Citations

Sympathetic neural control has a central role in the regulation of blood pressure. In humans, muscle sympathetic nerve activity (MSNA) is strongly controlled by the arterial baroreflex. Our goal was to evaluate a calculation of blood pressure "error signal" for MSNA burst occurrence and test if there was a gender difference in the relationship between this signal and resting blood pressure. Baseline MSNA was measured in healthy young men (n=49) and women (n=23). T50 (the DBP at which there is a 50% likelihood of an MSNA burst) was calculated. Mean DBP was subtracted from the T50 as an approximate "error signal" for burst activation. We found a positive relationship between this "error signal" and MSNA (bursts/100 heartbeats; BI) in both young men (slope=0.19, r 2 =0.67, p<0.001) and women (slope=0.32, r 2 =0.78, p<0.001). Thus, if DBP was lower than T50, there was an increased likelihood of MSNA bursts and vice versa. Women had a greater average "error signal" (i.e., mean T50 ‐ DBP = ‐5 ± 1 in women and ‐2 ± 0.4 in men), a 59 % steeper slope of the error signal:MSNA relationship, and lower mean BI (31 ± 2 vs 42 ± 4, p<0.05), suggesting that mechanisms exist in women to counteract the larger "driving force" for generation of a MSNA burst. These apparent gender differences in control of MSNA may contribute to differences in prevalence of cardiovascular diseases such as hypertension. NIH HL83947, UL1‐RR24150, Swedish Research Council 12170.

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.

Aging is associated with altered mitochondrial physiology and exercise responsiveness in skeletal muscle. Activation of the unfolded protein response in the endoplasmic reticulum (UPR ER ) and mitochondria (UPR MT ) is linked with exercise‐induced adaptations in skeletal muscle, but the possibility that these processes impact exercise responsiveness and mitochondrial function in older humans has not been fully elucidated. The purpose of this study was to evaluate age‐related changes in UPR ER and UPR MT gene transcripts and protein abundance in response to a single bout of exercise. Muscle biopsies were obtained from 12 young (27±5 yr) and 12 older (75±5 yr) well‐matched, healthy men and women before exercise and 18h following a single bout of unilateral leg extension. Before exercise, a gene set enrichment analysis (GSEA) revealed that 27 genes associated with the UPR ER were upregulated in the older subjects compared to the young (enrichment false discovery rate [FDR] = 0.0842). After exercise, GSEA indicated upregulated UPR ER genes in both the young (FDR = 0.0405) and older subjects (FDR = 0.0619), however, pathway activation analysis revealed significantly greater activation of UPR ER and UPR MT gene transcripts post‐exercise in the younger subjects ( P < 0.05). In contrast, age did not affect key UPR‐regulatory protein abundance 18h post‐exercise. Interestingly, statistically significant correlations were observed in the young subjects between the mitochondrial transcriptional coactivator, peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α) and key regulatory genes associated with the UPR ER (GRP78, R = 0.67; ATF6, R = 0.70) and the UPR MT (HSPE1, R = 0.61; HSPD1, R = 0.55; and HSPA9, R = 0.79), which were not evident in the older subjects. In conclusion, transcriptomic analysis revealed an age‐related decline in the adaptive UPR ER and UPR MT transcriptional response following a single bout of exercise that could potentially explain, in part, impaired exercise responsiveness and mitochondrial dysfunction with age. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

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.