Sympathetic Transduction Research Articles

Sympathetic-transduction in untreated hypertension

Transduction of muscle sympathetic nerve activity (MSNA) into vascular tone varies with age and sex. Older normotensive men have reduced sympathetic transduction so that a given level of MSNA causes less arteriole vasoconstriction. Whether sympathetic transduction is altered in hypertension (HTN) is not known. We investigated whether sympathetic transduction is impaired in untreated hypertensive men compared to normotensive controls. Eight untreated hypertensive men and 10 normotensive men (age 50 ± 15 years vs. 45 ± 12 years (mean ± SD); p = 0.19, body mass index (BMI) 24.7 ± 2.7 kg/m2 vs. 26.0 ± 4.2 kg/m2; p = 0.21) were recruited. MSNA was recorded from the peroneal nerve using microneurography; beat-to-beat blood pressure (BP; Finapres) and heart rate (ECG) were recorded simultaneously at rest for 10 min. Sympathetic-transduction was quantified using a previously described method. The relationship between MSNA burst area and subsequent diastolic BP was measured for each participant with the slope of the regression indicating sympathetic transduction. MSNA was higher in the hypertensive group compared to normotensives (73 ± 17 bursts/100 heartbeats vs. 49 ± 19 bursts/100 heart bursts; p = 0.007). Sympathetic-transduction was lower in the hypertensive versus normotensive group (0.04%/mmHg/s vs. 0.11%/mmHg/s, respectively; R = 0.622; p = 0.006). In summary, hypertensive men had lower sympathetic transduction compared to normotensive individuals suggesting that higher levels of MSNA are needed to cause the same level of vasoconstrictor tone.

Sex Differences in Muscle Metaboreflex Activation after Static Handgrip Exercise.

Larger blood pressure (BP) responses to relative-intensity static exercise in men versus women are thought to involve altered muscle metaboreflex activation, but whether this is because of an intrinsic sex difference in metabolite production or differences in muscle strength and absolute load is unknown. Continuous BP and heart rate were recorded in 200 healthy young men and women (women: n = 109) during 2 min of static handgrip exercise at 30% of maximal voluntary contraction (MVC), followed by 2 min of postexercise circulatory occlusion (PECO). Muscle sympathetic nerve activity (MSNA) was recorded in a subset of participants (n = 39; women, n = 21), permitting calculation of signal-averaged resting sympathetic transduction (MSNA-diastolic BP). Sex differences were examined with and without statistical adjustment for MVC. Multivariate regression analyses were performed to identify predictors of BP responses. Men had larger systolic BP responses (interactions, P < 0.0001) to static handgrip exercise (24 ± 10 vs 17 ± 9 mm Hg [mean ± SD], P < 0.0001) and PECO (20 ± 11 vs 16 ± 9 mm Hg, P < 0.0001). Adjustment for MVC abolished these sex differences in BP (interactions, P > 0.7). In the subset with MSNA, neither burst frequency or incidence responses to static handgrip exercise or PECO differed between men and women (interactions, P > 0.2). Resting sympathetic transduction was also similar (P = 0.8). Multiple linear regression analysis showed that MVC or the change in MSNA, were predictors of BP responses to static handgrip, but only MVC was associated with BP responses during PECO. Sex differences in absolute contraction load contribute to differences in BP responses during muscle metaboreflex isolation using PECO. These data do not support an intrinsic effect of sex as being responsible for exercise BP differences between men and women.

Signal-averaged resting sympathetic transduction of blood pressure: is it time to account for prevailing muscle sympathetic burst frequency?

Calculating the blood pressure (BP) response to a burst of muscle sympathetic nerve activity (MSNA), termed sympathetic transduction, may be influenced by an individual's resting burst frequency. We examined the relationships between sympathetic transduction and MSNA in 107 healthy males and females and developed a normalized sympathetic transduction metric to incorporate resting MSNA. Burst-triggered signal averaging was used to calculate the peak diastolic BP response following each MSNA burst (sympathetic transduction of BP) and following incorporation of MSNA burst cluster patterns and amplitudes (sympathetic transduction slope). MSNA burst frequency was negatively correlated with sympathetic transduction of BP (r = -0.42; P < 0.01) and the sympathetic transduction slope (r = -0.66; P < 0.01), independent of sex. MSNA burst amplitude was unrelated to sympathetic transduction of BP in males (r = 0.04; P = 0.78), but positively correlated in females (r = 0.44; P < 0.01) and with the sympathetic transduction slope in all participants (r = 0.42; P < 0.01). To control for MSNA, the linear regression slope of the log-log relationship between sympathetic transduction and MSNA burst frequency was used as a correction exponent. In subanalysis of males (38 ± 10 vs. 14 ± 4 bursts/min) and females (28 ± 5 vs. 12 ± 4 bursts/min) with high versus low MSNA, sympathetic transduction of BP and sympathetic transduction slope were lower in participants with high MSNA (all P < 0.05). In contrast, normalized sympathetic transduction of BP and normalized sympathetic transduction slope were similar in males and females with high versus low MSNA (all P > 0.22). We propose that incorporating MSNA burst frequency into the calculation of sympathetic transduction will allow comparisons between participants with varying levels of resting MSNA.

Sympathetic Transduction During Euglycemic‐Hyperinsulinemia in Humans

Insulin plays an important role in post-prandial blood pressure (BP) regulation. Within the central nervous system insulin acts to stimulate sympathetic outflow to skeletal muscle. Concurrently, insulin acts locally in the periphery to promote vasodilation and is suggested to also attenuate sympathetically-mediated vasoconstriction. Given these divergent actions, the ‘net effect’ of insulin on the sympathetic control of BP remains incompletely understood. Therefore, the purpose of this study was to examine the effect of hyperinsulinemia on sympathetic transduction to BP. To accomplish this, in 10 young healthy men, heart rate (ECG), BP (finometer or brachial arterial line) and muscle sympathetic nerve activity (MSNA) were measured at rest and during euglycemic-hyperinsulinemia. Signal-averaging was used to characterize the changes in mean arterial pressure (MAP) and total vascular conductance (TVC; derived from ModelFlow) over 10 cardiac cycles following spontaneous bursts of MSNA at rest and during hyperinsulinemia. No significant differences were found in the peak MAP (Rest: ∆2.8 ± 0.3; Insulin: ∆2.4 ± 0.2 mmHg, P=0.15) or TVC (Rest: ∆-3.0 ± 0.4; Insulin: ∆-2.7 ± 0.5 mL/min/mmHg, P=0.38) responses following bursts of MSNA between rest and hyperinsulinemia (i.e., ‘net’ sympathetic transduction was unchanged). Notably, the average size of normalized MSNA bursts was increased during hyperinsulinemia (Rest: 45.6 ± 1.8; Insulin 65.3 ± 5.0 Au, P<0.01). To take into account changes in burst height, MSNA bursts were divided into amplitude-matched bins. When MSNA burst amplitude bins were matched between rest and hyperinsulinemia, sympathetic transduction for a given burst amplitude was blunted during insulin infusion (e.g., largest resting bursts: MAP, Rest: ∆4.4 ± 0.5; Insulin: ∆3.0 ± 0.3 mmHg, P=0.02; TVC, Rest: ∆-5.2 ± 0.8; Insulin: ∆-3.1 ± 0.7 mL/min/mmHg, P=0.05). However, it is important to note that 15 ± 5% of MSNA bursts exhibited amplitudes greater than that which existed at rest and overall during hyperinsulinemia ~50% of all MSNA bursts were comparable or greater in amplitude to the largest bursts present at rest. Collectively, these preliminary findings suggest that during hyperinsulinemia, sympathetic transduction for a given burst amplitude is attenuated while ‘net’ sympathetic transduction remains unchanged due to the generation of larger MSNA bursts.

Augmented pressor responses to individual bursts of muscle sympathetic nerve activity in human obesity

Obesity is associated with increased sympathetic outflow and hypertension. However, it remains unclear whether the systemic pressor response to spontaneous bursts of sympathetic nerve activity (i.e., sympathetic transduction) is augmented in obesity. Therefore, we tested the hypothesis that transduction of muscle sympathetic nerve activity (MSNA) to arterial blood pressure (BP) is significantly higher in obese vs. lean adults. Also, because obesity alters regulation of BP over the 24-hour period, we further examined the extent to which sympathetic transduction is associated with ambulatory 24-hour BP variability (standard deviation). MSNA (microneurography) and arterial BP (finger cuff) were measured continuously for 10 min under resting conditions in 20 young/middle-age obese participants and 20 age- and sex-matched lean controls. Signal averaging was used to characterize beat-by-beat changes in mean arterial pressure (MAP) for 15 cardiac cycles following each MSNA burst. MSNA was not significantly elevated in obese vs. lean participants (25±11 vs. 21±10 bursts/min, P=0.27). However, transduction of MSNA to BP was significantly elevated in obese vs. lean participants when considering multiple successive bursts (P<0.01) and all bursts (P<0.01). Similarly, increases in burst amplitude evoked greater MAP responses with obese having the largest peak increases (3.8±1.7 vs. 2.7±1.6 mmHg, P=0.03). Multiple regression indicated that sympathetic transduction was a significant determinant of 24-hour MAP variability (β=0.47, P<0.01), independent of age, BMI, MSNA, and 24-hour MAP (all P>0.05). These findings demonstrate that transduction of MSNA to BP is augmented in human obesity. Sympathetic transduction also appears to contribute to higher BP variability independent of obesity.

Assessing static and dynamic sympathetic transduction using microneurography.

The relationship between sympathetic nerve activity and the vasculature has been of great interest due to its potential role in various cardiovascular-related diseases. This relationship, termed "sympathetic transduction," has been quantified using several different laboratory and analytical techniques. The most common method is to assess the association between relative changes in muscle sympathetic nerve activity, measured via microneurography, and physiological outcomes (e.g., blood pressure, total peripheral resistance, blood flow, etc.) in response to a sympathetic stressor (e.g., exercise, cold stress, orthostatic stress). This approach, however, comes with its own caveats. For instance, elevations in blood pressure and heart rate during a sympathetic stressor can have an independent impact on muscle sympathetic nerve activity. Another assessment of sympathetic transduction was developed by Wallin and Nerhed in 1982, where alterations in blood pressure and heart rate were assessed immediately following bursts of muscle sympathetic nerve activity at rest. This approach has since been characterized and further innovated by others, including the breakdown of consecutive burst sequences (e.g., singlet, doublet, triplet, and quadruplet), and burst height (quartile analysis) on specific vascular outcomes (e.g., blood pressure, blood flow, vascular resistance). The purpose of this review is to provide an overview of the literature that has assessed sympathetic transduction using microneurography and various sympathetic stressors (static sympathetic transduction) and using the same or similar approach established by Wallin and Nerhed at rest (dynamic neurovascular transduction). Herein, we discuss the overlapping literature between these two methodologies and highlight the key physiological questions that remain.

An open-source program to analyze spontaneous sympathetic neurohemodynamic transduction.

The sympathetic nervous system is important for the beat-by-beat regulation of arterial blood pressure and the control of blood flow to various organs. Microneurographic recordings of pulse-synchronous muscle sympathetic nerve activity (MSNA) are used by numerous laboratories worldwide. The transduction of hemodynamic and vascular responses elicited by spontaneous bursts of MSNA provides novel, mechanistic insight into sympathetic neural control of the circulation. Although some of these laboratories have developed in-house software programs to analyze these sympathetic transduction responses, they are not openly available and most require higher level programming skills and/or costly platforms. In the present paper, we present an open-source, Microsoft Excel-based analysis program designed to examine the pressor and/or vascular responses to spontaneous resting bursts of MSNA, including across longer, continuous MSNA burst sequences, as well as following heartbeats not associated with MSNA bursts. An Excel template with embedded formulas is provided. Detailed written and video-recorded instructions are provided to help facilitate the user and promote its implementation among the research community. Open science activities such as the dissemination of analytical programs and instructions may assist other laboratories in their pursuit to answer novel and impactful research questions regarding sympathetic neural control strategies in human health and disease.NEW & NOTEWORTHY The pressor responses to spontaneous bursts of muscle sympathetic nerve activity provide important information regarding sympathetic regulation of the circulation. Many laboratories worldwide quantify sympathetic neurohemodynamic transduction using in-house, customized software requiring high-level programming skills and/or costly computer programs. To overcome these barriers, this study presents a simple, open-source, Microsoft Excel-based analysis program along with video instructions to assist researchers without the necessary resources to quantify sympathetic neurohemodynamic transduction.

Effects of muscle sympathetic burst size and burst pattern on time-to-peak sympathetic transduction.

The current study evaluated the influence of resting muscle sympathetic nerve activity (MSNA) burst size and firing pattern on time-to-peak sympathetic transduction in 36 young healthy men and women. Participants underwent a 5-10 min resting baseline with beat-to-beat measures of heart rate, mean arterial pressure (MAP), and MSNA (microneurography). Cardiac output and total vascular conductance were calculated using the Modelflow algorithm. Sympathetic transduction was quantified using the burst-triggered signal averaging technique to examine the changes in MAP, cardiac output, and total vascular conductance for 15 cardiac cycles after each MSNA burst or non-burst. A stepwise increase in the peak MAP (i.e., sympathetic transduction) was observed throughout all quartiles of normalized MSNA burst area (quartile 1 (Q1): 1.7 ± 1.3 mm Hg; Q2: 2.1 ± 1.3 mm Hg; Q3: 2.6 ± 1.4 mm Hg; Q4: 3.5 ± 1.4 mm Hg; P < 0.01). The largest quartile of normalized MSNA burst area demonstrated faster time-to-peak MAP responses (5.7 ± 2.5 s) than both Q1 (10.1 ± 3.9 s, P < 0.01) and Q2 (9.3 ± 4.1 s, P < 0.01), as well as, faster time-to-peak cardiac output and time-to-nadir total vascular conductance compared with Q1 and Q2 (All P < 0.05). Larger clusters of sympathetic bursts (i.e., triplets and ≥ quadruplets) did not have increased time-to-peak transduction compared with singlets and doublet bursts across all MSNA quartiles. These results highlight intraindividual variability in the time-course of sympathetic transduction and reveal an intrinsic property of larger sympathetic bursts to increase time-to-peak sympathetic transduction in humans. Novelty: Muscle sympathetic burst size can modulate time-to-peak sympathetic transduction in young healthy men and women. These observations appear independent of the pattern of sympathetic firing.

Sympathetic transduction in humans: recent advances and methodological considerations.

Ever since their origin more than one half-century ago, microneurographic recordings of sympathetic nerve activity have significantly advanced our understanding of the generation and regulation of central sympathetic outflow in human health and disease. For example, it is now appreciated that a myriad of disease states exhibit chronic sympathetic overactivity, a significant predictor of cardiovascular morbidity and mortality. Although microneurographic recordings allow for the direct quantification of sympathetic outflow, they alone do not provide information with respect to the ensuing sympathetically mediated vasoconstriction and blood pressure (BP) response. Therefore, the study of vascular and/or BP responses to sympathetic outflow (i.e., sympathetic transduction) has now emerged as an area of growing interest within the field of neural cardiovascular control in human health and disease. To date, studies have primarily examined sympathetic transduction under two distinct paradigms: when reflexively evoking sympatho-excitation through the induction of a laboratory stressor (i.e., sympathetic transduction during stress) and/or following spontaneous bursts of sympathetic outflow occurring under resting conditions (i.e., sympathetic transduction at rest). The purpose of this brief review is to highlight how our physiological understanding of sympathetic transduction has been advanced by these studies and to evaluate the primary analytical techniques developed to study sympathetic transduction in humans. We also discuss the framework by which the assessment of sympathetic transduction during stress reflects a fundamentally different process relative to sympathetic transduction at rest and why findings from investigations using these different techniques should be interpreted as such and not necessarily be considered one and the same.

Abstract P101: Sympathetic Transduction In Young Adults With A Family History Of Hypertension

Exaggerated sympathetic transduction (i.e., the vascular response to a burst of muscle sympathetic nerve activity; MSNA) has recently been demonstrated in certain populations of young adults at risk for future hypertension. However, it remains unknown the degree to which a family history of hypertension (FH), a risk factor for future hypertension, may influence sympathetic transduction. Purpose: The purpose of this study was to test the hypothesis that a +FH augments the pressor response following spontaneous bursts of MSNA at rest in young adults. A secondary purpose was to compare the influence of a +FH on sympathetic transduction between young men and women. Methods: We retrospectively examined beat-by-beat blood pressure (finger photoplethysmography) and MSNA (peroneal microneurography) in 21 +FH young adults (9 +FH men: 26 ± 2 yr, 25 ± 4 kg/m 2 , 12 +FH women: 22 ± 2 yr, 22 ± 3 kg/m 2 ) and 15 -FH young adults (8 -FH men: 24 ± 5 yr, 25 ± 2 kg/m 2 , 7 -FH women: 22 ± 3 yr, 23 ± 3 kg/m 2 ) during 10 minutes of supine rest. Signal averaging was used to characterize changes in BP for the 10 cardiac cycles following a spontaneous MSNA burst. Resting baseline variables were compared using 2-way ANOVAs. Mean arterial pressure (MAP) changes over 10 cardiac cycles following a burst of MSNA were compared using a 2-way repeated measures ANOVA (Time, FH status) and a 3-way repeated measures ANOVA (Time, FH status, Sex). Data are presented as mean ± SD. Results: Resting MAP (+FH: 86 ± 9 vs. -FH: 82 ± 7 mmHg; P = 0.14) and resting MSNA (+FH: 10 ± 6 vs. -FH: 9 ± 6 mmHg; P = 0.65) did not differ by FH status. The increase in MAP over the 10 cardiac cycles following a spontaneous burst of MSNA did not differ by FH status (Time, P &lt; 0.0001; FH status, P = 0.17; Time * FH status, P = 0.70) and this influence did not differ between the sexes (Time * FH status, P = 0.58; Time * Sex, P = 0.06; Time * FH status * Sex, P = 0.99). Conclusions: These preliminary data suggest that spontaneous MSNA bursts do not elicit greater increases in MAP in +FH young adults, regardless of sex. Additional data are needed to determine the interactions between FH status, sex, and sympathetic transduction. Supported by NIH Grant P20 GM 113125, P20 GM 103446, U54 GM 104941, K99/R00 HL133414, and The University of Delaware Research Foundation.

Sympathetic Vascular Transduction is Elevated in Hypertensive Premenopausal and Postmenopausal Women

The transduction of muscle sympathetic nerve activity (MSNA) to vasoconstrictor tone is lower in healthy young women versus both healthy young men and healthy postmenopausal women, and may account for the lower risk of hypertension in young women. However, hypertension can occur before menopause in some women but whether sympathetic transduction is increased in this group is unknown. We aimed to determine whether sympathetic transduction is different in hypertensive (HTN) pre‐ and post‐menopausal women relative to normotensive (NTN) controls. MSNA (peroneal microneurography) and continuous blood pressure (Finometer Pro) were measured in HTN (n=5) and NTN (n=5) premenopausal and HTN (n=4) and NTN (n=6) postmenopausal women. HTN and NTN groups were matched for age (premenopausal; 46±2 vs. 46±5 years, p=0.97, postmenopausal; 59±4 vs. 62 ±2 years; p=0.17). Sympathetic transduction was measured by associating beat‐to‐beat diastolic blood pressure (DBP) with MSNA burst area between the 6th and 8th previous cardiac cycles to account for transduction delay. Transduction was expressed as the slope of the linear regression between burst area and mean DBP, plotted as 1 %.s bins. HTN and NTN were compared within pre‐ or postmenopausal groups by unpaired Student’s T‐test or Mann‐Whitney test, where data were not normally distributed. Data are presented as mean ± SD. Both sympathetic transduction and MSNA were greater in HTN versus NTN premenopausal women (0.16±0.11 vs. 0.03±0.02 mmHg/%.s, p=0.03; 57±17 vs. 32±7 bursts/100 heartbeats, p=0.0185). Sympathetic transduction was also greater in HTN vs. NTN postmenopausal women (0.19±0.08 vs. 0.07±0.02 mmHg/%.s, p=0.02), although MSNA was similar (53±8 vs. 60±15 bursts/100 heartbeats, p=0.4255). Both HTN groups had increased clinic systolic BP and DBP versus the respective NTN group (premenopausal women 153±11/97±6 vs. 119±9/73±8 mmHg, p=0.0007 and p=0.0079; postmenopausal women 155±8/92±15 vs. 123±8/70±7 mmHg, p=0.0095 and p=0.0132 respectively). These results indicate that sympathetic transduction is elevated in both premenopausal and postmenopausal women with HTN vs. NTN controls. As such, increased sympathetic transduction may help to explain the development of hypertension in premenopausal women. These data will assist with more precise management of hypertension in pre‐ and postmenopausal women.Support or Funding InformationZoe Adams is funded by a British Heart Foundation Non‐Clinical PhD Studentship (FS/17/38/32935).

Sympathetic Transduction in Type 2 Diabetes Mellitus.

Approximately 60% of patients with type 2 diabetes mellitus (T2D) develop hypertension. Recent work also indicates greater blood pressure (BP) excursions throughout the day in T2D. Collectively, these findings suggest altered BP control in T2D. Although muscle sympathetic nerve activity (MSNA) recordings in T2D have provided equivocal results, quantification of MSNA alone does not account for ensuing vasoconstriction and BP responses elicited by MSNA. Thus, we tested the hypothesis that patients with T2D exhibit enhanced sympathetic transduction to BP. MSNA (microneurography) and beat-to-beat BP (Finometer) were measured at rest in 21 T2D and 13 age-matched and body mass index-matched control subjects and, signal-averaging was performed to quantify the mean arterial pressure and total vascular conductance responses to spontaneous bursts of MSNA. The peak mean arterial pressure and total vascular conductance responses to spontaneous MSNA were similar between T2D and control (both P>0.05). However, further analysis, separating T2D into those taking statins (n=13, T2D +statin) and not taking statins (n=8, T2D -statin), indicated that T2D -statin patients (4.2±0.6 mm Hg) exhibited greater peak mean arterial pressure responses compared with both T2D +statin patients (2.5±0.3 mm Hg, P=0.01) and control (control: 2.8±0.3 mm Hg, P=0.02). Likewise, nadir total vascular conductance responses to spontaneous MSNA bursts were greater in T2D -statin patients (T2D -statin: -3.3±0.6 mL/(min·mm Hg), T2D +statin: -1.6±0.3 mL/(min·mm Hg), P=0.03; control -2.2±0.3 mL/(min·mm Hg), P=0.08). Notably, T2D +statin patients exhibited similar peak mean arterial pressure and total vascular conductance responses to MSNA compared with control. Collectively, these findings demonstrate, for the first time, that patients with T2D exhibit augmented sympathetic transduction and this effect seems to be offset by statin therapy.

Sympathetic Transduction in Young Women with a Family History of Hypertension

Exaggerated sympathetic transduction has recently been demonstrated in certain populations of young adults at risk for future hypertension. Our laboratory has previously reported that young women with a family history of hypertension (+FH), a population with a greater risk for future hypertension, have exaggerated sympathetic and blood pressure (BP) reactivity compared to women without a family history of hypertension (−FH). However, it is unclear whether resting sympathetic transduction may partially explain the exaggerated BP reactivity in +FH women.PURPOSETherefore, the purpose of this study was to test the hypothesis that +FH young women would display augmented pressor responses following spontaneous bursts of muscle sympathetic nerve activity (MSNA) at rest.METHODSWe retrospectively examined beat‐by‐beat BP (finger photoplethysmography) and MSNA (peroneal microneurography) in 5 +FH (22 ± 1 yr, 20 ± 2 kg/m2) and 7 −FH young women (24 ± 3 yr, 21 ± 1 kg/m2) during 10 minutes of supine rest. Signal averaging was used to characterize changes in BP for the 10 cardiac cycles following spontaneous MSNA bursts. Resting baseline variables were compared using unpaired t‐tests. A 2‐way repeated measures ANOVA was used to compared BP changes over 10 cardiac cycles following a burst of MSNA, and peak BP changes were compared using unpaired t‐tests. Data are presented as mean ± SD.RESULTSResting mean arterial pressure (MAP) (+FH: 76 ± 12 vs. −FH: 83 ± 19 mmHg, p=0.72), MSNA (+FH: 8 ± 2 vs. −FH: 8 ± 5 bursts/min, p=0.89), heart rate (+FH: 70 ± 13 vs. −FH: 61 ± 4 bpm, p=0.12), and total peripheral resistance (+FH: 1811 ± 683 vs. −FH: 1432 ± 293 mmHg·min/mL, p=0.77) were not different between groups. Following spontaneous bursts of MSNA, the increase in MAP over the subsequent 10 cardiac cycles was not different between groups (time: p&lt;0.01, group: p=0.16, interaction: p=0.89). Additionally, the peak change in MAP (+FH: Δ 1.5 ± 0.9 vs. −FH: Δ 2.4 ± 1.8 mmHg, p=0.35) systolic BP (+FH: Δ 1.6 ± 1.2 vs. −FH: Δ 3.7 ± 2.2 mmHg, p=0.18) and diastolic BP (+FH: Δ 2.2 ± 0.9 vs. −FH: Δ 3.5 ± 2.9 mmHg, p=0.73) were not different between groups.CONCLUSIONSThese preliminary data suggest that sympathetic transduction following a burst of MSNA at rest does not elicit greater increases in BP in +FH young women. Further research is needed in order to more specifically examine whether the degree to which a sympathetic burst influences vascular tone is altered in +FH women.Support or Funding InformationSupported by NIH Grant P20 GM 113125, P20 GM 103446, U54 GM 104941, and The University of Delaware Research FoundationThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Muscle Sympathetic Nerve Activity and Hemodynamic Responses to Venous Distension: Does Sex Play a Role?

Peripheral venous distension mechanically stimulates type III/IV sensory fibers in veins and evokes pressor and sympathoexcitatory reflex responses in humans. As young females have reduced venous compliance, smaller increases in arterial pressure to type III/IV sensory fibers activation and impaired sympathetic transduction, we tested the hypothesis that pressor and sympathoexcitatory responses to venous distension may be attenuated in women compared to men. Mean arterial pressure (MAP, photoplethysmography), heart rate (HR), stroke volume (SV, Modelflow), cardiac output (CO = HR x SV), muscle sympathetic nerve activity (MSNA), femoral artery blood flow and conductance (FABF and FACT, Doppler ultrasound) were quantified in 8 males (27 ± 4 yrs.) and 9 females (28 ± 4 yrs.) before (CON) during (INF) and after (Post‐INF) a local infusion of normal saline (5% of the forearm volume) through a retrograde catheter inserted into an antecubital vein of the forearm, to which venous drainage and arterial supply had been occluded. MAP increased during and after infusion in both groups (vs. CON, p ≤ 0.05) but women showed a smaller pressor response in the Post‐INF period (Δ+7.2 ± 2.0 vs. men Δ+18.3 ± 3.9 mmHg, p = 0.019). MSNA increased and FACT decreased similarly in both groups (vs. CON, p ≤ 0.05) at Post‐INF. While HR changes were similar, increases in SV (Δ+20.4 ± 8.6 vs. Δ+2.6 ± 2.7 mL, p = 0.05) and CO (Δ+0.84 ± 0.17 vs. Δ+0.34 ± 0.10 L/min, p = 0.024) were greater in men than women. Therefore, these findings indicate that venous distension evokes a smaller pressor response in young women due to attenuated cardiac adjustments rather than to reduced venous compliance or sympathetic transduction.Support or Funding InformationSupport: CNPq, CAPES, FAPERJThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Global REACH Expedition: Chronic Hypoxia Attenuates the Contribution α‐Adrenergic Receptors to Sympathetic Transduction in Exercising Humans

IntroductionAcute exposure to hypoxia causes a rise in sympathetic nervous system activity (SNA) that restrains peripheral vasodilation. In normoxia, α‐adrenergic receptors are the primary mechanism eliciting vasoconstriction in response to increased SNA at rest and during exercise. However, exposure to chronic hypoxia (CH) causes a sustained and marked increase in SNA that is offset by reduced neurovascular transduction (vasoconstriction). Data from animal models indicate that CH blunts α‐adrenergic vasoconstrictor signaling, termed ‘hypoxic sympatholysis’. In humans it is unknown how CH alters α‐adrenergic restraint of skeletal muscle vascular tone at rest and during exercise.PurposeTo test the hypothesis that CH reduces α‐adrenergic restraint of forearm skeletal muscle vascular tone at rest and during sympathoexcitation in response to cycle exercise.MethodIn 9 healthy lowland natives, we measured forearm blood flow (Doppler ultrasound), mean arterial pressure (MAP, intra‐arterial catheter), heart rate (HR, ECG) and calculated changes in vascular conductance (ΔFVC) during semi‐recumbent cycle exercise (60% VO2 max) at baseline (BL: 344m) and after three weeks sojourn at high‐altitude (CH: 4,380m). Sympathetic α‐adrenergic restraint of vascular tone was assessed via intra‐arterial infusion of phentolamine (PHT, α‐adrenergic antagonist) to achieve local forearm α‐adrenoceptor blockade. All data are quantified as mean ± SD.ResultsAt rest, FVC was not lower in CH (BL: 38.0 ± 9.3 vs. CH: 32.6 ± 15.1 ml/100 mmHg/min; p=0.17). Local α‐adrenergic blockade increased FVC at BL and in CH (ΔFVC during PHT: BL: 70.0 ± 35.5 vs. CH: 87.7 ± 69.2 ml/100mmHg/min; P=0.59), indicative of significant residual basal α‐adrenergic restraint of vascular tone in CH. In contrast, the forearm vasoconstrictor response to 60% cycle exercise was attenuated by ~50% in CH (%ΔFVC during exercise: BL: −42.7 ± 29.6 vs. CH: −21.6 ± 19.4; P&lt;0.05). Local α‐adrenergic blockade attenuated the vasoconstrictor response to exercise by 80% at BL (%ΔFVC during exercise: BL: −38.7 ± 34.2 vs. PHT: −6.1 ± 26.3; P&lt;0.05). However, local α‐adrenergic blockade had no impact on the vasoconstrictor response to exercise in CH (%ΔFVC during exercise: CH: −21.6 ± 19.4 vs. PHT: −18.9 ± 12.1; P=0.77).ConclusionExposure to CH did not significantly alter basal α‐adrenergic restraint of forearm skeletal muscle vascular tone. However, CH attenuates the forearm vasoconstrictor response to cycle exercise, and the contribution of α‐adrenergic receptor‐mediated vasoconstriction is abolished, indicating a reliance on alternative vasoconstrictor mechanisms.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Reducing Dietary Sodium to 1000 mg per Day Reduces Neurovascular Transduction Without Stimulating Sympathetic Outflow.

The American Heart Association recommends no more than 1500 mg of sodium/day as ideal. Some cohort studies suggest low-sodium intake is associated with increased cardiovascular mortality. Extremely low-sodium diets (≤500 mg/d) elicit activation of the renin-angiotensin-aldosterone system and stimulate sympathetic outflow. The effects of an American Heart Association-recommended diet on sympathetic regulation of the vasculature are unclear. Therefore, we assessed whether a 1000 mg/d diet alters sympathetic outflow and sympathetic vascular transduction compared with the more commonly recommended 2300 mg/d. We hypothesized that sodium reduction from 2300 to 1000 mg/d would not affect resting sympathetic outflow but would reduce sympathetic transduction in healthy young adults. Seventeen participants (age: 26±2 years, 9F/8M) completed 10-day 2300 and 1000 mg/d sodium diets in this randomized controlled feeding study (crossover). We measured resting renin activity, angiotensin II, aldosterone, blood pressure, muscle sympathetic nerve activity, and norepinephrine. We quantified beat-by-beat changes in mean arterial pressure and leg vascular conductance (femoral artery ultrasound) following spontaneous sympathetic bursts to assess sympathetic vascular transduction. Reducing sodium to 1000 mg/d increased renin activity, angiotensin II, and aldosterone ( P<0.01 for all) but did not alter mean arterial pressure (78±2 versus 77±2 mm Hg, P=0.56), muscle sympathetic nerve activity (13.9±1.3 versus 13.9±0.8 bursts/min, P=0.98), or plasma/urine norepinephrine. Sympathetic vascular transduction decreased ( P<0.01). These data suggest that reducing sodium from 2300 to 1000 mg/d stimulates the renin-angiotensin-aldosterone system, does not increase resting basal sympathetic outflow, and reduces sympathetic vascular transduction in normotensive adults.

Muscle sympathetic nerve activity and hemodynamic responses to venous distension: does sex play a role?

Peripheral venous distension mechanically stimulates type III/IV sensory fibers in veins and evokes pressor and sympathoexcitatory reflex responses in humans. As young women have reduced venous compliance and impaired sympathetic transduction, we tested the hypothesis that pressor and sympathoexcitatory responses to venous distension may be attenuated in women compared with men. Mean arterial pressure (photoplethysmography), heart rate (HR), stroke volume (SV; Modelflow), cardiac output (CO = HR × SV), muscle sympathetic nerve activity (MSNA), femoral artery blood flow, and femoral artery conductance (Doppler ultrasound) were quantified in eight men (27 ± 4 yr) and nine women (28 ± 4 yr) before [control (CON)], during (INF), and immediately after (post-INF) a local infusion of saline [5% of the total forearm volume (30 ml/min); the infusion time was 2 ± 1 and 1 ± 1 min ( P = 0.0001) for men and women, respectively] through a retrograde catheter inserted into an antecubital vein, to which venous drainage and arterial supply had been occluded. Mean arterial pressure increased during and after infusion in both groups (vs. the CON group, P < 0.05), but women showed a smaller pressor response in the post-INF period (Δ+7.2 ± 2.0 vs. Δ+18.3 ± 3.9 mmHg in men, P = 0.019). MSNA increased and femoral artery conductance decreased similarly in both groups (vs. the CON group, P < 0.05) at post-INF. Although HR changes were similar, increases in SV (Δ+20.4 ± 8.6 vs. Δ+2.6 ± 2.7 ml, P = 0.05) and CO (Δ+0.84 ± 0.17 vs. Δ+0.34 ± 0.10 l/min, P = 0.024) were greater in men compared with women. Therefore, venous distension evokes a smaller pressor response in young women due to attenuated cardiac adjustments rather than reduced venous compliance or sympathetic transduction. NEW & NOTEWORTHY We found that the pressor response to venous distension was attenuated in young women compared with age-matched men. This was due to attenuated cardiac adjustments rather than reduced venous compliance, sympathetic activation, or impaired transduction and vascular control. Collectively, these findings suggest that an attenuated venous distension reflex could be involved in orthostatic intolerance in young women.

Quantification of Sympathetic Transduction in Type 2 Diabetes Patients

Type 2 Diabetes patients (T2D) have been shown to have greater alpha-adrenergic sensitivity. How this impacts the transduction of muscle sympathetic nerve activity (MSNA) to arterial blood pressure under resting conditions using spontaneous fluctuations in MSNA, as well as during stressors known to elicit sympatho-excitation (e.g., cold pressor test (CPT)) is unclear. PURPOSE: We tested the hypothesis that T2D patients would exhibit greater sympathetic transduction compared to age- and BMI-matched, healthy controls. METHODS: MSNA (microneurography), heart rate (ECG), and beat-to-beat arterial blood pressure (finger photoplethysmography) were continuously recorded during a 10 minute baseline period, and in response to a 2-minute CPT in six T2D patients and six age- and BMI-matched, healthy controls (CON). To quantify sympathetic transduction at rest, normalized burst heights were divided into four quartiles (smallest to largest), related to the corresponding peak change in mean arterial pressure (MAP) within those quartiles and a slope was determined. To quantify sympathetic transduction in response to a stressor, the change in MAP was related to the change in MSNA from rest to the last minute of CPT. RESULTS: There were no differences in resting sympathetic transduction between groups (CON slope: 0.0103±0.0023 mmHg/AU, T2D slope: 0.0095±0.0016 mmHg/AU; p=0.78). Indeed, signal averaging of MSNA bursts indicated a similar peak increase in blood pressure in CON (+4.2±0.6 mmHg) and T2D (+4.0±0.9 mmHg) (p=0.66). Although the peak increase in blood pressure to CPT tended to be higher in T2D (T2D: +31.6±3.4 mmHg, CON: +21.4±3.7 mmHg; p=0.096), the Δ MAP/Δ MSNA relationship during CPT was not different between groups (CON: 0.4158±0.21, T2D: 0.1862±0.05; p=0.36). CONCLUSIONS: Despite clear sympathetically-mediated increases in blood pressure in T2D patients and healthy CON subjects both at rest and during the CPT, neither of the methodologies used to estimate sympathetic transduction, with respect to changes in arterial blood pressure, detected group differences. Supported by AHA-20160072.

Quantifying sympathetic neuro-haemodynamic transduction at rest in humans: insights into sex, ageing and blood pressure control.

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. 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±0.01mmHg (%s)(-1) , n=23 vs. 0.06±0.01mmHg (%s)(-1) , n=18; P=0.003). Transduction was lowest in YW (0.02±0.01mmHg (%s)(-1) , n=23) and increased during β-blockade (0.11±0.01mmHg (%s)(-1) ; P<0.001). Transduction in PMW (0.07±0.01mmHg (%s)(-1) , n=23) was greater compared to YW (P=0.001), and was not altered during β-blockade (0.06±0.01mmHg (%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±1.5years. 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.

Blood Pressure Increases in OSA due to Maintained Neurovascular Sympathetic Transduction: Impact of CPAP.

To test the hypothesis that greater resting sympathetic activity in obstructive sleep apnea (OSA) syndrome would not induce a lesser sympathetic neurovascular transduction. Case-controlled cohort study. 33 patients with newly diagnosed OSA without comorbidities and 14 healthy controls. 6 months of continuous positive airway pressure (CPAP) treatment for OSA patients and follow-up for 9 healthy controls. We assessed resting sympathetic outflow and sympathetic neurovascular transduction. Sympathetic activity was directly measured (microneurography) at rest and in response to sustained isometric handgrip exercise. Neurovascular transduction was derived from the relationship of sympathetic activity and blood pressure to leg blood flow during exercise. Despite an elevated sympathetic activity of ∼50% in OSA compared to controls, neurovascular transduction was not different (i.e., absence of tachyphylaxis). After six months of CPAP, there were significant declines in diastolic pressure, averaging ∼4 mm Hg, and in sympathetic activity, averaging ∼20% with no change in transduction. Greater sympathetic activity in obstructive sleep apnea does not appear to be associated with lesser neurovascular transduction. Hence, elevated sympathetic outflow without lesser transduction may underlie the prevalent development of hypertension in this population that is well controlled by continuous positive airway pressure treatment.