Skip to main content
NCBI home page
The Journal of Physiology logoLink to The Journal of Physiology
. 2015 Jan 26;593(Pt 5):1159–1168. doi: 10.1113/jphysiol.2014.282277

Asian women have attenuated sympathetic activation but enhanced renal–adrenal responses during pregnancy compared to Caucasian women

Yoshiyuki Okada 1,2, Stuart A Best 1,2, Sara S Jarvis 1,2, Shigeki Shibata 1,2, Rosemary S Parker 1,2, Brian M Casey 2, Benjamin D Levine 1,2, Qi Fu 1,2,✉
PMCID: PMC4358677  PMID: 25545472

Abstract

Asians have a lower prevalence of hypertensive disorders of pregnancy than Caucasians. Since sympathetic overactivity and dysregulation of the renal–adrenal system (e.g. low aldosterone levels) have been found in preeclamptic women, we hypothesized that Asians have lower muscle sympathetic nerve activity (MSNA) and greater aldosterone concentrations during normal pregnancy than Caucasians. In a prospective study, blood pressure (BP), heart rate (HR), and MSNA were measured during supine and upright tilt (30 deg and 60 deg for 5 min each) in 9 Asians (32 ± 1 years (mean ± SEM)) and 12 Caucasians (29 ± 1 years) during pre-, early (≤8 weeks of gestation) and late (32–36 weeks) pregnancy, and post-partum (6–10 weeks after delivery). Supine MSNA increased with pregnancy in both groups (P < 0.001); it was significantly lower in Asians than Caucasians (14 ± 3 vs. 23 ± 3 bursts min−1 and 16 ± 5 vs. 30 ± 3 bursts min−1 in early and late pregnancy, respectively; P = 0.023). BP decreased during early pregnancy (P < 0.001), but was restored during late pregnancy. HR increased during pregnancy (P < 0.001) with no racial difference (P = 0.758). MSNA increased during tilting and it was markedly lower in Asians than Caucasians in late pregnancy (31 ± 6 vs. 49 ± 3 bursts min−1 at 60 deg tilt; P = 0.003). Upright BP was lower in Asians, even in pre-pregnancy (P = 0.006), and this racial difference persisted during pregnancy. Direct renin and aldosterone increased during pregnancy (both P < 0.001); these hormones were greater in Asians (P = 0.086 and P = 0.014). Thus, Asians have less sympathetic activation but more upregulated renal–adrenal responses than Caucasians during pregnancy. These results may explain, at least in part, why Asian women are at low risk of hypertensive disorders in pregnancy.

Key points

  • Asian women have a lower prevalence of hypertensive disorders of pregnancy than Caucasian women.

  • This is the first longitudinal study to investigate neural and humoral responses during pregnancy in Asians and Caucasians.

  • The key finding was that Asians had attenuated sympathetic activation but enhanced renal–adrenal responsiveness during pregnancy compared to Caucasians.

  • These results may provide insights into the pathophysiological mechanisms for racial differences in the prevalence of hypertensive disorders during pregnancy.

Introduction

Hypertensive disorders of pregnancy affect up to 10% of pregnant women worldwide. Gestational hypertension occupies 25% of all antenatal admissions (Roberts et al. 2003), and sometimes it leads to a serious condition − preeclampsia, one major cause of maternal, fetal and neonatal death. The mechanism(s) underlying these medical conditions are still unknown. Recently, it was reported that Asian women had a lower prevalence of hypertensive disorders in pregnancy than any other races and their odds ratio compared with Caucasian women was 0.41 (Cabacungan et al. 2012). However, how blood pressure (BP) is regulated during normal pregnancy in Asian vs. Caucasian women is unknown.

Sympathetic neural control plays a critical role in BP maintenance through a baroreflex-mediated mechanism in humans (Johnson et al. 1974; Wallin & Sundlof, 1982; Fu et al. 2004, 2006). Previous cross-sectional studies showed that muscle sympathetic nerve activity (MSNA) during late pregnancy was greater in pregnant women than non-pregnant women (Greenwood et al. 2001), while it was greater in hypertensive than normotensive pregnant women (Schobel et al. 1996; Greenwood et al. 1998, 2003). Longitudinal studies from our laboratory demonstrated that sympathetic activation occurs even during early pregnancy in healthy women (Jarvis et al. 2012). These results suggest that sympathetic activation during pregnancy may help to keep BP at the pre-pregnancy level; however, when sympathetic activation is excessive, hypertension may ensue (Greenwood et al. 2001). So far there is no information available regarding racial differences in sympathetic neural control during normal pregnancy as well as during hypertensive pregnancy.

In addition to neural control, renal–adrenal responsiveness also contributes importantly to BP regulation during pregnancy. Maternal plasma renin level becomes higher than the non-pregnant level (Skinner et al. 1972; Derkx et al. 1987) even in early pregnancy (Jarvis et al. 2012). Angiotensinogen synthesis increases with oestrogen (Skinner et al. 1972; Immonen et al. 1983), resulting in increased angiotensin II and aldosterone (Jarvis et al. 2012). Despite the upregulated renal–adrenal system and aldosterone-induced blood volume expansion, blunted vasoconstrictor responses to angiotensin II and a profound systemic vasodilatation associated with normal pregnancy (Abdul-Karim & Assalin, 1961; Chapman et al. 1998; Irani & Xia, 2011; Gennari-Moser et al. 2014) may contribute to the reduction or maintenance of BP in normotensive pregnant women. Recent research showed that high aldosterone availability increased BP in non-pregnant but not pregnant women (Escher et al. 2009; Gennari-Moser et al. 2014). In women with gestational hypertension or preeclampsia, enhanced vasoconstrictor responses to angiotensin II, low levels of aldosterone, and small blood volume have been observed (Yang et al. 2013), indicating that dysregulation of the renal–adrenal system may be involved in the pathogenesis of hypertensive disorders during pregnancy. The small blood volume could be one contributing factor for sympathetic overactivity in hypertensive disorders of pregnancy. Whether Asians and Caucasians have different renal–adrenal responses during normal pregnancy and hypertensive pregnancy remains unclear.

Based on previous findings showing that hypertensive pregnant women have sympathetic overactivity and dysregulation of the renal–adrenal system (e.g. low levels of aldosterone), we hypothesized that Asians would have lower MSNA and greater aldosterone concentrations during normal pregnancy than Caucasians. To test this hypothesis, we prospectively studied a group of pre-menopausal healthy Asian and Caucasian women before, during and after their pregnancies.

Methods

Subjects

Twenty Caucasian and 15 Asian women living in the Dallas-Fort Worth area were screened with a careful medical history and physical examination. Sixteen Caucasians and 10 Asians participated in the pre-pregnancy test, and 11 and 5 of them, respectively, had a successful pregnancy within 6 months. Four Caucasians and 4 Asians participated in the study shortly after they became pregnant (i.e. ≤8 weeks of gestation). Three Caucasian women dropped out after the early pregnancy testing. Twelve Caucasians and 9 Asians (1 Chinese, 4 Japanese, 1 Korean, 1 Vietnamese, and 2 Cambodians) eventually completed the longitudinal studies. Ethnicity/race was determined by self-report, and required that all four grandparents and both parents were of the same racial category as the subject. Subjects reporting more than one race were excluded.

All subjects were non-smokers and had no overt history of chronic diseases. All had no prior history of gestational hypertension or preeclampsia. They were excluded if they used recreational drugs or hormonal contraceptives within the previous 6 months, took hormonal fertility treatments/supplements, or had irregular menstrual cycles. All subjects gave their written informed consent to a study protocol approved by the Institutional Review Boards of the University of Texas Southwestern Medical Centre and Texas Health Presbyterian Hospital Dallas. This study followed guidelines set forth in the Declaration of Helsinki.

Measurements

Muscle sympathetic nerve activity

MSNA signals were obtained with microneurography (Sundlof & Wallin, 1977, 1978). Briefly, 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 s). Criteria for adequate MSNA recording include: (1) pulse synchrony; (2) facilitation during hypotension phase of the Valsalva manoeuvre, and suppression during the hypertensive overshoot phase after release; increase in response to breath holding; and (4) insensitivity to emotional stimuli (Vallbo et al. 1979).

Haemodynamics

Heart rate (HR) was determined from lead II of the ECG (78351A Hewlett-Packard, Palo Alto, CA, USA). Arm cuff BP was measured by electrosphygmomanometry (model 4240, SunTech Medical Instruments Inc., Raleigh, NC, USA) with a microphone placed over the brachial artery to detect Korotkoff sounds. Beat-by-beat BP was measured by finger photoplethysmography (model 1, BMEYE Nexfin HD monitor, Amsterdam, The Netherlands). Respiratory excursions were detected by a nasal cannula. Forearm blood flow (FBF) was measured by venous occlusion plethysmography (Model EC-5R, D.E. Hokanson, Inc., Bellevue, WA, USA) (Greenfield et al. 1963). Forearm vascular resistance (FVR) was calculated as mean BP (MBP) measured by arm cuff immediately after the FBF measurement, divided by FBF.

Study design and protocol

Two days prior to each testing, all subjects consumed an isocaloric constant diet consisting of: 200 mequiv sodium, 100 mequiv potassium, and 1000 mg calcium daily. Fluid intake was ad libitum. Pregnancy was confirmed in the morning of the testing day by measurement of beta-human chorionic gonadotropin level.

The experiment was performed ≥2 h after a light breakfast, ≥48 h after the last caffeinated or alcoholic beverage, and ≥24 h after strenuous exercise in a quiet, environmentally controlled laboratory with an ambient temperature of ∼25°C. The subject was placed in the supine position and an intravenous catheter was inserted into the antecubital vein of the left arm for blood samples. After at least 20 min in the supine position, and blood was taken for assessment of plasma catecholamine concentration (high performance liquid chromatography, HPLC, ARUP laboratories, Salt Lake City, UT, USA), aldosterone concentration (chemiluminescent immunoassay), and direct renin (radio-immunoassay). We also assessed oestradiol (chemiluminescent immunoassay) and progesterone concentration (HPLC).

At least 10 min after a satisfactory nerve recording site had been found, FBF was measured six times. The subjects rested in the supine position for 6 min (baseline). After that, they were passively tilted to 30 deg upright for 5 min, and then to 60 deg upright for 5 min, followed by a 3 min supine recovery. Throughout the entire procedures, beat-by-beat BP, HR, respiratory waveforms, and MSNA were recorded continuously.

Data analysis

Data were sampled at 625 Hz and stored on personal computer with a commercial data acquisition system (Biopac system, Santa Barbara, CA, USA). Sympathetic bursts were identified by a computer program (Cui et al. 2001), and then confirmed by an experienced microneurographer. The integrated neurogram was normalized by assigning a value of 100 to the largest amplitude of a sympathetic burst during the 6 min baseline in each test (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) and per 100 heart beats (burst incidence), and the burst area per minute (total activity) were used as quantitative indices.

Statistical analysis

Values are expressed as means ± SEM. Subject characteristics, supine BP, HR, MSNA, and FVR were compared by using two-way repeated measures ANOVA between groups (Asians and Caucasians), stages (early, late and post), and the interaction. These variables during pre-pregnancy were assessed separately from other pregnancy stages with a Student's unpaired t test. Responses in BP, HR, and MSNA indices during head-up tilt (HUT) were examined by using two-way repeated measures ANOVA between groups (Asians and Caucasians), posture (supine, 30 deg, 60 deg and recovery), and the interaction in each pregnancy stage. The Holm–Sidak method was used for multiple comparisons only when ANOVA P values for the interaction and/or main group effect were <0.05. Linear regression analysis was used to evaluate the correlation between MBP and total activity, as well as between MBP and aldosterone concentration. A P value of < 0.05 was considered statistically significant.

Results

Subject characteristics

As shown in Table1, there were no differences in age between the races, but height, weight, and body mass index (BMI) were lower in Asians than Caucasians. Weight and BMI increased during late pregnancy (both P < 0.001), while there were no interactions between race and pregnancy stage.

Table 1.

Subjects’ characteristics

Caucasians (n = 12) Asians (n = 9) P values
Variables Pre Early Late Post Pre Early Late Post Race Interaction
Age (years) 29 ± 1 30 ± 1 — — 32 ± 1 32 ± 1 — — 0.249 —
Height (cm) 163 ± 2 165 ± 2 — — 159 ± 3 157 ± 2 — — 0.013 —
Weight (kg) 69 ± 5 68 ± 4 80 ± 3 74 ± 3 52 ± 2 52 ± 2 63 ± 2 56 ± 2 <0.001 0.358
BMI (kg m−2) 26.2 ± 2.2 25.4 ± 1.5 29.7 ± 1.3 27.4 ± 1.5 20.6 ± 1.0 21.1 ± 0.6 25.1 ± 0.7 22.6 ± 0.8 0.017 0.611
Open in a new tab

Eight Caucasians and 5 Asians were assessed during the pre-pregnancy testing. Pre, Early, Late and Post indicate pre-, early, late, and post-pregnancy. BMI, body mass index. Values are means ± SEM.

Supine variables

Representative tracings of supine resting MSNA in one Asian and one Caucasian woman were demonstrated in Fig.1. MSNA burst frequency increased with pregnancy and the increase was smaller in Asian women (Fig.2A). Indeed, burst frequency was lower in Asians than Caucasians during pregnancy, but it was not different between groups during post-partum. Likewise, burst incidence was lower in Asians than Caucasians during early and late pregnancy stages (early: 21 ± 5 vs. 34 ± 4, P = 0.031; late: 20 ± 6 vs. 41 ± 3 bursts 100−1 beats, P = 0.001). Total activity increased during pregnancy in both groups, while it was smaller in Asians than Caucasians (Fig.2B). MBP decreased during early pregnancy but was restored during late pregnancy, and it returned to the pre-pregnancy level during post-partum (Fig. 2C). Asians tended to have a lower MBP than Caucasians during pregnancy, while MBP was similar during post-partum. HR increased during late pregnancy and decreased markedly during post-partum without any racial difference (Fig. 2D). All these variables were not different between Asian and Caucasian women during pre-pregnancy.

Figure 1.

Figure 1

Open in a new tab

Supine resting muscle sympathetic nerve activity

Original tracings of integrated muscle sympathetic nerve activity during pre-, early, late, and post-pregnancy from one Asian woman and one Caucasian woman.

Figure 2.

Figure 2

Open in a new tab

Supine resting variables

Supine resting muscle sympathetic nerve activity (MSNA) burst frequency (A), total activity (B), mean blood pressure (MBP; C) and heart rate (HR; D) during pre-, early, late, and post-pregnancy in Asians and Caucasians. Values are means ± SEM. *Significant difference vs. Caucasian women at P < 0.05.

Similar to the racial difference of MSNA during pregnancy, FVR was lower in Asian than Caucasian women (Table2). Contrary to the MSNA increase during pregnancy, FVR remained unchanged in either group.

Table 2.

Responses in limb vascular resistance and hormones during pregnancy

Caucasians Asians P values
Variables Pre Early Late Post Pre Early Late Post Race Interaction
FVR (units) 30.7 ± 5.5 31.4 ± 3.0 35.3 ± 3.4 34.9 ± 3.0 27.0 ± 5.2 23.4 ± 3.4 23.9 ± 3.8 27.8 ± 3.8 0.033 0.801
Noradrenaline (pg ml−1) 198 ± 35 299 ± 45 193 ± 16 150 ± 30 162 ± 26 135 ± 36* 124 ± 19* 124 ± 27 0.026 0.024
Direct renin (pg ml−1) 9 ± 1 23 ± 2 23 ± 1 7 ±1 15 ± 6 42 ± 9 36 ± 16 10 ± 2 0.086 0.191
Aldosterone (ng dl−1) 5 ± 2 13 ± 3 56 ± 7 3 ± 1 11 ± 3 24 ± 6 85 ± 9* 5 ± 2 0.014 0.025
Oestradiol (pg ml−1) 70 ± 7 349 ± 129 7341 ± 1042 31 ± 8 84 ± 19 833 ± 193 11760 ± 3291 25 ± 3 0.111 0.174
Progesterone (ng ml−1) 6.2 ± 2.8 22.2 ± 3.1 153.6 ± 18.6 0.3 ± 0.1 11.9 ± 2.4 22.1 ± 2.5 168.0 ± 23.8 0.3 ± 0.0 0.669 0.782
Open in a new tab

FVR, forearm vascular resistance. Values are means ± SEM. *P < 0.05 vs. Caucasians within each stage.

Responses to head-up tilt

MSNA burst frequency increased during HUT in both races for all pregnancy stages, while a racial difference was observed only during late pregnancy; it was smaller in Asians than Caucasians (Fig.3A). Likewise, upright burst incidence was smaller in Asians than Caucasians only during late pregnancy (30 deg HUT: 35 ± 6 vs. 52 ± 3; 60 deg HUT: 36 ± 6 vs. 57 ± 3 bursts (100 beats)−1; P < 0.001 for race, P < 0.001 for posture, and P = 0.248 for the interaction). Total activity showed similar responses and was lower in Asians during late pregnancy (Fig.3B). MBP was lower in Asians during HUT prior to pregnancy and throughout the entire gestation (Fig.3C). HR increased during HUT in all stages, while there was no racial difference of HR in pre- and early-pregnancy (Fig.3D). However, in late pregnancy and post-partum, the HR response to HUT was smaller in Asians compared to Caucasians.

Figure 3.

Figure 3

Open in a new tab

Sympathetic and cardiovascular responses to head-up tilt

Responses of muscle sympathetic nerve activity (MSNA) burst frequency (A), total activity (B), mean blood pressure (MBP; C) and heart rate (HR; D) to head-up tilt (HUT) during pre-, early, late, and post-pregnancy in Asians and Caucasians. Values are means ± SEM. *Significant difference vs. Caucasian women at P < 0.05.

Humoral responses

Plasma noradrenaline concentration increased during early pregnancy, but decreased during late pregnancy (Table2). Plasma noradrenaline was lower in Asians than Caucasians during pregnancy (P < 0.001); however, it did not differ between races during pre-pregnancy and post-partum (P = 0.463 and 0.557). Direct renin increased during early pregnancy (P < 0.001) and it remained elevated during late pregnancy in both groups (P < 0.001), with a tendency of a higher level in Asians. Aldosterone increased in early pregnancy (P = 0.016) and it continued to increase during late pregnancy (P < 0.001) in both groups. The increase of aldosterone level was greater in Asians, and aldosterone concentration was markedly higher in Asians than Caucasians during late pregnancy. Oestradiol was greater in Asians than Caucasians during late pregnancy (P < 0.010), while the increase in progesterone was similar between the races (P = 0.820).

Blood pressure, MSNA and aldosterone relations

Figure4 shows the relationships between MBP and total activity as well as aldosterone during early and late pregnancy in Asian and Caucasian women. MBP was significantly correlated with total activity in Caucasians but not Asians (Fig.4A). Conversely, a significant correlation between MBP and aldosterone was observed only in Asians (Fig.4B).

Figure 4.

Figure 4

Open in a new tab

Analysis of the inter-individual relationships between mean blood pressure, total activity, and aldosterone

Linear regression analysis of the inter-individual relationships between mean blood pressure (MBP) and total activity (A) and aldosterone levels (B) during early and late pregnancy in Asian and Caucasian women.

Discussion

This is the first longitudinal study to investigate neural and humoral responses during normal pregnancy in Asian and Caucasian women. The key finding from this study was that Asians had attenuated sympathetic activation but enhanced renal–adrenal responsiveness during pregnancy, especially in late pregnancy when compared with Caucasian women. These results may provide insights into the pathophysiological mechanisms for racial differences in the prevalence of hypertensive disorders during pregnancy.

Racial differences in sympathetic activation during pregnancy

Our study showed that sympathetic activation occurred early during pregnancy, was sustained throughout gestation, and returned to the pre-pregnancy level shortly after delivery in all subjects. These observations suggest that sympathetic activation is a common phenomenon in human pregnancy. Pregnancy-induced sympathetic activation may be a compensatory mechanism for peripheral vasodilatation (Chapman et al. 1998), which could be attributed to oestrogen and other vasodilator biomarkers. Oestrogen may stimulate an increase in nitric oxide synthesis (Williams et al. 1997), attenuate α-adrenergic sensitivity (Meyer et al. 1997), and/or enhance β-adrenergic-mediated vasodilatation (Hart et al. 2011). All of these could trigger a reflex increase in sympathetic activity. We found that direct renin increased during early pregnancy and remained elevated during late pregnancy, indicating a sustained increase in angiotensin II. Increased angiotensin II may cause sympathetic activation through central mechanisms (Ganten et al. 1984; Brooks, 1997; Ma et al. 2004). Additionally, aldosterone significantly increased during pregnancy, while chronic exposure to a high concentration of aldosterone may also result in sympathetic activation (Kontak et al. 2010; Jarvis et al. 2012; Okada et al. 2013).

In this study, Asian women had less sympathetic activation during pregnancy compared with Caucasians. There are several possible explanations for this observation. (1) BMI was smaller in Asians, which may contribute to their attenuated sympathetic activation during pregnancy. However, Tank et al. (2008) found that BMI was predictive for MSNA in men but not in women. We also did not see any correlation between BMI and supine resting MSNA before pregnancy in our subjects (R = 0.076, P = 0.815). (2) Gestational weight gain may play a role in racial differences in sympathetic activation during pregnancy. Although the actual weight was much lower in Asians than Caucasians during late pregnancy (63 ± 2 vs. 80 ± 3 kg, P < 0.001), gestational weight gain was not different between the races (11 ± 2 in Asians vs. 12 ± 1 kg in Caucasians, P = 0.277). (3) Consistent with previous studies (Lipworth et al. 1999; Shibata et al. 2002; Pinheiro et al. 2005), we also found that circulating oestradiol level was higher in Asians than Caucasians during pregnancy (especially in late pregnancy), which may be attributed to dietary impact. While the details of their own diets were unknown in this study, soy protein and n-3 polyunsaturated fatty acids are typical of Asian but not Caucasian diets, which could affect pregnancy oestrogen levels (Hilakivi-Clarke et al. 2002). Although we put all the subjects on a constant metabolic diet 2 days prior to each testing, we were unable to eliminate the long-term effects of their own diets on oestrogen levels during pregnancy. Oestrogen acts on the peripheral vasculature, causing profound vasodilatation and reflex-mediated sympathetic activation. Conversely, oestrogen also acts on the brain to reduce central sympathetic outflow (He et al. 1998, 1999; Ma et al. 2008; Carter et al. 2013). The net effect of peripheral and central action of oestrogen may result in the attenuated sympathetic activation during pregnancy in Asian women. (4) Aldosterone was greater in Asians than Caucasians during late pregnancy. Even though aldosterone may cause sympathoexcitation (Kontak et al. 2010; Jarvis et al. 2012), blood volume expansion associated with aldosterone could have inhibited sympathetic activity through a baroreflex mechanism in pregnant Asian women. Indeed, MBP was significantly correlated with MSNA only in Caucasians who had lower increases in aldosterone during pregnancy. This speculation needs to be verified in future studies.

Upright MSNA was lower in Asians than Caucasians especially during late pregnancy. The lower upright activity may depend on the racial difference of MSNA chronically observed during supine position, but not on the attenuation of sympathetic responses to orthostasis or displacement of the recording electrodes during tilting in Asians. It was difficult to think of any reasons why such a displacement only occurred in Asians but not Caucasians.

We found that plasma noradrenaline concentration was lower in Asians than Caucasians during pregnancy, which supports the racial difference in MSNA. Contrary to the changes in MSNA, noradrenaline increased during early pregnancy but decreased during late pregnancy. Plasma noradrenaline concentration can be affected by not only sympathetic activity but also many other factors, such as plasma volume, synaptic transmitter release, reuptake, clearance, or regional blood flow. The reduction of noradrenaline concentration during late pregnancy was likely to be due to a larger increase in blood volume associated with pregnancy relative to the increase in noradrenaline release from sympathetic nerve terminals.

Renal–adrenal responses in Asian and Caucasian women

Activation of the renin–angiotensin–aldosterone system (RAAS) occurs early during pregnancy, which contributes importantly to blood volume expansion. We found that direct renin and aldosterone concentration were greater in Asians than Caucasians during pregnancy, especially during late pregnancy. Angiotensinogen synthesis increases with oestrogen via the hepatic oestrogen receptor (Skinner et al. 1972; Immonen et al. 1983; Krattenmacher et al. 1994), while Asian women have higher levels of oestrogen during pregnancy compared with Caucasian women. Thus, oestrogen may be one determinant for the upregulated RAAS in pregnant Asian women. Indeed, previous studies have shown that oestrogen causes over-expression of the RAAS by augmenting both tissue and circulating levels of angiotensinogen and renin (Glorioso et al. 1986; Howard et al. 1988). In addition, racial/ethnic differences in the genetic polymorphisms in the RAAS (Ding et al. 2000; Ji et al. 2013) may also contribute to the enhanced renal–adrenal responsiveness during pregnancy in Asian women. Finally, it is possible that the upregulated RAAS is a compensatory response for the attenuated sympathetic activation to the skeletal muscle vasculature during pregnancy in Asian women. Figure5 depicts possible mechanisms underlying racial differences in sympathetic neural control and renal–adrenal responsiveness during normal pregnancy.

Figure 5.

Figure 5

Open in a new tab

Possible mechanisms underlying racial differences

Possible mechanisms underlying racial differences in sympathetic neural activity and renal–adrenal responsiveness during normal pregnancy. A, Asians. C, Caucasians. NO, nitric oxide. AR, adrenergic receptor. BP, blood pressure. MSNA, muscle sympathetic nerve activity. Aldo, aldosterone. Ang, angiotensin.

Perspectives

It has been suggested that sympathetic overactivity may be a precursor for gestational hypertension and pree-clampsia (Schobel et al. 1996). The attenuated sympathetic activation in pregnant Asian women may explain, at least in part, why this ethnic group has a low prevalence of hypertensive disorders during pregnancy. Conversely, low circulating levels of renin and aldosterone are common features of preeclampsia (Yang et al. 2013), which may be responsible for the low blood volume in preeclamptic women. The high direct renin and aldosterone concentration in Asian women during their pregnancies may help expand blood volume and plasma volume, resulting in sympathetic inhibition via the baroreflex mechanism (Metsaars et al. 2006; Krabbendam et al. 2009). Our findings have significant clinical implications. For example, interventions targeted at reducing sympathetic tone and improving renal–adrenal responsiveness, such as exercise training, may be effective in the prevention and early treatment of hypertensive disorders during pregnancy.

Acknowledgments

We are grateful to the study volunteers for their participation. We also thank Tiffany B. Bivens, Rhonda L. Meier, Jeffrey L. Hastings, M. Dean Palmer and Peggy Fowler for their valuable laboratory assistance.

Glossary

Abbreviations

Aldo

aldosterone

Ang

angiotensin

AR

adrenergic receptor

BMI

body mass index

BP

blood pressure

FBF

forearm blood flow

FVR

forearm vascular resistance

HR

heart rate

HUT

head-up tilt

MBP

mean blood pressure

MSNA

muscle sympathetic nerve activity

RAAS

renin–angiotensin–aldosterone system

Additional information

Competing interests

The authors have no disclosures.

Author contributions

This study was performed at the Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas. Y.O., S.A.B and S.S.J contributed to conception and design of the experiments; collection, analysis and interpretation of data; and drafting the article and revising it critically for important intellectual content. S.S and R.S.P. contributed to collection and analysis of data. B.M.C. and B.D.L. contributed to conception and design of the experiments; collection, analysis and interpretation of data; and revising the article for important intellectual content. Q.F. contributed to conception and design of the experiments; collection, analysis and interpretation of data; and drafting the article and revising it critically for important intellectual content. All authors approved the final version of the manuscript.

Funding

This study was supported by the National Institutes of Health R21 HL088184 grant.

References

  1. Abdul-Karim R. Assalin S. Pressor response to angiotonin in pregnant and nonpregnant women. Am J Obstet Gynecol. 1961;82:246–251. doi: 10.1016/0002-9378(61)90053-9. [DOI] [PubMed] [Google Scholar]
  2. Brooks VL. Interactions between angiotensin II and the sympathetic nervous system in the long-term control of arterial pressure. Clin Exp Pharmacol Physiol. 1997;24:83–90. doi: 10.1111/j.1440-1681.1997.tb01788.x. [DOI] [PubMed] [Google Scholar]
  3. Cabacungan ET, Ngui EM. McGinley EL. Racial/ethnic disparities in maternal morbidities: a statewide study of labor and delivery hospitalizations in Wisconsin. Matern Child Health J. 2012;16:1455–1467. doi: 10.1007/s10995-011-0914-6. [DOI] [PubMed] [Google Scholar]
  4. Carter JR, Fu Q, Minson CT. Joyner MJ. Ovarian cycle and sympathoexcitation in premenopausal women. Hypertension. 2013;61:395–399. doi: 10.1161/HYPERTENSIONAHA.112.202598. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chapman AB, Abraham WT, Zamudio S, Coffin C, Merouani A, Young D, Johnson A, Osorio F, Goldberg C, Moore LG, Dahms T. Schrier RW. Temporal relationships between hormonal and hemodynamic changes in early human pregnancy. Kidney Int. 1998;54:2056–2063. doi: 10.1046/j.1523-1755.1998.00217.x. [DOI] [PubMed] [Google Scholar]
  6. Cui J, Wilson TE, Shibasaki M, Hodges NA. Crandall CG. Baroreflex modulation of muscle sympathetic nerve activity during posthandgrip muscle ischemia in humans. J Appl Physiol (1985) 2001;91:1679–1686. doi: 10.1152/jappl.2001.91.4.1679. [DOI] [PubMed] [Google Scholar]
  7. Derkx FH, Alberda AT, de Jong FH, Zeilmaker FH, Makovitz JW. Schalekamp MA. Source of plasma prorenin in early and late pregnancy: observations in a patient with primary ovarian failure. J Clin Endocrinol Metab. 1987;65:349–354. doi: 10.1210/jcem-65-2-349. [DOI] [PubMed] [Google Scholar]
  8. Ding PY, Hu OY, Pool PE. Liao W. Does Chinese ethnicity affect the pharmacokinetics and pharmacodynamics of angiotensin-converting enzyme inhibitors? J Hum Hypertens. 2000;14:163–170. doi: 10.1038/sj.jhh.1000856. [DOI] [PubMed] [Google Scholar]
  9. Escher G, Cristiano M, Causevic M, Baumann M, Frey FJ, Surbek D. Mohaupt MG. High aldosterone-to-renin variants of CYP11B2 and pregnancy outcome. Nephrol Dial Transplant. 2009;24:1870–1875. doi: 10.1093/ndt/gfn763. [DOI] [PubMed] [Google Scholar]
  10. Fu Q, Shook RP, Okazaki K, Hastings JL, Shibata S, Conner CL, Palmer MD. Levine BD. Vasomotor sympathetic neural control is maintained during sustained upright posture in humans. J Physiol. 2006;577:679–687. doi: 10.1113/jphysiol.2006.118158. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fu Q, Witkowski S. Levine BD. Vasoconstrictor reserve and sympathetic neural control of orthostasis. Circulation. 2004;110:2931–2937. doi: 10.1161/01.CIR.0000146384.91715.B5. [DOI] [PubMed] [Google Scholar]
  12. Ganten D, Lang RE, Lehmann E. Unger T. Brain angiotensin: on the way to becoming a well-studied neuropeptide system. Biochem Pharmacol. 1984;33:3523–3528. doi: 10.1016/0006-2952(84)90132-1. [DOI] [PubMed] [Google Scholar]
  13. Gennari-Moser C, Escher G, Kramer S, Dick B, Eisele N, Baumann M, Raio L, Frey FJ, Surbek D. Mohaupt MG. Normotensive blood pressure in pregnancy: the role of salt and aldosterone. Hypertension. 2014;63:362–368. doi: 10.1161/HYPERTENSIONAHA.113.02320. [DOI] [PubMed] [Google Scholar]
  14. Glorioso N, Atlas SA, Laragh JH, Jewelewicz R. Sealey JE. Prorenin in high concentrations in human ovarian follicular fluid. Science. 1986;233:1422–1424. doi: 10.1126/science.3529392. [DOI] [PubMed] [Google Scholar]
  15. Greenfield AD, Whitney RJ. Mowbray JF. Methods for the investigation of peripheral blood flow. Br Med Bull. 1963;19:101–109. doi: 10.1093/oxfordjournals.bmb.a070026. [DOI] [PubMed] [Google Scholar]
  16. Greenwood JP, Scott EM, Stoker JB, Walker JJ. Mary DA. Sympathetic neural mechanisms in normal and hypertensive pregnancy in humans. Circulation. 2001;104:2200–2204. doi: 10.1161/hc4301.098253. [DOI] [PubMed] [Google Scholar]
  17. Greenwood JP, Scott EM, Walker JJ, Stoker JB. Mary DA. The magnitude of sympathetic hyperactivity in pregnancy-induced hypertension and preeclampsia. Am J Hypertens. 2003;16:194–199. doi: 10.1016/s0895-7061(02)03256-9. [DOI] [PubMed] [Google Scholar]
  18. Greenwood JP, Stoker JB, Walker JJ. Mary DA. Sympathetic nerve discharge in normal pregnancy and pregnancy-induced hypertension. J Hypertens. 1998;16:617–624. doi: 10.1097/00004872-199816050-00009. [DOI] [PubMed] [Google Scholar]
  19. Halliwill JR. Segregated signal averaging of sympathetic baroreflex responses in humans. J Appl Physiol (1985) 2000;88:767–773. doi: 10.1152/jappl.2000.88.2.767. [DOI] [PubMed] [Google Scholar]
  20. Hart EC, Charkoudian N, Wallin BG, Curry TB, Eisenach J. Joyner MJ. Sex and ageing differences in resting arterial pressure regulation: the role of the β-adrenergic receptors. J Physiol. 2011;589:5285–5297. doi: 10.1113/jphysiol.2011.212753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. He XR, Wang W, Crofton JT. Share L. Effects of 17β-estradiol on sympathetic activity and pressor response to phenylephrine in ovariectomized rats. Am J Physiol. 1998;275:R1202–R1208. doi: 10.1152/ajpregu.1998.275.4.R1202. [DOI] [PubMed] [Google Scholar]
  22. He XR, Wang W, Crofton JT. Share L. Effects of 17β-estradiol on the baroreflex control of sympathetic activity in conscious ovariectomized rats. Am J Physiol. 1999;277:R493–R498. doi: 10.1152/ajpregu.1999.277.2.R493. Regul Integr Comp Physiol. [DOI] [PubMed] [Google Scholar]
  23. Hilakivi-Clarke L, Cho E, Cabanes A, DeAssis S, Olivo S, Helferich W, Lippman ME. Clarke R. Dietary modulation of pregnancy estrogen levels and breast cancer risk among female rat offspring. Clin Cancer Res. 2002;8:3601–3610. [PubMed] [Google Scholar]
  24. Howard RB, Pucell AG, Bumpus FM. Husain A. Rat ovarian renin: characterization and changes during the estrous cycle. Endocrinology. 1988;123:2331–2340. doi: 10.1210/endo-123-5-2331. [DOI] [PubMed] [Google Scholar]
  25. Immonen I, Siimes A, Stenman UH, Karkkainen J. Fyhrquist F. Plasma renin substrate and oestrogens in normal pregnancy. Scand J Clin Lab Invest. 1983;43:61–65. [PubMed] [Google Scholar]
  26. Irani RA. Xia Y. Renin angiotensin signaling in normal pregnancy and preeclampsia. Semin Nephrol. 2011;31:47–58. doi: 10.1016/j.semnephrol.2010.10.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Jarvis SS, Shibata S, Bivens TB, Okada Y, Casey BM, Levine BD. Fu Q. Sympathetic activation during early pregnancy in humans. J Physiol. 2012;590:3535–3543. doi: 10.1113/jphysiol.2012.228262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ji L, Cai X, Zhang L, Fei L, Wang L, Su J, Lazar L, Xu J. Zhang Y. Association between polymorphisms in the renin–angiotensin–aldosterone system genes and essential hypertension in the Han Chinese population. PLoS One. 2013;8:e72701. doi: 10.1371/journal.pone.0072701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Johnson JM, Rowell LB, Niederberger M. Eisman MM. Human splanchnic and forearm vasoconstrictor responses to reductions of right atrial and aortic pressures. Circ Res. 1974;34:515–524. doi: 10.1161/01.res.34.4.515. [DOI] [PubMed] [Google Scholar]
  30. Kontak AC, Wang Z, Arbique D, Adams-Huet B, Auchus RJ, Nesbitt SD, Victor RG. Vongpatanasin W. Reversible sympathetic overactivity in hypertensive patients with primary aldosteronism. J Clin Endocrinol Metab. 2010;95:4756–4761. doi: 10.1210/jc.2010-0823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Krabbendam I, Courtar DA, Janssen BJ, Aardenburg R, Peeters LL. Spaanderman ME. Blunted autonomic response to volume expansion in formerly preeclamptic women with low plasma volume. Reprod Sci. 2009;16:105–112. doi: 10.1177/1933719108324136. [DOI] [PubMed] [Google Scholar]
  32. Krattenmacher R, Knauthe R, Parczyk K, Walker A, Hilgenfeldt U. Fritzemeier KH. Estrogen action on hepatic synthesis of angiotensinogen and IGF-I: direct and indirect estrogen effects. J Steroid Biochem Mol Biol. 1994;48:207–214. doi: 10.1016/0960-0760(94)90146-5. [DOI] [PubMed] [Google Scholar]
  33. Lipworth L, Hsieh CC, Wide L, Ekbom A, Yu SZ, Yu GP, Xu B, Hellerstein S, Carlstrom K, Trichopoulos D. Adami HO. Maternal pregnancy hormone levels in an area with a high incidence (Boston, USA) and in an area with a low incidence (Shanghai, China) of breast cancer. Br J Cancer. 1999;79:7–12. doi: 10.1038/sj.bjc.6690003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Ma HJ, Cao YK, Liu YX, Wang R. Wu YM. Microinjection of resveratrol into rostral ventrolateral medulla decreases sympathetic vasomotor tone through nitric oxide and intracellular Ca2+ in anesthetized male rats. Acta Pharmacol Sin. 2008;29:906–912. doi: 10.1111/j.1745-7254.2008.00827.x. [DOI] [PubMed] [Google Scholar]
  35. Ma X, Sigmund CD, Hingtgen SD, Tian X, Davisson RL, Abboud FM. Chapleau MW. Ganglionic action of angiotensin contributes to sympathetic activity in renin–angiotensinogen transgenic mice. Hypertension. 2004;43:312–316. doi: 10.1161/01.HYP.0000111835.16662.43. [DOI] [PubMed] [Google Scholar]
  36. Metsaars WP, Ganzevoort W, Karemaker JM, Rang S. Wolf H. Increased sympathetic activity present in early hypertensive pregnancy is not lowered by plasma volume expansion. Hypertens Pregnancy. 2006;25:143–157. doi: 10.1080/10641950600912927. [DOI] [PubMed] [Google Scholar]
  37. Meyer MC, Cummings K. Osol G. Estrogen replacement attenuates resistance artery adrenergic sensitivity via endothelial vasodilators. Am J Physiol. 1997;272:H2264–H2270. doi: 10.1152/ajpheart.1997.272.5.H2264. Heart Circ Physiol. [DOI] [PubMed] [Google Scholar]
  38. Okada Y, Jarvis SS, Best SA, Bivens TB, Adams-Huet B, Levine BD. Fu Q. Chronic renin inhibition lowers blood pressure and reduces upright muscle sympathetic nerve activity in hypertensive seniors. J Physiol. 2013;591:5913–5922. doi: 10.1113/jphysiol.2013.261362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Pinheiro SP, Holmes MD, Pollak MN, Barbieri RL. Hankinson SE. Racial differences in premenopausal endogenous hormones. Cancer Epidemiol Biomarkers Prev. 2005;14:2147–2153. doi: 10.1158/1055-9965.EPI-04-0944. [DOI] [PubMed] [Google Scholar]
  40. Roberts JM, Pearson G, Cutler J, Lindheimer M Pregnancy NWGoRoHD. Summary of the NHLBI working group on research on hypertension during pregnancy. Hypertension. 2003;41:437–445. doi: 10.1161/01.HYP.0000054981.03589.E9. [DOI] [PubMed] [Google Scholar]
  41. Schobel HP, Fischer T, Heuszer K, Geiger H. Schmieder RE. Preeclampsia – a state of sympathetic overactivity. N Engl J Med. 1996;335:1480–1485. doi: 10.1056/NEJM199611143352002. [DOI] [PubMed] [Google Scholar]
  42. Shibata A, Harris DT. Billings PR. Concentrations of estrogens and IGFs in umbilical cord blood plasma: a comparison among Caucasian, Hispanic, and Asian-American females. J Clin Endocrinol Metab. 2002;87:810–815. doi: 10.1210/jcem.87.2.8227. [DOI] [PubMed] [Google Scholar]
  43. Skinner SL, Lumbers ER. Symonds EM. Analysis of changes in the renin–angiotensin system during pregnancy. Clin Sci. 1972;42:479–488. doi: 10.1042/cs0420479. [DOI] [PubMed] [Google Scholar]
  44. Sundlof G. Wallin BG. The variability of muscle nerve sympathetic activity in resting recumbent man. J Physiol. 1977;272:383–397. doi: 10.1113/jphysiol.1977.sp012050. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Sundlof G. Wallin BG. Human muscle nerve sympathetic activity at rest. Relationship to blood pressure and age. J Physiol. 1978;274:621–637. doi: 10.1113/jphysiol.1978.sp012170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Tank J, Heusser K, Diedrich A, Hering D, Luft FC, Busjahn A, Narkiewicz K. Jordan J. Influences of gender on the interaction between sympathetic nerve traffic and central adiposity. J Clin Endocrinol Metab. 2008;93:4974–4978. doi: 10.1210/jc.2007-2820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Vallbo AB, Hagbarth KE, Torebjork HE. Wallin BG. Somatosensory, proprioceptive, and sympathetic activity in human peripheral nerves. Physiol Rev. 1979;59:919–957. doi: 10.1152/physrev.1979.59.4.919. [DOI] [PubMed] [Google Scholar]
  48. Wallin BG. Sundlof G. Sympathetic outflow to muscles during vasovagal syncope. J Auton Nerv Syst. 1982;6:287–291. doi: 10.1016/0165-1838(82)90001-7. [DOI] [PubMed] [Google Scholar]
  49. Williams DJ, Vallance PJ, Neild GH, Spencer JA. Imms FJ. Nitric oxide-mediated vasodilation in human pregnancy. Am J Physiol. 1997;272:H748–752. doi: 10.1152/ajpheart.1997.272.2.H748. Heart Circ Physiol. [DOI] [PubMed] [Google Scholar]
  50. Yang J, Shang J, Zhang S, Li H. Liu H. The role of the renin–angiotensin–aldosterone system in preeclampsia: genetic polymorphisms and microRNA. J Mol Endocrinol. 2013;50:R53–66. doi: 10.1530/JME-12-0216. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Physiology are provided here courtesy of The Physiological Society

RESOURCES