Sympathetic determinants of resting blood pressure in males and females.

Discharge of postganglionic muscle sympathetic nerve activity (MSNA) is related poorly to blood pressure (BP) in adults. Whether neural measurements beyond the prevailing level of MSNA can account for interindividual differences in BP remains unclear. The current study sought to evaluate the relative contributions of sympathetic-BP transduction and sympathetic baroreflex gain on resting BP in young adults. Data were analyzed from 191 (77 females) young adults (18-39 years) who underwent continuous measurement of beat-to-beat BP (finger photoplethysmography), heart rate (electrocardiography), and fibular nerve MSNA (microneurography). Linear regression analyses were computed to determine associations between sympathetic-BP transduction (signal-averaging) or sympathetic baroreflex gain (threshold technique) and resting BP, before and after controlling for age, body mass index, and MSNA burst frequency. K-mean clustering was used to explore sympathetic phenotypes of BP control and consequential influence on resting BP. Sympathetic-BP transduction was unrelated to BP in males or females (both R2 < 0.01; P > 0.67). Sympathetic baroreflex gain was positively associated with BP in males (R2 = 0.09, P < 0.01), but not in females (R2 < 0.01; P = 0.80), before and after controlling for age, body mass index, and MSNA burst frequency. K-means clustering identified a subset of participants with average resting MSNA, yet lower sympathetic-BP transduction and lower sympathetic baroreflex gain. This distinct subgroup presented with elevated BP in males (P < 0.02), but not in females (P = 0.10). Sympathetic-BP transduction is unrelated to resting BP, while the association between sympathetic baroreflex gain and resting BP in males reveals important sex differences in the sympathetic determination of resting BP.NEW & NOTEWORTHY In a sample of 191 normotensive young adults, we confirm that resting muscle sympathetic nerve activity is a poor predictor of resting blood pressure and now demonstrate that sympathetic baroreflex gain is associated with resting blood pressure in males but not females. In contrast, signal-averaged measures of sympathetic-blood pressure transduction are unrelated to resting blood pressure. These findings highlight sex differences in the neural regulation of blood pressure.

Sex differences in sympathetic neurovascular and neurohemodynamic relationships during cold pressor test.

Muscle sympathetic nerve activity (MSNA) affects vascular resistance differently in women and men. However, whether this sex difference persists during pronounced increases in MSNA remains unclear. Therefore, the purpose of this study was to examine sex differences in neurovascular transduction during cold pressor test (CPT)-mediated sympathoexcitation. Integrated peroneal MSNA (microneurography) was measured at rest and during a 3-min CPT in young healthy women (n = 11) and men (n = 10). Mean arterial pressure (MAP) was measured beat-by-beat (Finometer), and superficial femoral artery blood flow was measured using duplex ultrasound. Femoral vascular resistance (FVR) was quantified as MAP/femoral blood flow (mmHg/mL/min). Baseline MSNA was similar between women and men (14 ± 9 vs. 15 ± 9 bursts/100 heartbeat, respectively; P = 0.83), whereas MAP was lower (86 ± 7 vs. 92 ± 4 mmHg; P = 0.047), and FVR was greater in women than men (0.54 ± 0.16 vs. 0.36 ± 0.15 mmHg/mL/min; P = 0.02). CPT-induced increases in MSNA were similar between the sexes (19 ± 11 vs. 26 ± 14 bursts/100 heartbeat; P = 0.26) whereas increases in MAP (7 ± 3 vs. 10 ± 3 mmHg; P = 0.03) and FVR (3.2 ± 18.6 vs. 26.8 ± 12.8%; P < 0.01) were smaller in women than in men. Within men, CPT- induced increases in MSNA predicted increases in MAP (R2 = 0.51, P = 0.02) and FVR (R2 = 0.49, P = 0.02). However, MSNA did not predict MAP (R2 = 0.11, P = 0.35) or FVR (R2 = 0.07, P = 0.46) in women. Our findings demonstrate that men experience robust CPT-induced MAP responses that are driven by both neurovascular (MSNA-FVR) and neurohemodynamic (MSNA-MAP) coupling. These relationships were not observed in women, indicating that even during pronounced increases in sympathetic outflow, MSNA is not predictive of vascular nor blood pressure outcomes in young healthy women.

Sex differences in dynamic blood pressure regulation: beat-by-beat responses to muscle sympathetic nerve activity.

It has been suggested that sex differences in acute blood pressure fluctuations occur during the periods of time between bursts of muscle sympathetic nerve activity. Therefore, we tested the hypothesis that men experience more dynamic changes in mean arterial pressure (Finometer MIDI) than women during acute sympathoinhibition (i.e., slow breathing) in which bursts of sympathetic activity occur more infrequently than at rest. We tested healthy women (n = 9) and men (n = 9) of similar age (22 ± 2 vs. 23 ± 3 yr, P = 0.6). Custom software was used to calculate beat-by-beat changes in blood pressure following sympathetic burst and nonburst sequences (recorded using microneurography) during 10 min of supine rest and a 15-min bout of slow breathing. During slow breathing following nonburst sequences, women demonstrated smaller overall reductions in mean arterial pressure compared with men over the subsequent 15 cardiac cycles (P < 0.01). In addition, following a burst of sympathetic activity, women experienced greater overall increases in mean arterial pressure compared with men over the following 15 cardiac cycles (P < 0.01). Despite these differences, the peak and nadir changes in arterial pressure following burst and nonburst sequences were not different between the sexes (P = 0.45 and P = 0.48, burst and nonburst sequences, respectively). As such, these data suggest that women respond to a burst of sympathetic activity with more sustained increases in blood pressure than men, coupled with improved maintenance of blood pressure during acute periods of sympathetic quiescence. In other words, these findings suggest that men rely more on frequent bursts of sympathetic activity to acutely regulate arterial pressure than women.NEW & NOTEWORTHY We demonstrate that during acute sympathoinhibition, women demonstrate more sustained increases in blood pressure following sympathetic bursts of activity than men. Likewise, during prolonged sympathetic quiescence, blood pressure is less labile in women than men. This suggests that lower overall blood pressure in young women may not be mediated by smaller beat-by-beat changes in blood pressure in response to sympathetic outflow but may instead be mediated by a lower frequency of sympathetic bursts.

A recent history of preeclampsia is associated with elevated central pulse wave velocity and muscle sympathetic outflow.

Preeclampsia is associated with the development of cardiovascular diseases later in life. To investigate this phenomenon, we compared established markers of cardiovascular dysregulation between previously preeclamptic women (PPE; n = 12, 13 ± 6 mo postpartum, 34 ± 6 yr) and women who had previously had an uncomplicated pregnancy [control (CTRL); n = 12, 15 ± 4 mo postpartum; 29 ± 3 yr]. We hypothesized that PPE would present with elevated arterial stiffness (assessed as central and peripheral pulse wave velocity) and muscle sympathetic nerve activity (MSNA; microneurography) and blunted baroreflex sensitivity (BRS) relative to CTRL. Blood pressure (Finometer) was similar between PPE and CTRL (mean arterial pressure: 94 ± 11 vs. 89 ± 9, P = 0.16). Central (6.92 ± 0.21 vs. 6.24 ± 0.22 m/s, P = 0.04) but not peripheral arterial stiffness (7.52 ± 0.19 vs. 7.09 ± 0.19 m/s, P = 0.13) was elevated in PPE versus CTRL (values normalized to MAP). MSNA was also elevated in PPE versus CTRL (22 ± 7 vs. 13 ± 5 bursts/min, P = 0.01), although this was independent of arterial stiffness (central: r2 = 0.01, P = 0.74; peripheral: r2 = 0.01, P = 0.74). Cardiovagal BRS was blunted in PPE versus CTRL (15 ± 5 vs. 28 ± 1 ms/mmHg, P = 0.01), whereas sympathetic vascular BRS was similar (-3.2 ± 0.9 vs. -3.1 ± 1.4 bursts·100 hb-1·mmHg-1, P = 0.88). Cardiovagal and sympathetic BRS were inversely correlated in both CTRL (r2 = 0.43; P = 0.05) and PPE (r2 = 0.69; P = 0.04), supporting a compensatory mechanism resulting in normal blood pressures in both groups. Overall, these data indicate that PPE retain their ability to buffer elevated MSNA. We propose that the higher incidence of cardiovascular disease observed later in life in PPE results from this arterial stiffness, combined with the loss of protective vascular mechanisms and the "unmasking" of high MSNA.NEW & NOTEWORTHY We demonstrate that resting muscle sympathetic nerve activity is elevated in women with a recent history of preeclampsia relative to women who have recently had uncomplicated pregnancies and without a history of preeclampsia. Structural changes in the central arteries are associated with arterial stiffness following preeclampsia, independent of changes in the sympathetic nervous system. The structural changes are observed in these relatively young previously preeclamptic women, indicating elevated cardiovascular risk. Our data suggest that with aging (and the gradual loss of vascular protection for women, as established by others), this risk will become exaggerated compared with women who have had normal pregnancies.

Limb-specific muscle sympathetic nerve activity responses to the cold pressor test.

Recent studies have demonstrated that muscle sympathetic nerve activity (MSNA) responses to isometric exercise differs between active and inactive limbs. Whether limb-dependent responses are characteristic of responses to the cold pressor test (CPT) remains to be established. Therefore, we tested the hypothesis that CPT-induced MSNA responses differ between affected and unaffected limbs such that MSNA in the affected lower limb is greater than MSNA responses in the contralateral lower limb and the upper limb. Integrated peroneal MSNA (microneurography) was measured in young healthy individuals (n = 10) at rest and during three separate 3-min CPTs: the microneurography foot, opposite foot, and opposite hand. Peak MSNA responses were extracted for further analysis, as well as corresponding hemodynamic outcomes including mean arterial pressure (MAP; Finometer). MSNA responses were greater when the microneurography foot was immersed in ice water than when the opposite foot was immersed (38 ± 18 vs 28 ± 16 bursts/100hb: P < 0.01). MSNA responses when the opposite hand was immersed were greater than both the microneurography foot (46 ± 22 vs 38 ± 18 bursts/100hb: P < 0.01) and opposite foot (46 ± 22 vs 28 ± 16 bursts/100hb: P ≤0.01). Likewise, MAP responses were greater during the hand CPT than the microneurography foot (99 ± 9 vs 96 ± 8 mmHg: P < 0.01) and opposite foot CPT (99 ± 9 vs 96 ± 9 mmHg: P < 0.01). These data indicate that (a) upper limbs and (b) immersed limbs elicit greater MSNA responses to the CPT than lower and/or non-immersed limbs.

The effects of sex and menstrual cycle phase on sympathetic action potential recruitment patterns during hypercapnic-hypoxic apnea.

Previously, we demonstrated that integrated muscle sympathetic nerve activity (MSNA) responses to acute chemoreflex stress were augmented during the early follicular (EF) phase of the menstrual cycle relative to both the midluteal (ML) phase and males. These differences were most pronounced in the amplitude component of MSNA, suggesting EF-driven increases in action potential (AP) recruitment in females. Therefore, we tested the hypothesis that neural recruitment, quantified as MSNA AP discharge patterns during acute chemoreflex stress, is potentiated during EF. We retrospectively analyzed MSNA data from 9 young males and 7 young females tested during the EF and ML phases at rest and during a voluntary end-inspiratory hypercapnic-hypoxic apnea. Sympathetic AP discharge patterns were analyzed using wavelet-based methodology. Apnea-driven increases in AP frequency and AP content per integrated burst were greater in EF relative to ML (APs/min: P = 0.02; APs/burst: P = 0.03) and to males (APs/min: P = 0.04; APs/burst: P = 0.02). The recruitment of new larger AP clusters was greater in EF than ML (P < 0.01) but not different from males (P = 0.50). Interestingly, we observed a positive association between the magnitude of change in the estrogen/progesterone ratio from EF to ML and the change in AP cluster recruitment, as both decreased from EF to ML (R2 = 0.82; P < 0.01). This suggests that the enhanced progesterone dominance over estrogen during ML may blunt the recruitment of new larger APs. Overall, these data indicate that both sex and the menstrual cycle impact AP recruitment patterns in a manner which may be mediated, at least in part, by gonadal hormones.

Device-guided slow breathing reduces blood pressure and sympathetic activity in young normotensive individuals of both sexes.

Slow breathing (SLOWB) is recommended for use as an adjuvant treatment for hypertension. However, the extent to which blood pressure (BP) responses to SLOWB differ between men and women are not well-established. Therefore, we tested the hypothesis that an acute bout of SLOWB would induce larger decreases in BP in males than in females, given that males typically have higher resting BP. We also examined autonomic contributors to reduced BP during SLOWB; that is, muscle sympathetic nerve activity and spontaneous cardiovagal (sequence method) and vascular sympathetic baroreflex sensitivity. We tested normotensive females (n = 10, age: 22 ± 2 y, body mass index: 22 ± 2 kg/m2) and males (n = 12, age: 23 ± 3 y, body mass index: 26 ± 4 kg/m2). Subjects were tested at baseline and during the last 5 min of a 15-min RESPeRATE-guided SLOWB session. Overall, SLOWB reduced systolic BP by 3.2 ± 0.8 mmHg (main effect, P < 0.01). Females had lower systolic BP (main effect, P = 0.02); we observed no interaction between sex and SLOWB. SLOWB also reduced muscle sympathetic nerve activity burst incidence by -5.0 ± 1.4 bursts/100 heartbeats (main effect, P < 0.01). Although females tended to have lower burst incidence (main effect, P = 0.1), there was no interaction between sex and SLOWB. Cardiovagal baroreflex sensitivity improved during SLOWB (21.0 vs. 36.0 ms/mmHg, P = 0.03) with no effect of sex. Despite lower overall BP in females, our data support a lack of basement effect on SLOWB-induced reductions in BP, as SLOWB was equally effective in reducing BP in males and females. Our findings support the efficacy of the RESPeRATE device for reducing BP in both sexes, even in young, normotensive individuals.NEW & NOTEWORTHY We provide support for the effectiveness of device-guided slow breathing for blood pressure reduction in young normotensive women and men. Despite having lower baseline blood pressure and sympathetic nerve activity, women experienced equivalent reductions in both measures in response to RESPeRATE-guided slow breathing as men. Thus, slow breathing appears to be effective in young healthy normotensive individuals of both sexes and may be an ideal preventative therapy against future hypertension.