean frequency of s-MSNA was quantified over 100 cardiac beats, to avoid any interference by the length of the cardiac cycle. The multiunit bursts (b-MSNA) were identified by inspection when the signal-to-noise ratio was greater than 3, and were counted and quantified in a similar manner to s-MSNA. The variability of repeated measurements of 2-min segments of recordings of s-MSNA units and b-MSNA spanning a period of 30 min or those of two impalements performed within 60 min did not exceed 10%, in terms of twice the 95% confidence intervals around individual differences relative to the mean of the repeated measurements.17

Statistics

One-way analysis of variance with Newman–Keuls post-tests was used to compare data between groups. The least square technique was used for assessing the linear relationship between variables. Values of P<0.05 were considered statistically significant. Data were presented as mean±s.d.

Results

The details of the four groups are shown in Table 1. They were matched in respect of age, body mass index, waist circumference and heart rate. Also, the women and men of either the hypertensive or normal control groups were matched in respect of arterial blood pressure indices, while accepting that the hypertensive groups had greater arterial blood pressure indices than the normal control groups.

Table 1 Details of the four groups of subjects

The indices of MSNA were greater in the two hypertensive groups relative to their corresponding two control groups (Table 1, Figure 1). Thus, MSNA indices in the hypertensive groups were about one-sixth to one-fifth greater than that of their normotensive counterparts.

Figure 1
figure1

Data of muscle sympathetic nerve activity expressed as (a) single unit frequency and (b) multiunit burst frequency for hypertensive women (W-EHT) and men (M-EHT), normotensive control women (W-NC) and men (M-NC). Columns indicate mean values and bars s.d. Significant differences (P-values) between groups derived from analysis of variance post-tests (Newman–Keuls) are shown. Sympathetic nerve activity was greater for both genders in the hypertensive group than in their respective control groups. Normotensive and hypertensive women had lower sympathetic nerve activity than the corresponding groups of men.

Regarding the two hypertensive groups, the indices of MSNA were significantly lower in women than in men; in women it was about one-sixth lower than that in men. In addition, within the control normotensive groups, these indices were also significantly lower in women than in men. Thus, normal women had MSNA indices that were about one-sixth to one-fifth lower than that found in normal men (Figure 1).

Finally, in each individual of the four groups, there was no significant correlation between MSNA and arterial blood pressure indices (at least r<0.31 P>0.08), body mass index (at least r<0.31, P>0.08) or waist circumference (at least r<0.41, P>0.06).

Discussion

The study has shown for the first time that postmenopausal women with EHT had a lower central sympathetic hyperactivity than matched men with the same condition, a difference that was similar to that between normal postmenopausal women and matched men. These findings indicate that the lower level of sympathetic nerve activity in women relative to men was not influenced by the development of EHT. They also indicate that an excessive central sympathetic hyperactivity of hypertension cannot be considered as the main mechanism for the development and complications of hypertension in postmenopausal women known to approach those in men.

We quantified the mean frequency of MSNA as single units s-MSNA and multi-units b-MSNA. The former was considered as an index of the mean frequency of efferent sympathetic nerve activity from the central nervous system to the leg, as it is specifically based on defining a unit that has the same profile and responses to changes in arterial blood pressure throughout the recordings. In contrast, b-MSNA provides a measure of overall sympathetic output, because each burst of b-MSNA can be generated by the occurrence of one or more than one unit, the function of each is difficult to discern. Also, the units constituting the bursts of b-MSNA may change dynamically in time according to reflex effects and unit recruitments.29 Our findings of a lower level of b-MSNA in normal postmenopausal women than in matched men are similar to those previously reported,21 but are different from others that did not detect significant differences.22, 23 In the present study, we also found that s-MSNA was lower in postmenopausal women than in matched men. In addition, it was shown for the first time that both s-MSNA and b-MSNA to be significantly lower in postmenopausal hypertensive women than in corresponding men. All the present findings were obtained after matched equal numbers of women and men were recruited, while avoiding confounding factors that can interfere with sympathetic nerve activity. Thus, individual patients of the groups were Caucasians and were examined using the same protocol, under similar laboratory conditions, while avoiding the influence of age, dietary intake, body weight, large meal or visceral distension; factors that are known to affect sympathetic activity or its control as described previously.17, 20, 27, 29 These considerations, made it likely that factors other than those associated with gender did not confound our findings.

The present findings have possible implications when considered with previously reported evidence that sympathetic hyperactivity is associated with EHT and its cardiovascular complications,14, 15, 16, 17, 18, 19 and that the prevalence of hypertension and its cardiovascular complications in postmenopausal women approaches or exceeds that in age-matched men.1, 2, 3, 4, 5, 8, 13 The present results of a lower central sympathetic hyperactivity in postmenopausal women with hypertension than in matched hypertensive men suggest that the magnitude of chronic sympathetic activation is not related to their cardiovascular risks of hypertension. Apart from the severity of hypertension and lipid disorders, other possible factors related to cardiovascular risk in postmenopausal women have included vascular responsiveness to neural and neurotransmitter effects, as well as the levels of various hormonal systems.2, 5, 28, 31 Such considerations assume relevance when considering the choice of hypertension management and antihypertensive therapy.

There are other possible implications related to the mechanisms of our findings of gender-related differences in MSNA. For instance firstly, in the present study, subjects were matched in respect of confounding factors as mentioned above. In particular, the groups of women and men with hypertension had similar levels of arterial blood pressure, although we found that it has previously been shown that there is no significant correlation between sympathetic nerve activity and arterial blood pressure level in individual subjects.17, 20, 32 Also, essential hypertension has previously been reported not to affect the baroreceptor reflex gain relating arterial blood pressure to MSNA.15 Secondly, there could be differences in the plasma levels of sex hormones between the study groups. However, in normal women the increases of plasma levels of oestrogen and progesterone during the menstrual cycle were found to be associated with increased MSNA,33 although the rise of plasma levels of oestrogen during the menstrual cycle was found not to increase the level of MSNA.34 Also, cross-sectional and longitudinal trials of oestrogen therapy in postmenopausal women has been found either to reduce MSNA,35, 36 or have no effect.37, 38 Thirdly, we have previously demonstrated in young and middle-aged women that indices of MSNA had a greater effect on peripheral blood flow in men than in women,27 thus, making it likely that hypertension in women was not related to increased vascular responsiveness to MSNA. Fourthly, in the same study,27 we have demonstrated that women had a greater sympatho-inhibitory baroreceptor reflexes than those in men.27 Finally, the design of present study of carefully matching our female and male subjects has not unexpectedly resulted in examining older age groups with high body mass index. These subject details carry the potentials of including subjects with insulin resistance, which in turn can affect sympathetic nerve activity. Although insulin resistance was not measured, we considered its potential confounding effect as nonsignificant in view of the similarities between men and women groups with respect to age, body mass index and waist circumference. Indeed, we did not examine the mechanisms underlying the observed gender-related differences in the present study; however, our previous findings27 and those of others28, 39 raise the possibility that one mechanism for our findings involves greater sympatho-inhibitory baroreceptor reflexes in women that continue to be present after the development of hypertension.

Clearly, the above considerations require further studies. Firstly, the present investigation involved a cross-sectional design, and longitudinal studies would be warranted to establish our results. However, our subjects were carefully matched to avoid confounding factors that can affect MSNA. Secondly, we did not quantify differences related to baroreceptor reflex control of sympathetic nerve activity in the present study population. However, we have previously shown that the gain of this reflex was greater in women than in men.27 Also, the baroreceptor reflex gain relating arterial blood pressure to MSNA have been found to remain within normal limits in essential hypertension.15 These findings support the proposition that the lower MSNA in the two groups of women involved their greater sympatho-inhibitory baroreceptor reflexes than those in men. Finally, it is known that the central output of sympathetic nerve activity to the periphery could differ from that destined to supply visceral organs. However, in EHT patients, an increase of MSNA as well as the sympathetic drive to the heart and the kidney has been found indicating a generalized activation of the sympathetic drive.19

In conclusion, the present study has demonstrated that postmenopausal women with EHT had lower muscle sympathetic nerve hyperactivity than matched men with the same condition, a difference that was similar to that in normal women and men. These findings raise the possibility that one mechanism of the lower sympathetic drive in hypertensive postmenopausal women could be related to the greater sympatho-inhibitory baroreceptor reflexes in women than in men that persist after the development of EHT. As such, the findings indicate that an excessive central sympathetic hyperactivity of hypertension cannot be considered as the main mechanism for the occurrence and complications of hypertension in postmenopausal women.

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Acknowledgements

We thank Mr Jeff Bannister and Mrs Julie Corrigan for technical assistance and the British Heart Foundation for sponsorship (Grant No: FS/04/085).

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Correspondence to A J Hogarth.

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The authors state no financial disclosures or conflict of interest.

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Hogarth, A., Burns, J., Mackintosh, A. et al. Sympathetic nerve hyperactivity of essential hypertension is lower in postmenopausal women than men. J Hum Hypertens 22, 544–549 (2008) doi:10.1038/jhh.2008.31

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Keywords

  • gender
  • menopause
  • sympathetic nervous system

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