Hart, Emma C.

Abstract The autonomic nervous system is a key regulator of the cardiovascular system. In this review, we focus on how sex and aging influence autonomic regulation of blood pressure in humans in an effort to understand general issues related to the cardiovascular system as a whole. Younger women generally have lower blood pressure and sympathetic activity than younger men. However, both sexes show marked interindividual variability across age groups with significant overlap seen. Additionally, while men across the lifespan show a clear relationship between markers of whole body sympathetic activity and vascular resistance, such a relationship is not seen in young women. In this context, the ability of the sympathetic nerves to evoke vasoconstriction is lower in young women likely as a result of concurrent β 2 ‐mediated vasodilation that offsets α‐adrenergic vasoconstriction. These differences reflect both central sympatho‐inhibitory effects of estrogen and also its influence on peripheral vasodilation at the level of the vascular smooth muscle and endothelium. By contrast postmenopausal women show a clear relationship between markers of whole body sympathetic traffic and vascular resistance, and sympathetic activity rises progressively in both sexes with aging. These major findings in humans are discussed in the context of differences in population‐based trends in blood pressure and orthostatic intolerance. The many areas where there is little sex‐specific data on how the autonomic nervous system participates in the regulation of the human cardiovascular system are highlighted. © 2015 American Physiological Society. Compr Physiol 5:193‐215, 2015.

The current study demonstrates that respiratory modulation of sympathetic nerve activity (SNA) is reduced in healthy postmenopausal (PMF) versus premenopausal females (YF). Furthermore, respiratory sympathetic modulation was negatively related to resting blood pressure in postmenopausal females, such that blood pressure was greater in individual with less modulation. Reduced respiratory sympathetic modulation may have implications for the autonomic control of blood pressure in aging postmenopausal females, by contributing to age-related sympathetic activation and reducing acute, respiratory-linked blood pressure variation.

The sensitivity of the baroreflex control of muscle sympathetic nerve activity (MSNA) represents the responsiveness of MSNA to changes in blood pressure, whereas the baroreflex threshold diagram evaluates the likelihood of a burst occurrence over a range of resting blood pressure values. We hypothesized that the slope of the threshold diagram would show a significant positive correlation with sympathetic baroreflex sensitivity (BRS). We compared BRS calculated by the Modified Oxford technique (ModOx) with the slope and midpoint (T50) values from threshold analysis (threshold) in 10 participants (9M, age 26 yrs ± 3[mean ± SEM]). MSNA (peroneal microneurography) and blood pressure (brachial catheter) were measured at rest and during vasoactive drug boluses (ModOx). A threshold diagram was created for each subject during rest by associating DBP to the % occurrence of a burst over a 4 min period prior to the ModOx drugs. The midpoint (T50) of this diagram was defined as the DBP at which 50% of the diastoles were associated with a burst. ModOx‐derived BRS positively correlated with the slope of the threshold diagram (r = 0.64, P<0.05), but not with the T50 (r =0.11, P > 0.2). Our results suggest that the slope of the threshold diagram may be a better index of ModOx‐derived BRS values compared to more commonly used "spontaneous" baroreflex techniques. NIH HL‐083947

Alterations in the carotid baroreflex (CBR) control of arterial pressure may explain the reduction in arterial pressure and left ventricular (LV) function observed after prolonged exercise. We examined the CBR control of heart rate (HR) and mean arterial pressure (MAP), in addition to changes in LV function, pre‐ to post exercise. Seven males (age, 29 ± 7 yrs) completed 4 h of ergometer rowing at a workload 10–15% below lactate threshold. CBR control of HR and MAP was assessed before and after exercise via the rapid neck suction/pressure method. LV systolic function was assessed by echocardiography, where ejection fraction (EF), systolic pressure/volume ratio (SBP/ESV) and stroke volume (SV) were estimated. After exercise MAP was reduced (12 ± 3%) and HR was elevated (35 ± 5%; P <0.05), indicating a relocation of the CBR operating point. Furthermore, the CBR operating pressure was relocated to the left on the HR and MAP stimulus‐response curve ( P <0.05) demonstrating that the CBR operated at a lower arterial pressure. Concomitantly, EF (22 ± 2%), SBP/ESV (32 ± 14%) and SV (25 ± 5%, P <0.05) were reduced after exercise. The reduced EF and SBP/ESV were associated with the decreased MAP operating point (r 2 =0.71 and r 2 =0.47, P <0.05). In conclusion, the CBR is reset to a lower prevailing arterial pressure after prolonged exercise, which may contribute to the reduction arterial pressure and LV function observed.

Previous data indicate that endothelin‐1 may have a direct excitatory effect on sympathetic nerve activity in animals and hypertensive humans. Whether this is true in normotensive humans is unclear. We investigated the relationship between endogenous endothelin‐1 and muscle sympathetic nerve activity (MSNA) in 15 normotensive young men and 15 women (age; 25 ± 1 vs. 25 ± 2 yrs, BMI; 25 ± 1 vs. 23 ± 1 kg/m2). MSNA was recorded via peroneal microneurography, arterial pressure was estimated from brachial arterial line and serum levels of endothelin‐1 (brachial artery) was measured by a quantitative two‐site chemiluminescent immunoassay. Mean arterial pressure (MAP, 90 ± 2 vs. 93 ± 2 mmHg), MSNA (37 ± 3 vs. 34 ± 4 bursts/100 heart beats) and endothelin‐1 (0.72 ± 0.03 vs. 0.63 pg/mL) were not different between men and women respectively. Interestingly, resting MSNA was positively related to arterial levels of endothelin‐1 in men (r = 0.69, P<0.05) but not in women (r = 0.03). Thus, men with high MSNA had high levels of endothelin‐1. These data suggest that endogenous endothelin‐1 is linked to tonic levels of sympathetic nerve activity in men but not in women. AHA 2170087 (ECJH); HL083947 (NC, MJJ, BGW); NIH RR024150 (CTSA).

Baroreflex sensitivity is calculated from the slope of the relationship between blood pressure and muscle sympathetic nerve activity (MSNA) or cardiac R‐R interval. The magnitude of decrease in blood pressure during a vasoactive drug bolus (i.e. modified Oxford) to test the baroreflex may be associated with the calculated baroreflex sensitivity (BRS) slope. We investigated whether the cardiac or sympathetic BRS are associated with the acute decrease in blood pressure during a modified Oxford in young healthy men and women. Forty‐five women (27 ± 1 yrs, BMI 22.9 ± 0.3 kg/m2) and 30 men (27 ± 1 yrs, 24.2 ± 0.4 kg/m2) were studied. MSNA was measured via peroneal microneurography and blood pressure was measured with a brachial intraarterial catheter. Women and men had similar mean arterial pressures (91 ± 1 vs. 90 ± 1 mmHg), cardiac BRS (19 ± 1 vs. 21 ± 2 ms/mmHg), and sympathetic BRS (−6 ± 0.4 vs. −7 ± 0.6 AU/beat/mmHg), respectively. The decrease in systolic blood pressure (SBP) and pulse pressure (PP) was positively related to cardiac BRS in men (r=.47; p<0.01; r=.49; p<0.01). However, there was no relationship between the decrease in blood pressure and sympathetic BRS in men. In addition, there was no association between any blood pressure transients with either cardiac or sympathetic BRS in women. Our results suggest the magnitude of decrease in blood pressure is associated with cardiac BRS in men, but not women. Funded by NIH

Pulse wave velocity (PWV) and sympathetic nerve activity increase with age. However, it is unknown if the age‐related increase in sympathetic activity influences PWV. We determined the effect of autonomic blockade on peripheral and central arterial stiffness in young (23 ± 4 yr) and older, postmenopausal (57 ± 3 yr) women before and during administration of trimethaphan camsylate. Arterial tonometry was used to measure carotid‐radial (peripheral) and carotid‐femoral (central) PWV. The groups did not differ in height, weight, BMI, or mean arterial pressure (MAP). At baseline, peripheral PWV did not differ between the groups. However, central PWV was significantly greater in older women compared with young women (8.2 vs. 6.1 m/s, respectively; p<0.05). Trimethaphan infusion caused a substantial drop in MAP; therefore, we corrected PWV for the change in MAP. Peripheral PWV was greater in older women compared with young women (0.12 vs. 0.08 m/s·mmHg −1 ; p<0.05). In addition, central PWV remained higher in older women during trimethaphan infusion (0.11 vs. 0.08 m/s·mmHg −1 in young; p<0.05). In conclusion, central PWV was greater in older women before and during autonomic blockade, whereas peripheral PWV was only higher in the older women after autonomic blockade. This suggests that peripheral PWV is influenced by sympathetic activity to a greater extent in young vs. older women. Funded by NIH

Acute ß‐adrenergic blockade (BB) increases aortic wave reflection in young women, however, it is unknown if this effect extends to post‐menopausal women. Thus, we examined systemic BB on aortic wave reflection in 14 post‐menopausal women (58 ± 2 yr). Non‐invasive aortic pressure waveforms were synthesized from high‐fidelity radial pressure waveforms obtained from applanation tonometry before and during systemic BB (0.25mg/kg bolus, with 0.004 mg/kg/min continuous infusion of propranolol). Aortic blood pressure, augmentation index (AIx), AIx adjusted for heart rate (AIx@75), aortic augmented pressure (AP), and wasted left ventricular energy (Ew) were calculated from the aortic pressure waveform. Heart rate (60 ± 2 vs. 51 ± 2 bpm) and mean arterial pressure (95 ± 3 vs. 91 ± 3 mmHg) were reduced with BB (P < 0.05 for both). AIx increased during BB (32 ± 2 vs. 35 ± 2%, P < 0.01), however, AIx@75 was unchanged (25 ± 2 vs. 24 ± 2%, ns). Additionally, AP (20 ± 2 vs. 20 ± 2 mmHg, ns) and Ew (4313 ± 538 vs. 4277 ± 537 dyne*cm2/sec, ns) remained unchanged during BB. When compared to our previously published study in young women, indices of aortic wave reflection were significantly less affected in post‐menopausal women in response to acute systemic BB. Taken together, our data suggest that the negative effects (i.e. increased aortic wave reflection) of non‐selective BB are less pronounced in post‐menopausal women.

In young women, tonic autonomic nervous system activity contributes less to resting blood pressure than that in men. It is unknown whether the autonomic support of blood pressure increases in postmenopausal women, therefore we examined the effect of autonomic blockade on blood pressure and how this relates to baseline muscle sympathetic nerve activity (MSNA) in women. Five young (23±4 yr) and 6 older (57±3 yr) women were examined before and during autonomic blockade using trimethaphan camsylate (TM). MSNA burst frequency and burst incidence were higher in older women (24±2 vs. 14±3 bursts/min; 41±3 vs. 23±5 bursts/100hb, respectively; p<0.05). Older women had a greater drop in mean arterial pressure (MAP; −25±2 vs. −8±3 mmHg; p<0.01) and total peripheral resistance (−0.7±0.1 vs. −0.2±0.1 AU; p<0.01) during autonomic blockade. MSNA bursts were abolished by TM within minutes. Baseline burst frequency and burst incidence were associated with the decrease in MAP during autonomic blockade (r=−0.64, r=−0.63; respectively; p<0.05). In conclusion, autonomic blockade reduces MAP to a greater extent in older women, and this decrease in blood pressure is associated with resting levels of MSNA. Our results suggest that autonomic support of blood pressure is greater in older women compared to young women. Elevated sympathetic nerve activity may explain the increased incidence of hypertension after menopause.