Hart, Emma C.

Key points We have developed a simple analytical method for quantifying the transduction of sympathetic activity into vascular tone. This method demonstrates that as women age, the transfer of sympathetic nerve activity into vascular tone is increased, so that for a given level of sympathetic activity there is more vasoconstriction. In men, this measure decreases with age. Test–re‐test analysis demonstrated that the new method is a reliable estimate of sympathetic transduction. We conclude that increased sympathetic vascular coupling contributes to the age‐related increase in blood pressure that occurs in women only. This measure is a reliable estimate of sympathetic transduction in populations with high sympathetic nerve activity. Thus, it will provide information regarding whether treatment targeting the sympathetic nervous system, which interrupts the transfer of sympathetic nerve activity into vascular tone, will be effective in reducing blood pressure in hypertensive patients. This may provide insight into which populations will respond to certain types of anti‐hypertensive medication. Abstract Sex and age differences in the sympathetic control of resting blood pressure (BP) may be due to differences in the transduction of sympathetic nerve activity (SNA) into vascular tone. Current methods for dynamically quantifying transduction focus on the relationship between SNA and vasoconstriction during a pressor stimulus, which increases BP and may be contra‐indicated in patients. We describe a simple analytical method for quantifying transduction under resting conditions. We performed linear regression analysis of binned muscle SNA burst areas against diastolic BP (DBP). We assessed whether the slope of this relationship reflects the transduction of SNA into DBP. To evaluate this, we investigated whether this measure captures differences in transduction in different populations. Specifically, we (1) quantified transduction in young men (YM), young women (YW), older men (OM) and postmenopausal women (PMW); and (2) measured changes in transduction during β‐blockade using propranolol in YW, YM and PMW. YM had a greater transduction vs . OM (0.10 ± 0.01 mmHg (% s) −1 , n = 23 vs . 0.06 ± 0.01 mmHg (% s) −1 , n = 18; P = 0.003). Transduction was lowest in YW (0.02 ± 0.01 mmHg (% s) −1 , n = 23) and increased during β‐blockade (0.11 ± 0.01 mmHg (% s) −1 ; P < 0.001). Transduction in PMW (0.07 ± 0.01 mmHg (% s) −1 , n = 23) was greater compared to YW ( P = 0.001), and was not altered during β‐blockade (0.06 ± 0.01 mmHg (% s) −1 ; P = 0.98). Importantly, transduction increased in women with age, but decreased in men. Transduction in women intersected that in men at 55 ± 1.5 years. This measure of transduction captures age‐ and sex‐differences in the sympathetic regulation of DBP and may be valuable in quantifying transduction in disease. In particular, this measure may help target treatment strategies in specific hypertensive subpopulations.

Endogenous female sex hormones influence muscle sympathetic nerve activity (MSNA), a regulator of arterial blood pressure and important factor in hypertension development. Although ≈80% of American women report using hormonal contraceptives sometime during their life, the influence of combined oral contraceptives (OCs) on MSNA and systemic hemodynamics remains equivocal. The goal of this study was to determine whether women taking OCs have altered MSNA and hemodynamics (cardiac output and total peripheral resistance) at rest during the placebo phase of OC use compared with women with natural menstrual cycles during the early follicular phase. We retrospectively analyzed data from studies in which healthy, premenopausal women (aged 18–35 years) participated. We collected MSNA values at rest and hemodynamic measurements in women taking OCs (n=53; 25±4 years) and women with natural menstrual cycles (n=74; 25±4 years). Blood pressure was higher in women taking OCs versus those with natural menstrual cycles (mean arterial pressure, 89±1 versus 85±1 mm Hg, respectively; P =0.01), although MSNA was similar in both groups (MSNA burst incidence, 16±1 versus 18±1 bursts/100 heartbeats, respectively; P =0.19). In a subset of women in which detailed hemodynamic data were available, those taking OCs (n=33) had similar cardiac output (4.9±0.2 versus 4.7±0.2 L/min, respectively; P =0.47) and total peripheral resistance (19.2±0.8 versus 20.0±0.9 U, respectively; P =0.51) as women with natural menstrual cycles (n=22). In conclusion, women taking OCs have higher resting blood pressure and similar MSNA and hemodynamics during the placebo phase of OC use when compared with naturally menstruating women in the early follicular phase.

Interindividual variability in sympathetic nerve activity (SNA) has provided insight into integrative mechanisms contributing to blood pressure (BP) regulation in humans. In young people, the influence of high SNA on BP is balanced by lower cardiac output and less adrenergic vasoconstrictor responsiveness. Older people have higher SNA and higher BP. We hypothesized that SNA has a restraining effect on peripheral vasodilator responsiveness in young and older men, such that individuals with higher tonic SNA would show less forearm vasodilatation to exogenous vasodilators. We measured muscle SNA (MSNA; microneurography) and forearm vasodilator responses to intra-arterial infusions of acetylcholine (ACh; endothelium dependent) and sodium nitroprusside (SNP; endothelium independent) in 13 young (age; 27 ± 1 yr) and 16 older (61 ± 2 yr) men. Forearm vascular conductance (FVC) responses to ACh were lower in the older men at the two highest doses (2 and 4 μg·100 ml−1·min−1; Δ395 ± 81 vs. 592 ± 87% and 412 ± 87 vs. 616 ± 132%, P < 0.05), and MSNA was higher (64 ± 4 vs. 41 ± 2 bursts/100 hb; P < 0.05). There was no difference in the FVC response to SNP between young and older men ( P > 0.05). In young men, there was an inverse relationship between resting MSNA and FVC responses (%change) to both ACh and SNP ( r = −0.83 and r = −0.83, respectively; P < 0.05). In older men, however, this relationship was not observed. Tonic SNA may act to restrain vasodilator responses in young men, whereas in older men a lack of such restraint may be protective against the pressor effects of higher SNA.

The autonomic nervous system plays a central role in both acute and chronic blood pressure regulation in humans. The activity of the sympathetic branch of the autonomic nervous system is positively associated with peripheral resistance, an important determinant of mean arterial pressure in men. In contrast, there is no association between sympathetic nerve activity and peripheral resistance in women before menopause, yet a positive association after menopause. We hypothesized that autonomic support of blood pressure is higher after menopause in women. We examined the effect of ganglionic blockade on arterial blood pressure and how this relates to baseline muscle sympathetic nerve activity in 12 young (25±1 years) and 12 older postmenopausal (61±2 years) women. The women were studied before and during autonomic blockade using trimethaphan camsylate. At baseline, muscle sympathetic nerve activity burst frequency and burst incidence were higher in the older women (33±3 versus 15±1 bursts/min; 57±5 versus 25±2 bursts/100 heartbeats, respectively; P <0.05). Muscle sympathetic nerve activity bursts were abolished by trimethaphan within minutes. Older women had a greater decrease in mean arterial pressure (−29±2 versus −9±2 mm Hg; P <0.01) and total peripheral resistance (−10±1 versus −5±1 mm Hg/L per minute; P <0.01) during trimethaphan. Baseline muscle sympathetic nerve activity was associated with the decrease in mean arterial pressure during trimethaphan ( r =−0.74; P <0.05). In summary, our results suggest that autonomic support of blood pressure is greater in older women compared with young women and that elevated sympathetic nerve activity in older women contributes importantly to the increased incidence of hypertension after menopause.

The sympathetic nervous system is critical for the beat-to-beat regulation of arterial blood pressure (BP). Although studies have examined age- and sex-related effects on BP control, findings are inconsistent and limited data are available in postmenopausal women. In addition, the majority of studies have focused on time-averaged responses without consideration for potential beat-to-beat alterations. Thus we examined whether the ability of muscle sympathetic nerve activity (MSNA) to modulate BP on a beat-to-beat basis is affected by age or sex. BP and MSNA were measured during supine rest in 40 young (20 men) and 40 older (20 men) healthy subjects. Beat-to-beat fluctuations in mean arterial pressure (MAP) were characterized for 15 cardiac cycles after each MSNA burst using signal averaging. The rise in MAP following an MSNA burst was similar between young men and women (+2.64 ± 0.3 vs. +2.57 ± 0.3 mmHg, respectively). However, the magnitude of the increase in MAP after an MSNA burst was reduced in older compared with young subjects ( P < 0.05). Moreover, the attenuation of the pressor response was greater in older women (+1.20 ± 0.1 mmHg) compared with older men (+1.72 ± 0.2 mmHg; P < 0.05). Interestingly, in all groups, MAP consistently decreased after cardiac cycles without MSNA bursts (nonbursts) with the magnitude of fall greatest in older men. In summary, healthy aging is associated with an attenuated beat-to-beat increase in BP after a spontaneous MSNA burst, and this attenuation is more pronounced in postmenopausal women. Furthermore, our nonburst findings highlight the importance of sympathetic vasoconstrictor activity to maintain beat-to-beat BP, particularly in older men.

Acute β-adrenergic blockade increases aortic wave reflection; however, the mechanisms remain unclear. Evidence suggests that β-adrenergic receptor sensitivity in the peripheral vasculature differs between sexes. Therefore, the goal of this study was to examine whether β-adrenergic blockade alters aortic wave reflection to a similar extent in young men and women. In 31 subjects (16 men and 15 women; 26±1 years) noninvasive aortic pressure waveforms were synthesized from high-fidelity radial pressure waveforms via applanation tonometry before and during systemic β-blockade (0.25 mg/kg bolus, followed by 0.004 mg/kg per minute of continuous infusion of propranolol). β-Blockade increased aortic augmentation index and wave reflection amplitude (aortic augmented pressure) in both sexes ( P <0.01). Although the increase in augmentation index was not significantly different between sexes (7.5±1.1% versus 4.6±1.5%; P =0.07), the increase in aortic augmented pressure was greater in women compared with men (2.8±0.5 versus 1.4±0.5 mm Hg; P <0.05). Aortic augmentation index adjusted for a heart rate of 75 bp increased in women (4.1±1.1%; P <0.05) after β-blockade, whereas it was unchanged in men (0.6±1.3%; P =0.33). Moreover, the change in aortic augmentation index was inversely associated with the change in heart rate only in men ( r =−0.54; P <0.05). Our data suggest that aortic wave reflection is increased to a greater extent in women after systemic β-blockade, and enhanced aortic wave reflection appears to be mediated by a reduced heart rate in men, whereas the mechanism is unclear in women.

This study tested the hypothesis that acute isocapnic hypoxia results in persistent resetting of the baroreflex to higher levels of muscle sympathetic nerve activity (MSNA), which outlasts the hypoxic stimulus. Cardiorespiratory measures were recorded in humans (26 ± 1 yr; n = 14; 3 women) during baseline, exposure to 20 min of isocapnic hypoxia, and for 5 min following termination of hypoxia. The spontaneous baroreflex threshold technique was used to determine the change in baroreflex function during and following 20 min of isocapnic hypoxia (oxyhemoglobin saturation = 80%). From the spontaneous baroreflex analysis, the linear regression between diastolic blood pressure (DBP) and sympathetic burst occurrence, the T50 (DBP with a 50% likelihood of a burst occurring), and DBP error signal (DBP minus the T50) provide indexes of baroreflex function. MSNA and DBP increased in hypoxia and remained elevated during posthypoxia relative to baseline ( P < 0.05). The DBP error signal became progressively less negative (i.e., smaller difference between DBP and T50) in the hypoxia and posthypoxia periods (baseline: −3.9 ± 0.8 mmHg; hypoxia: −1.4 ± 0.6 mmHg; posthypoxia: 0.2 ± 0.6 mmHg; P < 0.05). Hypoxia caused no change in the slope of the baroreflex stimulus-response curve; however, there was a shift toward higher pressures that favored elevations in MSNA, which persisted posthypoxia. Our results indicate that there is a resetting of the baroreflex in hypoxia that outlasts the stimulus and provide further explanation for the complex control of MSNA following acute hypoxia.

Increased arterial stiffness is associated with higher levels of aortic wave reflection and aortic blood pressure. Recent evidence suggests a link between muscle sympathetic nerve activity and indices of arterial stiffness. Therefore, the aims of this study were to examine the relationship between resting muscle sympathetic nerve activity and characteristics of aortic pressure wave reflection and the influence of sex on these relationships. In 44 subjects (23 females and 21 males; 25±1 years of age), we measured muscle sympathetic nerve activity via peroneal microneurography. In addition, noninvasive aortic pressure waveforms were synthesized from radial pressure waveforms obtained from applanation tonometry. Aortic blood pressure, augmentation index, wave reflection amplitude, and wasted left ventricular energy were calculated. Resting sympathetic activity (bursts/100 heart beats) was not associated with any of the aortic pressure wave reflection characteristics for all patients. However, there was a positive relationship between sympathetic activity and augmentation index ( r =0.46; P =0.05) in men. Further, sympathetic activity in men was related to wave reflection amplitude ( r =0.53; P <0.05) and wasted left ventricular energy ( r =0.57; P <0.01). In contrast to men, women demonstrated strong inverse relationships between sympathetic activity and augmentation index ( r =−0.63), wave reflection amplitude ( r =−0.59), and wasted left ventricular energy ( r =−0.58; P <0.01 for all). Our results suggest another possible mechanism by which young women are protected against the development of cardiovascular disease.

The purpose of this study was to evaluate the relationship between the cardiac and sympathetic baroreflex sensitivities within healthy, young humans. The sensitivities of the cardiac and sympathetic baroreflexes were compared in 53 normotensive individuals (28 men and 25 women; age: 24.0±0.9 years; body mass index: 24.0±0.3 cm/kg 2 , mean±SEM). Heart rate, arterial blood pressure, and peroneal muscle sympathetic nerve activity were recorded under resting conditions (heart rate: 58±1 bpm; systolic blood pressure: 126±2 mm Hg; diastolic blood pressure: 72±1 mm Hg; mean arterial blood pressure: 89±1 mm Hg; muscle sympathetic nerve activity: 18±1 bursts per min) and during rapid changes in blood pressure induced by sequential boluses of nitroprusside and phenylephrine. Cardiac and sympathetic baroreflex sensitivities were analyzed using the slopes of the linear portions of the muscle sympathetic nerve activity-diastolic blood pressure and R-R interval-systolic blood pressure relationships, respectively. When individual cardiac baroreflex sensitivity was compared with sympathetic baroreflex sensitivity, no correlation (R-R interval: r =−0.13; heart rate: r =0.21) was observed when studied as a group. Analysis by sex unveiled a correlation in women between the cardiac and sympathetic baroreflex sensitivities (R-R interval: r =−0.54; P =0.01; no correlation with hazard ratio: r =0.29). No relationship was found in men (R-R interval: r =0.17; heart rate: r =0.12). These results indicate that, although both cardiac and sympathetic efferents function in baroreflex control of arterial pressure, there is no correlation in their sensitivities within healthy normotensive humans. However, sex-stratified data indicate that sex-based differential correlations might exist.