Neurovascular Transduction Research Articles

Acute intermittent hypercapnic hypoxia and sympathetic neurovascular transduction in men.

Intermittent hypoxia leads to long-lasting increases in muscle sympathetic nerve activity and blood pressure, contributing to increased risk for hypertension in obstructive sleep apnoea patients. We determined whether augmented vascular responses to increasing sympathetic vasomotor outflow, termed sympathetic neurovascular transduction (sNVT), accompanied changes in blood pressure following acute intermittent hypercapnic hypoxia in men. Lower body negative pressure was utilized to induce a range of sympathetic vasoconstrictor firing while measuring beat-by-beat blood pressure and forearm vascular conductance. IH reduced vascular shear stress and steepened the relationship between diastolic blood pressure and sympathetic discharge frequency, suggesting greater systemic sNVT. Our results indicate that recurring cycles of acute intermittent hypercapnic hypoxia characteristic of obstructive sleep apnoea could promote hypertension by increasing sNVT. Acute intermittent hypercapnic hypoxia (IH) induces long-lasting elevations in sympathetic vasomotor outflow and blood pressure in healthy humans. It is unknown whether IH alters sympathetic neurovascular transduction (sNVT), measured as the relationship between sympathetic vasomotor outflow and either forearm vascular conductance (FVC; regional sNVT) or diastolic blood pressure (systemic sNVT). We tested the hypothesis that IH augments sNVT by exposing healthy males to 40 consecutive 1min breathing cycles, each comprising 40s of hypercapnic hypoxia ( : +4±3mmHg above baseline; : 48±3mmHg) and 20s of normoxia (n=9), or a 40min air-breathing control (n=7). Before and after the intervention, lower body negative pressure (LBNP; 3min at -15, -30 and -45mmHg) was applied to elicit reflex increases in muscle sympathetic nerve activity (MSNA, fibular microneurography) when clamping end-tidal gases at baseline levels. Ventilation, arterial pressure [systolic blood pressure, diastolic blood pressure, mean arterial pressure (MAP)], brachial artery blood flow ( BA ), FVC ( BA /MAP) and MSNA burst frequency were measured continuously. Following IH, but not control, ventilation [5Lmin-1 ; 95% confidence interval (CI)=1-9] and MAP (5mmHg; 95% CI=1-9) were increased, whereas FVC (-0.2mLmin-1 mmHg-1 ; 95% CI=-0.0 to -0.4) and mean shear rate (-21.9s-1 ; 95% CI=-5.8 to -38.0; all P<0.05) were reduced. Systemic sNVT was increased following IH (0.25mmHgburst-1 min-1 ; 95% CI=0.01-0.49; P<0.05), whereas changes in regional forearm sNVT were similar between IH and sham. Reductions in vessel wall shear stress and, consequently, nitric oxide production may contribute to heightened systemic sNVT and provide a potential neurovascular mechanism for elevated blood pressure in obstructive sleep apnoea.

Acute effects of salbutamol on systemic vascular function in people with asthma.

Asthmatics are at increased cardiovascular disease risk, which has been linked to beta2(β2)-agonist use. Inhalation of β2-agonists increases sympathetic nerve activity (SNA) in healthy individuals, however the systemic impact of salbutamol in asthmatics using β2-agonists regularly is unknown. This study compared the systemic vascular responses to a clinical dose of salbutamol (Phase I) and following an acute increase in SNA (Phase II) in asthmatics and controls. Fourteen controls and 14 asthmatics were recruited for Phase I. On separate days, flow-mediated dilation (FMD) and peripheral arterial stiffness (pPWV) were evaluated at baseline and following either 400 μg inhaled salbutamol or a placebo inhaler. For Phase II, heart rate, blood pressure, vascular conductance, pPWV, and central (c)PWV were evaluated in response to a large increase in SNA brought on by cold-water hand immersion (i.e. cold-pressor test) or body-temperature water hand immersion (i.e. control) in 10 controls and 10 asthmatics. Following salbutamol, asthmatics demonstrated reduced FMD (-3.0%, p<0.05) and increased pPWV (+0.7m/s, p<0.05); however, salbutamol had no effect in controls. The cold-pressor test resulted in similar increases in blood pressure, vascular flow rates and conductance, pPWV, and cPWV in both asthmatics and controls, suggesting similar neurovascular transduction in asthmatics and controls. Inhaled Salbutamol leads to increased arterial stiffness and reduced FMD in asthmatics. As asthmatics and controls had similar vascular responses to an increase in SNA, these findings suggest asthmatics have heightened sympathetic responses to β2-agonists which may contribute to the increased cardiovascular risk in asthma.

Vascular α1-adrenergic sensitivity is enhanced in chronic kidney disease.

Chronic kidney disease (CKD) is often complicated by difficult-to-control hypertension, in part due to chronic overactivation of the sympathetic nervous system (SNS). CKD patients also exhibit a greater increase in arterial blood pressure for a given increase in sympathetic nerve activation, suggesting an augmented vasoconstrictive response to SNS activation (i.e., neurovascular transduction). One potential mechanism of increased sympathetic neurovascular transduction is heightened sensitivity of the vascular α1-adrenergic receptors (α1ARs), the major effectors of vasoconstriction in response to norepinephrine release at the sympathetic nerve terminals. Therefore, we hypothesized that patients with CKD have increased vascular α1AR sensitivity. We studied 32 patients with CKD stages III and IV (age 59.9 ± 1.3 yr) and 19 age-matched controls (CON, age 63.2 ± 1.6 yr). Using a linear variable differential transformer (LVDT), we measured change in venoconstriction in response to exponentially increasing doses of the selective α1AR agonist phenylephrine (PE) administered sequentially into a dorsal hand vein. Individual semilogarithmic PE dose-response curves were constructed for each participant to determine the PE dose at which 50% of maximum venoconstriction occurred (ED50), reflecting α1AR sensitivity. In support of our hypothesis, CKD patients had a lower PE ED50 than CON (CKD = 2.23 ± 0.11 vs. CON = 2.63 ± 0.20, P = 0.023), demonstrating increased vascular α1AR sensitivity. Additionally, CKD patients had a greater venoconstrictive capacity to PE than CON (P = 0.015). Augmented α1AR sensitivity may contribute mechanistically to enhanced neurovascular transduction in CKD and may explain, in part, the greater blood pressure reactivity exhibited in these patients.

Blunted sympathetic neurovascular transduction during normotensive pregnancy.

Normotensive pregnancy is associated with elevated sympathetic nervous system activity yet normal or reduced blood pressure. It represents a unique period of apparent healthy sympathetic hyperactivity. The present study models the blood pressure and heart rate (ECG R-R interval) responses to fluctuations in sympathetic nervous system activity aiming to understand neurocardiovascular transduction. The reported data clearly demonstrate that transduction of sympathetic nervous system signalling to systemic cardiovascular outcomes is reduced in normotensive pregnancy. These data are important for understanding how blood pressure regulation adapts during normotensive pregnancy and set the foundation for exploring similar mechanisms in hypertensive pregnancies. Previously, we described sympathetic nervous system hyperactivity yet decreased blood pressure responses to stress in normotensive pregnancy. To address the hypothesis that pregnant women have blunted neurocardiovascular transduction we assessed the relationship between spontaneous bursts of sympathetic nerve activity (SNA) and fluctuations in mean arterial blood pressure and R-R interval. Resting SNA, blood pressure and ECG were obtained in pregnant (third trimester, n=18) and non-pregnant (n=18) women matched for age and pre-/non-pregnant body mass index. Custom software modelled beat-by-beat pressure (photoplethysmography) and R-R interval in relation to sequences of SNA bursts and non-bursts (peroneal microneurography). Sequences were grouped by the number of bursts and non-bursts [singlets, doublets, triplets and quadruplet (four or more)] and mean blood pressure and R-R interval were tracked for 15 subsequent cardiac cycles. Similar sequences were overlaid and averaged. Peak mean pressure in relation to sequences of SNA was reduced in pregnant vs. non-pregnant women (doublets: 1.6±1.1mmHg vs. 3.6±3.1mmHg, P<0.05; triplets: 2.4±1.2mmHg vs. 3.4±2.1mmHg, P<0.05; quadruplets: 3.0±1.0mmHg vs. 5.5±3.7mmHg, P<0.05). The nadir R-R interval following burst sequences was also smaller in pregnant vs. non-pregnant women (singlets: -0.01±0.01s vs. -0.04±0.04s, P<0.05; doublets: -0.02±0.03s vs. -0.05±0.04s, P<0.05; triplets: -0.02±0.01s vs. -0.07±0.04s, P<0.05; quadruplets: -0.01±0.01s vs. -0.09±0.09s, P<0.05). There were no differences between groups in the mean arterial pressure and R-R interval responses to non-burst sequences. Our data clearly indicate blunted systemic neurocardiovascular transduction during normotensive pregnancy. We propose that blunted transduction is a positive adaptation protecting pregnant women from the cardiovascular consequences of sympathetic hyperactivity.

Sympathetic Discharge Patterns and Neurovascular Transduction Following Acute Intermittent Hypoxia

BackgroundMuscle sympathetic nerve activity (MSNA) is augmented in patients with sleep apnea. This increase in activity is due to increases in firing probability and mean firing rates of individual vasoconstrictor neurons, in addition to multiple within‐burst firing; however, contributing mechanisms and the impact of such firing patterns on peripheral vascular tone are less clear. We examined the effect of acute intermittent hypoxia (IH) on sympathetic neural firing and recruitment strategies and the relationship between changes in MSNA and neurovascular transduction following acute IH. We hypothesized exposure to acute IH would increase MSNA via an increase in action potential (AP) discharge rates and within‐burst firing. We further hypothesized any change in discharge patterns following acute IH would be positively related to a change in neurovascular transduction.MethodsBlood pressure (brachial arterial catheter) and MSNA (microneurography of the peroneal nerve) were assessed in 17 healthy adults (11M/6F; 31 ± 1 yrs) during quiet normoxic rest prior to and following 30‐min of experimental IH [30‐s hypoxic (0.05 FiO2) exposures alternating with 90‐s room air breathing]. AP patterns were studied from the filtered raw MSNA signal using wavelet‐based methodology. The slope of the relationship between diastolic blood pressure (DBP) and the preceding MSNA burst area at a fixed cardiac cycle lag was used to quantify neurovascular transduction.ResultsIH resulted in 15 events where oxygen saturation was reduced (SpO2: 99 ± 1% vs 92 ± 1%, P&lt;0.01). Compared to baseline, multi‐unit MSNA burst incidence (33 ± 4 to 43 ± 5 bursts/100 heart beats), AP incidence (272 ± 50 to 501 ± 112 AP/100 heart beats) and AP content per integrated burst (7 ± 1 to 10 ± 1 AP/burst; 4 ± 1 to 5 ± 1 clusters/burst) were increased following IH (all P&lt;0.05). Neurovascular transduction was not altered following IH (P=0.34); however, there was a positive relationship between the change (Δ) in neurovascular transduction (mmHg/%/s) and changes in AP discharge rate (AP/100 heart beats; R=0.52, P=0.03) and within‐burst firing (AP/burst; R=0.38, P=0.14) following IH.ConclusionsAcute IH increases sympathetic neuronal discharge by increasing within‐burst firing of low‐threshold axons. A positive relationship exists between increases in the neural discharge rates and neurovascular transduction following acute IH, such that those individuals with the greatest increase in AP firing exhibited the greatest increase in transduction of sympathetic activity into blood pressure. These data may have important implications for mechanistic understanding of sympathetic activation in sleep apnea and its down‐stream effects, including the development of hypertension and cardiovascular disease.Support or Funding InformationFunding: NIH HL130339, Mayo Clinic Center for Biomedical Discovery, Mizzou HES PURE, APS UGSRF.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of Acute Leg Heating on Neurovascular Control in Aged Humans

There is a sustained reduction in arterial blood pressure that occurs in aged adults following acute exposure to leg heating. Concurrent with this blood pressure response is an increase in systemic vascular conductance that is not fully offset by an increase in cardiac output, which suggests that acute leg heating may alter neurovascular control. Therefore, the purpose of this study was to test the hypothesis that acute leg heating reduces sympathetic neurovascular transduction in aged humans. Six healthy young adults (3 females; age 25 ± 4 yrs; height 175 ± 9 cm; weight 74 ± 17 kg; mean ± SD) and 4 healthy aged adults (3 females; age 69 ± 4 yrs; height 163 ± 3 cm; weight 66 ± 7 kg) were exposed to 45 min of acute leg heating. Subjects wore a tube‐lined water‐circulating garment that allowed leg skin temperature to be clamped at ~40 °C during heating. Intestinal temperature was measured throughout via a telemetric pill. Systemic vascular conductance was calculated as cardiac output (Modelflow) divided by mean arterial pressure. Femoral vascular conductance was calculated as blood flow (Doppler ultrasound) divided by mean arterial pressure. Neurovascular transduction was estimated before and 30 min after leg heating by measuring the percent reduction in femoral vascular conductance (ΔFVC) during isometric handgrip exercise performed to fatigue. Compared to pre‐heat, intestinal temperature was increased for both groups at 45 min of leg heating (young adults, Δ0.5 ± 0.1 °C; aged adults, Δ0.9 ± 0.2 °C; both P &lt; 0.05 vs. 0 change) and remained elevated 30 min after heating (young adults, Δ0.3 ± 0.1 °C; aged adults, Δ0.5 ± 0.2 °C; both P &lt; 0.05 vs. 0 change). Thirty min after heating, mean arterial pressure did not differ from pre‐heat in young adults (pre 86 ± 3 mmHg vs. post 87 ± 3 mmHg; P = 0.9) but was decreased in aged adults (pre 102 ± 3 mmHg vs. post 96 ± 2 mmHg; P = 0.06). Resting systemic vascular conductance (pre 65.8 ± 3.6 ml min−1 mmHg−1 vs. post 66.4 ± 4.5 ml min−1 mmHg−1; P = 1.0) and femoral vascular conductance (pre 3.1 ± 0.4 ml min−1 mmHg−1 vs. post 3.3 ± 0.6 ml min−1 mmHg−1; P = 0.5) did not differ from pre‐heat in young adults. However, in aged adults, both resting systemic vascular conductance (pre 46.5 ± 3.7 ml min−1 mmHg−1 vs. post 59.2 ± 8.8 ml min−1 mmHg−1; P = 0.03) and femoral vascular conductance (pre 2.6 ± 0.6 ml min−1 mmHg−1 vs. post 3.4 ± 0.6 ml min−1 mmHg−1; P = 0.07) remained elevated 30 min after heating. Neurovascular transduction was reduced after heating in both groups (young adults, pre ΔFVC −28 ± 8 % vs. post ΔFVC −13 ± 10 %; aged adults, pre ΔFVC −30 ± 6 % vs. post ΔFVC −23 ± 7 %; P = 0.03). Taken together, it appears that the reduction in arterial blood pressure that occurs in aged adults after acute leg heating is mediated by a persistent vasodilation that is due, at least in part, to reduced neurovascular transduction. In young adults, blood pressure is well maintained after leg heating despite reduced neurovascular transduction, which may be related to an increase in basal sympathetic vasoconstrictor outflow.This 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.

Activity of muscle sympathetic neurons during normotensive pregnancy.

In pathological populations, elevated sympathetic activity is associated with increased activity of individual sympathetic neurons. We used custom action potential detection software to analyze multiunit sympathetic activity in 18 normotensive pregnant women (third trimester; 33 ± 5 wk) and 19 nonpregnant women at rest and a subset (10 and 13, respectively) during a cold pressor challenge. Although the number of action potentials per burst and number of active amplitude-based "clusters" were not different between groups, the total number of sympathetic action potentials per minute was higher in pregnant women at rest. Individual clusters were active predominately once per burst, suggesting they represent single neurons. Action potentials occurred in closer succession in normotensive pregnant (interspike interval 36 ± 10 ms) versus nonpregnant women (50 ± 27 ms; P < 0.001) at rest. Pregnant women had a lower total peripheral resistance (11.7 ± 3.0 mmHg·l-1·min) than nonpregnant women (15.1 ± 2.7 mmHg·l-1·min; P < 0.001), indicating a blunted neurovascular transduction. The cold pressor reduced the number of action potentials per burst in both groups due to shortening of the R-R interval in conjunction with increased burst frequency; total neural firing per minute was unchanged. Thus elevated sympathetic activity during normotensive pregnancy is specific to increased incidence of multiunit bursts. This is likely due to decreased central gating of burst output as opposed to generalized increases in central drive. These data also reinforce the concept that pregnancy appears to be the only healthy state of chronic sympathetic hyperactivity of which we are aware.

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.

Regulation of sympathetic nerve activity during the cold pressor test in normotensive pregnant and nonpregnant women.

Baseline neurovascular transduction is reduced in normotensive pregnancy; however, little is known about changes to neurovascular transduction during periods of heightened sympathetic activation. We tested the hypothesis that, despite an exacerbated muscle sympathetic nerve activity (microneurography) response to cold pressor stimulation, the blunting of neurovascular transduction in normotensive pregnant women would result in similar changes in vascular resistance and mean arterial pressure (Finometer) relative to nonpregnant controls. Baseline neurovascular transduction was reduced in pregnant women relative to controls when expressed as the quotient of both total resistance and mean arterial pressure and sympathetic burst frequency (0.32±0.07 versus 0.58±0.16 mm Hg/L/min/bursts/min, P<0.001 and 2.4±0.7 versus 3.6±0.8 mm Hg/bursts/min, P=0.001). Sympathetic activation was greater across all 3 minutes of cold pressor stimulation in the pregnant women relative to the nonpregnant controls. Peak sympathoexcitation was also greater in pregnant than in nonpregnant women, whether expressed as sympathetic burst frequency (+17±13 versus +7±8 bursts/min, P=0.049), burst incidence (+17±9 versus +6±11 bursts/100 hb, P=0.03), or total activity (+950±660 versus +363±414 arbitrary units, P=0.04). However, neurovascular transduction during peak cold pressor-induced sympathoexcitation remained blunted in pregnant women (0.25±0.11 versus 0.45±0.08 mm Hg/L/min/bursts/min, P<0.001 and 1.9±1.0 versus 3.2±0.9 mm Hg/bursts/min, P=0.006). Therefore, mean arterial pressure (93±21 versus 99±6 mm Hg, P=0.4) and total peripheral resistance (12±3 versus 14±3 mm Hg/L/min) were not different between pregnant and nonpregnant women during peak sympathoexcitation. These data indicate that the third trimester of normotensive pregnancy is associated with reductions in neurovascular transduction, which result in the dissociation of sympathetic outflow from hemodynamic outcomes, even during cold pressor-induced sympathoexcitation.

Effect of Pregnancy on Sympathetic and Peripheral Vascular Responses to the Cold Pressor Test

Little is known regarding sympathetic neurovascular regulation during pregnancy. We hypothesized that, despite elevated muscle sympathetic nerve activity (MSNA; peroneal microneurography) in normotensive pregnant women (NP) versus non‐pregnant controls (CT), neurovascular transduction would be blunted in NP, resulting in similar mean arterial pressure (MAP) between groups. Integrated MSNA was obtained during 3 min of rest and 3 min of reflex sympathetic activation (cold pressor test; CPT). Total peripheral resistance (TPR; MAP/Q) and burst frequency (BF) were used to calculate neurovascular transduction (TPR/BF). CPT data were analyzed in 30s bins; the bin corresponding to the highest BF value was selected for analysis. Baseline MAP and TPR were not different between NP vs CT (90±16 vs 90±5 mmHg,P=0.9 and 12±2 vs 13±2 mmHg/L/min, P=0.5, respectively) whereas BF (36±7 vs 24±2, P&lt;0.01) and total MSNA (BF x normalized burst amplitude; 1743±286 vs 1145±191, P&lt;0.01) were higher and neurovascular transduction lower (0.3±0.1 vs 0.5±0.1, P=0.01) in NP. During CPT, BF and total MSNA were higher in NP vs CT (56±17 vs 34±10, P=0.03; 2677±650 vs 1529±515, P=0.01), while no differences in MAP or TPR were observed between NP vs CT (99±24 vs 101±7, P=0.8; 13±4 vs 13±3, P=0.7). Neurovascular transduction during CPT was lower in NP than CT (0.24±0.10 vs 0.40±0.07, P=0.01), indicating a vascular adaptation to pregnancy. Supported by WCHRI, NSERC &amp; University of Alberta Human Performance Scholarship Fund.

Sympathetic Neurovascular Regulation During Pregnancy: A Longitudinal Case Study

Pregnancy is associated a ~50% increase in blood volume, ~40% increase in cardiac output (Q), offset by a drop in total peripheral resistance (TPR). While limited data indicate a concurrent increase in sympathetic nerve activity (SNA) in normal pregnancy, suggesting reduced transduction of SNA into TPR, longitudinal neurovascular adaptation during gestation remains poorly understood.We conducted a longitudinal assessment of SNA and TPR in a 36 year old woman during her second pregnancy. Measures were made on 2 occasions in the month prior to conception, 4 occasions during pregnancy (9, 24, 30, and 38 wks gestation) and again 10 wks postpartum. Mean arterial pressure (MAP; Finometer) and Q (ModelFlow) were measured and used to calculate TPR. SNA was measured using microneurography (peroneal nerve).There was a gestationally dependent increase in SNA burst frequency (r2=0.970, P&lt;0.01) and incidence (r2=0.977, P&lt;0.01); frequency (24 bpm to 59 bpm) and incidence (34 b/100hb to 65 b/100hb) increased 145% and 89% respectively by 38 wks compared to early follicular values. However, transduction (TPR/SNA Burst Frequency) decreased throughout pregnancy (r2=0.952, P&lt;0.05; 0.80 au to 0.21 au). By 10 wks postpartum, SNA (24 bpm; 28 b/100hb) had returned to pre‐pregnant values whereas transduction (0.44au) remained lower.These longitudinal data highlight the progressive sympoathoexcitation during pregnancy which is offset by a concurrent reduction in neurovascular transduction. Sympathetic hyperactivity reverses early in the post‐partum whereas transduction remains decreased. Funded by WCHRI, NSERC, HPF

Post‐Junctional Adrenergic Neurotransmission is Inhibited by Nitric Oxide (NO) in Humans

NO, can modulate adrenergic vasoconstriction by central reduction of sympathetic outflow and by peripheral effects in animal models. We investigated whether NO inhibits post–synaptic α‐1‐adrenergic neurotransmission in humans. To accomplish this we performed intravenous phenylephrine dose‐response experiments under three conditions: during a control saline infusion, after NOS inhibition with L‐NG‐monomethyl Arginine (L‐NMMA), and following restoration of NO by adding sodium nitroprusside (SNP) to L‐NMMA. We studied 11 healthy controls (21 ±3 yrs) using repeated measures ANOVA. All subjects received at least 0.5, 1.0, and 2.0 µg/kg/min in sequence. Patients were instrumented with an oscillometric BP cuff, EKG, and beat‐to‐beat BP, cardiac output (CO), and total peripheral resistance using a Finometer with ModelFlow software. We measured cerebral blood flow velocity (CBFv) in the middle cerebral artery with transcranial Doppler ultrasound. Saline and L‐NMMA experiments were performed on different days. L‐NMMA increased pre‐phenylephrine MAP by 7% while reducing HR by 8% and increasing CBFv by 13%. The change in MAP, and TPR were significantly increased with L‐NMMA (P &lt; 0.001) and returned to baseline following administration of SNP (P &gt; 0.05) for all levels of the dose‐response. HR and CO were significantly decreased with L‐NMMA (P &lt; 0.001) and was returned to baseline with SNP (P &gt; 0.05) for all levels of the dose‐response. The change in CBFv was unaffected (curves were parallel). We conclude that post‐junctional adrenergic neurotransmission is inhibited by NO in humans. Inhibition could occur by reduction of α‐1‐adrenergic properties or of neurovascular transduction.

Sympathetic Baroreflex Sensitivity in Normotensive Pregnant Women

Muscle sympathetic nerve activity (MSNA) is increased during pregnancy while mean arterial pressure (MAP) is maintained or reduced, suggesting baroreflex resetting. We hypothesized that sympathetic baroreflex sensitivity (BRS) would be reduced in normotensive pregnant women (PREG) relative to similarly aged non-pregnant controls (CTRL). Integrated MSNA burst incidence (microneurography), MAP and diastolic blood pressure (DBP; Finometer), cardiac output (Q; ModelFlow), and total peripheral resistance (TPR; MAP/Q) were assessed at rest in 11 PREG (33±1 weeks gestation, 31±1y, pre-pregnancy BMI: 24±1 kg/m2) and 10 CTRL (29±1y; BMI: 25±2). MSNA was higher in PREG than CTRL (43±2 vs 33±2 bursts/100hb, P<0.01) while DBP was similar between groups, indicating an upward resetting of the BRS set-point in PREG. Spontaneous BRS slope, calculated from the linear relationship between MSNA burst incidence and DBP, was reduced in PREG vs CTRL (-5.3±0.5 vs -3.7±0.5 bursts/100hb/mmHg). PREG was also associated with a blunting of neurovascular transduction (TPR/MSNA) relative to CTRL (0.28±0.01 vs 0.45±0.03 a.u., P<0.01), resulting in the maintenance of normal MAP in PREG. Supported by WCHRI, NSERC & University of Alberta Human Performance Scholarship Fund.

Neurovascular control following small muscle mass exercise in humans (1170.10)

Sympathetic vascular transduction is blunted and the arterial baroreflex curve is reset to a lower operating pressure after dynamic large muscle mass exercise in humans. It is unknown whether these neural adaptations contribute to sustained post‐exercise vasodilation in small muscle mass exercise. The purpose of this study was to determine if cardiovagal, vascular, and integrated baroreflex sensitivity as well as sympathetic neurovascular transduction were altered following dynamic knee extension (DKE) exercise. It was hypothesized that sympathetic vascular transduction would be reduced after DKE, the arterial baroreflex would be reset to a lower operating point, and baroreflex sensitivity would be enhanced. Eleven healthy, college‐aged subjects completed one‐leg DKE exercise for one hour at 60% of peak power. Neurovascular transduction was estimated by measuring the percent change in femoral vascular conductance due to external neck pressure. There was no effect of exercise on transduction (P = 0.46) and no difference in integrated baroreflex sensitivity across time (P = 0.77). Cardiovagal baroreflex sensitivity increased 25% relative to baseline and had not recovered at 60 minutes post‐exercise (P = 0.02). Vascular baroreflex sensitivity was reduced in both the exercised (P = 0.05) and rested leg (P = 0.09). There is likely no effect of small muscle mass exercise on postexercise sympathetic transduction, the carotid baroreflex, or integrated baroreflex sensitivity. Cardiovagal baroreflex sensitivity was augmented and vascular baroreflex sensitivity was reduced after exercise and this has not been previously shown after small muscle mass exercise.Grant Funding Source: NIH R01 HL115027

Output vs. outcome: neurovascular transduction at rest

Microneurography techniques that allow the direct recording of sympathetic nerve activity (SNA) in humans have been used to examine the neural control of cardiovascular regulation in a wide variety of populations. In the context of vascular control, SNA directed at the vasculature within skeletal muscle (muscle SNA; MSNA) occurs in a ‘bursting’ pattern, which is typically quantified as burst frequency (in bursts per minute), burst incidence (in bursts per 100 heart beats), burst amplitude (in arbitrary units) and total activity (frequency × amplitude). Each burst of activity represents the summation of multiple action potentials from multiple neurons, resulting in the downstream release of vasoactive neurotransmitters. However, due to the irregular bursting pattern and relatively low frequency of basal MSNA typically observed in in young, healthy individuals (e.g. 20–30 bursts (100 heart beats)−1; Steinback et al. 2010; Vianna et al. 2012; Fairfax et al. 2013a,b2013b; Tan et al. 2013), the standard metrics of activity are typically averaged over time (minutes) at rest or during the steady state following an initiating stimulus. Due to this limitation, little information is currently available regarding the specific vascular effects of ongoing MSNA (i.e. on a burst-by-burst basis) or the time course of activation in response to various stimuli. A related series of publications, including the recent work published in The Journal of Physiology by Fairfax et al. (2013a), have attempted to address these issues using an adapted approach to measure neurovascular ‘transduction’. The authors have built upon an earlier description of transduction by Wallin & Nerhed (1982) to describe the functional effect of a given burst (or group of bursts) of MSNA on the cardiovascular system. They achieved this by using burst-triggered averaging to define the time course and magnitude of cardiovascular responses (i.e. mean arterial pressure, vascular conductance and cardiac output) over 15 cardiac cycles immediately following a spontaneous sympathetic burst. Categorization of bursts by size and frequency (clusters) was used to evaluate the influence of variations in total MSNA. Furthermore, analysis of the time course of responses following cardiac cycles without bursts and sampling of white noise during random cardiac cycles (with and without bursts) acted as a control analysis. Similar to previous accounts (Wallin & Nerhed, 1982; Vianna et al. 2012; Fairfax et al. 2013b), the authors describe a peak vascular response graded in proportion to the total activity, which occurs approximately five to eight cardiac cycles following a given burst or group of bursts (Fairfax et al. 2013a). In the most recent publication in this series, appearing in The Journal of Physiology, the authors expand upon their previous findings to evaluate the direct contribution of α-receptor-mediated pathways to basal transduction and regional differentiation between upper and lower limbs (Fairfax et al. 2013a).

Alterations in sympathetic neurovascular transduction during acute hypoxia in humans

Resting vascular sympathetic outflow is significantly increased during and beyond exposure to acute hypoxia without a parallel increase in either resistance or pressure. This uncoupling may indicate a reduction in the ability of sympathetic outflow to effect vascular responses (sympathetic transduction). However, the effect of hypoxia on sympathetic transduction has not been explored. We hypothesized that transduction would either remain unchanged or be reduced by isocapnic hypoxia. In 11 young healthy individuals, we measured beat-by-beat pressure, multiunit sympathetic nerve activity, and popliteal blood flow velocity at rest and during isometric handgrip exercise to fatigue, before and during isocapnic hypoxia (~80% SpO₂), and derived sympathetic transduction for each subject via a transfer function that reflects Poiseuille's law of flow. During hypoxia, heart rate and sympathetic nerve activity increased, whereas pressure and flow remained unchanged. Both normoxic and hypoxic exercise elicited significant increases in heart rate, pressure, and sympathetic activity, although sympathetic responses to hypoxic exercise were blunted. Hypoxia slightly increased the gain relation between pressure and flow (0.062 ± 0.006 vs. 0.074 ± 0.004 cm·s(-1)·mmHg(-1); P = 0.04), but markedly increased sympathetic transduction (-0.024 ± 0.005 vs. -0.042 ± 0.007 cm·s(-1)·spike(-1); P < 0.01). The pressor response to isometric handgrip was similar during normoxic and hypoxic exercise due to the balance of interactions among the tachycardia, sympathoexcitation, and transduction. This indicates that the ability of sympathetic activity to affect vasoconstriction is enhanced during brief exposure to isocapnic hypoxia, and this appears to offset the potent vasodilatory stimulus of hypoxia.

Characterizing Sympathetic Neurovascular Transduction in Humans

Despite its critical role for cardiovascular homeostasis in humans, only a few studies have directly probed the transduction of sympathetic nerve activity to regional vascular responses – sympathetic neurovascular transduction. Those that have variably relied on either vascular resistance or vascular conductance to quantify the responses. However, it remains unclear which approach would better reflect the physiology. We assessed the utility of both of these as well as an alternative approach in 21 healthy men. We recorded arterial pressure (Finapres), peroneal sympathetic nerve activity (microneurography), and popliteal blood flow (Doppler) during isometric handgrip exercise to fatigue. We quantified and compared transduction via the relation of sympathetic activity to resistance and to conductance and via an adaptation of Poiseuille’s relation including pressure, sympathetic activity, and flow. The average relationship between sympathetic activity and resistance (or conductance) was good when assessed over 30-second averages (mean R2 = 0.49±0.07) but lesser when incorporating beat-by-beat time lags (R2 = 0.37±0.06). However, in a third of the subjects, these relations provided relatively weak estimates (R2<0.33). In contrast, the Poiseuille relation reflected vascular responses more accurately (R2 = 0.77±0.03, >0.50 in 20 of 21 individuals), and provided reproducible estimates of transduction. The gain derived from the relation of resistance (but not conductance) was inversely related to transduction (R2 = 0.37, p<0.05), but with a proportional bias. Thus, vascular resistance and conductance may not always be reliable surrogates for regional sympathetic neurovascular transduction, and assessment from a Poiseuille relation between pressure, sympathetic nerve activity, and flow may provide a better foundation to further explore differences in transduction in humans.

Effect of Fitness on Reflex Sympathetic Neurovascular Transduction in Middle-Age Men

Muscle sympathetic nerve activity (MSNA) is increased in older endurance-trained men, yet the reflex sympathetic forearm vasoconstrictor response to graded lower body negative pressure (LBNP) diminishes with age. The aim of this study was to assess the influence of aerobic exercise capacity on this altered neurovascular coupling. We hypothesized that during graded LBNP, the forearm vascular resistance (FVR)-MSNA relationship would be steeper in sedentary versus fit men. We therefore studied 20 healthy middle-age men (age = 52 ± 2 yr, mean ± SE), 10 physically active (FIT) and 10 sedentary (SED) (129% ± 4% vs 85% ± 3% of predicted peak oxygen uptake) during 4 min each of LBNP at -5, -10, -20, and -40 mm Hg, applied in a random order. We determined HR, plasma norepinephrine, and MSNA (microneurography) and derived FVR from blood pressure and forearm blood flow (plethysmography). The FVR-MSNA relationship was determined by linear regression in each group separately, and groups were compared using multiple linear regression. MSNA burst frequency and FVR at rest and during LBNP (P < 0.003) were similar in the two groups, whereas HR was significantly lower (P < 0.002) both at rest and during LBNP in FIT men (P < 0.05). FVR during LBNP correlated positively with MSNA in the SED group (r = 0.44, P < 0.001) but not in the FIT group (r = 0.19, P = 0.10). Multiple linear regression confirmed that both MSNA (P < 0.001) and fitness level (P = 0.04) contribute to the forearm vascular response. Thus, during simulated orthostasis, middle-age SED men exhibit a significant FVR-MSNA relationship, which is not evident in age-matched FIT men. This alteration in neurovascular coupling may potentially affect cardiovascular risk in middle-age men.