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

O’Brien M.W., Ramsay D., Johnston W., Kimmerly D.S.

Lower aerobic fitness increases the risk of developing hypertension. Muscle sympathetic nerve activity (MSNA) is important for the beat-by-beat regulation of blood pressure. Whether the cardiovascular consequences of lower aerobic fitness are due to augmented transduction of MSNA into vascular responses is unclear. We tested the hypothesis that aerobic fitness is inversely related to peak increases in total peripheral resistance (TPR) and mean arterial pressure (MAP) in response to spontaneous MSNA bursts in young males. Relative peak oxygen consumption (VO2peak, indirect calorimetry) was assessed in 18 young males (23 ± 3 years; 41 ± 8 ml/kg/min). MSNA (microneurography), cardiac intervals (electrocardiogram) and arterial pressure (finger photoplethysmography) were recorded continuously during supine rest. Stroke volume and cardiac output (CO) were estimated via the ModelFlow method. TPR was calculated as MAP/CO. Changes in TPR and MAP were tracked for 12 cardiac cycles following heartbeats associated with or without spontaneous bursts of MSNA. Overall, aerobic fitness was inversely correlated to the peak ΔTPR (0.8 ± 0.7 mmHg/l/min; R = − 0.61, P = 0.007) and ΔMAP (2.3 ± 0.8 mmHg; R = − 0.69, P < 0.001), but not with the peak ΔCO (0.2 ± 0.1 l/min; P = 0.50), MSNA burst frequency (14 ± 5 bursts/min; P = 0.43) or MSNA relative burst amplitude (65 ± 12%; P = 0.13). Heartbeats without an associated burst of MSNA did not increase TPR, MAP or CO. Although unrelated to traditional MSNA characteristics, aerobic fitness was inversely associated with spontaneous sympathetic neurovascular transduction in young males. This may be a potential mechanism by which aerobic fitness modulates the regulation of arterial blood pressure through the sympathetic nervous system.

Coovadia Y., Adler T.E., Steinback C.D., Fraser G.M., Usselman C.W.

We demonstrate that during acute sympathoinhibition, women demonstrate more sustained increases in blood pressure following sympathetic bursts of activity than men. Likewise, during prolonged sympathetic quiescence, blood pressure is less labile in women than men. This suggests that lower overall blood pressure in young women may not be mediated by smaller beat-by-beat changes in blood pressure in response to sympathetic outflow but may instead be mediated by a lower frequency of sympathetic bursts.

Incognito A.V., Nardone M., Teixeira A.L., Lee J.B., Kathia M.M., Millar P.J.

Muscle sympathetic single units respond differentially to sympathoexcitatory stress such that single units can increase firing to contribute to the sympathoexcitatory response or can be nonresponsive or even inhibited. We observed a subgroup of single units that can respond bidirectionally, being first inhibited before activated by progressive increases in forearm muscle metaboreflex activation. These results suggest convergent neural inputs (i.e., inhibitory and excitatory), which yield heterogenous muscle sympathetic single-unit activation thresholds.

Incognito A.V., Samora M., Shepherd A.D., Cartafina R.A., Guimarães G.M., Daher M., Millar P.J., Vianna L.C.

The arterial baroreflex has dominant control over multiunit muscle sympathetic nerve activity (MSNA) burst occurrence, but whether this extends to all single units or is influenced by resting blood pressure status is unclear. In 22 men (32 ± 8 yr), we assessed 68 MSNA single units during sequential bolus injections of nitroprusside and phenylephrine (modified Oxford). Sympathetic baroreflex sensitivity (sBRS) was quantified as the weighted negative linear regression slope between diastolic blood pressure (DBP) and single-unit spike firing probability and multiple spike firing. Strong negative linear relationships ( r ≥ −0.50) between DBP and spike firing probability were observed in 63/68 (93%) single units (−2.27 ± 1.27%·cardiac cycle−1·mmHg−1 [operating range, 18 ± 8 mmHg]). In contrast, only 45/68 (66%) single units had strong DBP-multiple spike firing relationships (−0.13 ± 0.18 spikes·cardiac cycle−1·mmHg−1 [operating range, 14 ± 7 mmHg]). Participants with higher resting DBP (65 ± 3 vs. 77 ± 3 mmHg, P < 0.001) had similar spike firing probability sBRS (low vs. high, −2.08 ± 1.08 vs. −2.46 ± 1.42%·cardiac cycle−1·mmHg−1, P = 0.33), but a smaller sBRS operating range (20 ± 6 vs. 16 ± 9 mmHg, P = 0.01; 86 ± 24 vs. 52 ± 25% of total range, P < 0.001) and a higher proportion of single units without arterial baroreflex control outside this range [6/31 (19%) vs. 21/32 (66%), P < 0.001]. Participants with higher resting DBP also had fewer single units with arterial baroreflex control of multiple spike firing (79 vs. 53%, P = 0.04). The majority of MSNA single units demonstrate strong arterial baroreflex control over spike firing probability during pharmacological manipulation of blood pressure. Changes in single-unit sBRS operating range and control of multiple spike firing may represent altered sympathetic recruitment patterns associated with the early development of hypertension. NEW & NOTEWORTHY Muscle sympathetic single units can be differentially controlled during stress. In contrast, we demonstrate that 93% of single units maintain strong arterial baroreflex control during pharmacological manipulation of blood pressure. Interestingly, the operating range and proportion of single units that lose arterial baroreflex control outside of this range are influenced by resting blood pressure levels. Altered single unit, but not multiunit, arterial baroreflex control may represent changes in sympathetic recruitment patterns in early stage development of hypertension.

Steinback C.D., Fraser G.M., Usselman C.W., Reyes L.M., Julian C.G., Stickland M.K., Chari R.S., Khurana R., Davidge S.T., Davenport M.H.

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 ± 1.1 mmHg vs. 3.6 ± 3.1 mmHg, P < 0.05; triplets: 2.4 ± 1.2 mmHg vs. 3.4 ± 2.1 mmHg, P < 0.05; quadruplets: 3.0 ± 1.0 mmHg vs. 5.5 ± 3.7 mmHg, P < 0.05). The nadir R-R interval following burst sequences was also smaller in pregnant vs. non-pregnant women (singlets: -0.01 ± 0.01 s vs. -0.04 ± 0.04 s, P < 0.05; doublets: -0.02 ± 0.03 s vs. -0.05 ± 0.04 s, P < 0.05; triplets: -0.02 ± 0.01 s vs. -0.07 ± 0.04 s, P < 0.05; quadruplets: -0.01 ± 0.01 s vs. -0.09 ± 0.09 s, 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.

Young B.E., Holwerda S.W., Vranish J.R., Keller D.M., Fadel P.J.

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.

Herring N., Tapoulal N., Kalla M., Ye X., Borysova L., Lee R., Dall’Armellina E., Stanley C., Ascione R., Lu C., Banning A.P., Choudhury R.P., Neubauer S., Dora K., Kharbanda R.K., et. al.

Abstract Aims The co-transmitter neuropeptide-Y (NPY) is released during high sympathetic drive, including ST-elevation myocardial infarction (STEMI), and can be a potent vasoconstrictor. We hypothesized that myocardial NPY levels correlate with reperfusion and subsequent recovery following primary percutaneous coronary intervention (PPCI), and sought to determine if and how NPY constricts the coronary microvasculature. Methods and results Peripheral venous NPY levels were significantly higher in patients with STEMI (n = 45) compared to acute coronary syndromes/stable angina ( n = 48) or with normal coronary arteries (NC, n = 16). Overall coronary sinus (CS) and peripheral venous NPY levels were significantly positively correlated (r = 0.79). STEMI patients with the highest CS NPY levels had significantly lower coronary flow reserve, and higher index of microvascular resistance measured with a coronary flow wire. After 2 days they also had significantly higher levels of myocardial oedema and microvascular obstruction on cardiac magnetic resonance imaging, and significantly lower ejection fractions and ventricular dilatation 6 months later. NPY (100–250 nM) caused significant vasoconstriction of rat microvascular coronary arteries via increasing vascular smooth muscle calcium waves, and also significantly increased coronary vascular resistance and infarct size in Langendorff hearts. These effects were blocked by the Y1 receptor antagonist BIBO3304 (1 μM). Immunohistochemistry of the human coronary microvasculature demonstrated the presence of vascular smooth muscle Y1 receptors. Conclusion High CS NPY levels immediately after reperfusion correlate with microvascular dysfunction, greater myocardial injury, and reduced ejection fraction 6 months after STEMI. NPY constricts the coronary microcirculation via the Y1 receptor, and antagonists may be a useful PPCI adjunct therapy.

Notay K., Seed J.D., Incognito A.V., Doherty C.J., Nardone M., Burns M.J., Millar P.J.

Resting muscle sympathetic nerve activity (MSNA) demonstrates high intraindividual reproducibility when sampled over 5–30 min epochs, although shorter sampling durations are commonly used before and during a stress to quantify sympathetic responsiveness. The purpose of the present study was to examine the intratest validity and reliability of MSNA sampled over 2 and 1 min and 30 and 15 s epoch durations. We retrospectively analyzed 68 resting fibular nerve microneurographic recordings obtained from 53 young, healthy participants (37 men; 23 ± 6 yr of age). From a stable 7-min resting baseline, MSNA (burst frequency and incidence, normalized mean burst amplitude, total burst area) was compared among each epoch duration and a standard 5-min control. Bland-Altman plots were used to determine agreement and bias. Three sequential MSNA measurements were collected using each sampling duration to calculate absolute and relative reliability (coefficients of variation and intraclass correlation coefficients). MSNA values were similar among each sampling duration and the 5-min control (all P > 0.05), highly correlated ( r = 0.69–0.93; all P < 0.001), and demonstrated no evidence of fixed bias (all P > 0.05). A consistent proportional bias ( P < 0.05) was present for MSNA burst frequency (all sampling durations) and incidence (1 min and 30 and 15 s), such that participants with low and high average MSNA underestimated and overestimated the true value, respectively. Reliability decreased progressively using the 30- and 15-s sampling durations. In conclusion, short 2 and 1 min and 30 s sampling durations can provide valid and reliable measures of MSNA, although increased sample size may be required for epochs ≤30 s, due to poorer reliability.

Briant L.J., Burchell A.E., Ratcliffe L.E., Charkoudian N., Nightingale A.K., Paton J.F., Joyner M.J., Hart E.C.

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 ± 0.01 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.

Fairfax S.T., Padilla J., Vianna L.C., Holwerda S.H., Davis M.J., Fadel P.J.

Large increases in muscle sympathetic nerve activity (MSNA) can decrease the diameter of a conduit artery even in the presence of elevated blood pressure, suggesting that MSNA acts to regulate conduit artery tone. Whether this influence can be extrapolated to spontaneously occurring MSNA bursts has not been examined. Therefore, we tested the hypothesis that MSNA bursts decrease conduit artery diameter on a beat-by-beat basis during rest. Conduit artery responses were assessed in the brachial (BA), common femoral (CFA) and popliteal (PA) arteries to account for regional differences in vascular function. In 20 young men, MSNA, mean arterial pressure (MAP), conduit artery diameter, and shear rate (SR) were continuously measured during 20-min periods of supine rest. Spike-triggered averaging was used to characterize beat-by-beat changes in each variable for 15 cardiac cycles following all MSNA bursts, and a peak response was calculated. Diameter increased to a similar peak among the BA (+0.14 ± 0.02%), CFA (+0.17 ± 0.03%), and PA (+0.18 ± 0.03%) following MSNA bursts (all P < 0.05 vs. control). The diameter rise was positively associated with an increase in MAP in relation to increasing amplitude and consecutive numbers of MSNA bursts ( P < 0.05). Such relationships were similar between arteries. SR changes following MSNA bursts were heterogeneous between arteries and did not appear to systematically alter diameter responses. Thus, in contrast to our hypothesis, spontaneously occurring MSNA bursts do not directly influence conduit arteries with local vasoconstriction or changes in shear, but rather induce a systemic pressor response that appears to passively increase conduit artery diameter.

Fairfax S.T., Holwerda S.W., Credeur D.P., Zuidema M.Y., Medley J.H., Dyke II P.C., Wray D.W., Davis M.J., Fadel P.J.

Sympathetic vascular transduction is commonly understood to act as a basic relay mechanism, but under basal conditions, competing dilatory signals may interact with and alter the ability of sympathetic activity to decrease vascular conductance. Thus, we determined the extent to which spontaneous bursts of muscle sympathetic nerve activity (MSNA) mediate decreases in forearm vascular conductance (FVC) and the contribution of local α-adrenergic receptor-mediated pathways to the observed FVC responses. In 19 young men, MSNA (microneurography), arterial blood pressure and brachial artery blood flow (duplex Doppler ultrasound) were continuously measured during supine rest. These measures were also recorded in seven men during intra-arterial infusions of normal saline, phentolamine (PHEN) and PHEN with angiotensin II (PHEN+ANG). The latter was used to control for increases in resting blood flow with α-adrenergic blockade. Spike-triggered averaging was used to characterize beat-by-beat changes in FVC for 15 cardiac cycles following each MSNA burst and a peak response was calculated. Following MSNA bursts, FVC initially increased by +3.3 ± 0.3% (P = 0.016) and then robustly decreased to a nadir of -5.8 ± 1.6% (P < 0.001). The magnitude of vasoconstriction appeared graded with the number of consecutive MSNA bursts; while individual burst size only had a mild influence. Neither PHEN nor PHEN+ANG infusions affected the initial rise in FVC, but both infusions significantly attenuated the subsequent decrease in FVC (-2.1 ± 0.7% and -0.7 ± 0.8%, respectively; P < 0.001 vs. normal saline). These findings indicate that spontaneous MSNA bursts evoke robust beat-by-beat decreases in FVC that are exclusively mediated via α-adrenergic receptors.

Fairfax S.T., Padilla J., Vianna L.C., Davis M.J., Fadel P.J.

Previous studies in humans attempting to assess sympathetic vascular transduction have related large reflex-mediated increases in muscle sympathetic nerve activity (MSNA) to associated changes in limb vascular resistance. However, such procedures do not provide insight into the ability of MSNA to dynamically control vascular tone on a beat-by-beat basis. Thus we examined the influence of spontaneous MSNA bursts on leg vascular conductance (LVC) and how variations in MSNA burst pattern (single vs. multiple bursts) and burst size may affect the magnitude of the LVC response. In 11 young men, arterial blood pressure, common femoral artery blood flow, and MSNA were continuously recorded during 20 min of supine rest. Signal averaging was used to characterize percent changes in LVC for 15 cardiac cycles following heartbeats associated with and without MSNA bursts. LVC significantly decreased following MSNA bursts, reaching a nadir during the 6th cardiac cycle (single bursts, −2.9 ± 1.1%; and multiple bursts, −11.0 ± 1.4%; both, P < 0.001). Individual MSNA burst amplitudes and the total amplitude of consecutive bursts were related to the magnitude of peak decreases in LVC. In contrast, cardiac cycles without MSNA bursts were associated with a significant increase in LVC (+3.1 ± 0.5%; P < 0.001). Total vascular conductance decreased in parallel with LVC also reaching a nadir around the peak rise in arterial blood pressure following an MSNA burst. Collectively, these data are the first to assess beat-by-beat sympathetic vascular transduction in resting humans, demonstrating robust and dynamic decreases in LVC following MSNA bursts, an effect that was absent for cardiac cycles without MSNA bursts.

Tan C.O., Tamisier R., Hamner J.W., Taylor J.A.

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 (R20.50 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

Vianna L.C., Hart E.C., Fairfax S.T., Charkoudian N., Joyner M.J., Fadel P.J.

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.

Jackson D.N., Noble E.G., Shoemaker J.K.

The role of endogenous Y1-receptor activation on skeletal muscle vasculature under baseline conditions is currently debated and no in vivo studies have been performed to address this issue. Therefore, this study was designed to address the effect of Y1-receptor and/or α1-adrenoceptor antagonism on basal hindlimb vascular conductance in male Sprague-Dawley rats in vivo. Left hindlimb vascular conductance, carotid artery mean arterial pressure, and heart rate were measured during low volume infusion of N2-(diphenylacetyl)- N-[(4-hydroxyphenyl)methyl]-d-arginine amide (BIBP3226; 100 μg/kg), prazosin (20 μg/kg), and combined blockade to the left hindlimb. Vascular conductance increased 1.5 ± 0.5 μl·min−1·mmHg−1 with BIBP3226 infusion, 1.7 ± 0.5 μl·min−1·mmHg−1 with prazosin infusion, and 4.8 ± 1.0 μl·min−1·mmHg−1 with combined blockade ( P < 0.05). Interestingly, systolic vascular conductance increased in all three conditions, but diastolic vascular conductance only increased in the two conditions where BIBP3226 was present. These data indicate that Y1-receptor activation plays an important role in the regulation of vascular conductance in the resting rat hindlimb. Furthermore, this effect was of the same magnitude as the α1-adrenoceptor contribution. The differential flow profiles following α1 blockade with and without Y1-receptor blockade supports local differences in receptor distribution.

Teixeira A.L., Millar P.J.

D'Souza A.W., Hissen S.L., Manabe K., Washio T., Annis M.C., Sanchez B., Usselman C.W., Fu Q., Shoemaker J.K.

While previous work has demonstrated that oral contraceptive pill (OCP) use does not affect resting muscle sympathetic nerve activity (MSNA), growing evidence indicates that it attenuates neurogenic vasoconstriction. Despite these advances, it remains unknown how OCP use affects the ability of MSNA to dynamically control vascular tone and arterial blood pressure (BP) on a beat-by-beat basis. Thus, we tested the hypothesis that, compared to naturally menstruating females (MC), those using OCPs will exhibit attenuated sympathetic vascular transduction at rest. Fourty-three females (MC: n=21, 26 [4] yrs; OCP: n=22, 24 [4] yrs) completed 10 minutes of supine rest with continuous measurements of beat-by-beat BP, femoral artery blood flow (26 females; MC: n=13, OCP: n=13) and MSNA. Spike-triggered averaging was used to determine sympathetic transduction into leg vascular conductance (LVC) and BP for 12 cardiac cycles following MSNA bursts. Overall sympathetic-BP transduction (P=0.293), as well as sympathetic-BP transduction of MSNA burst quartiles (P=0.741) and burst firing patterns (P=0.452) were not different between the MC and OCP groups. Conversely, sympathetic vascular transduction per unit MSNA burst amplitude (P=0.026) and burst firing pattern (P=0.014) were attenuated among females using OCPs. Additionally, females using OCPs demonstrated progressively smaller leg vasoconstrictor responses as a function of MSNA burst firing pattern compared to MC females (P=0.021). Collectively, these data indicate that, in premenopausal females, OCP use attenuates the leg vasoconstrictor responses to bursts of MSNA, particularly during periods of increased sympathetic neural drive, without affecting the transduction of MSNA bursts into beat-by-beat changes in BP.

McCarthy D.G., Nardone M., Pfundt K., Millar P.J.

A burst of muscle sympathetic nerve activity (MSNA) induces vasoconstriction that transiently reduces regional vascular conductance and increases systemic blood pressure (BP) over the subsequent 4-8 cardiac cycles. These responses are termed sympathetic neurovascular transduction and sympathetic transduction of BP, respectively. Sympathetic transduction of BP is commonly calculated and interpreted as a proxy measure for regional sympathetic neurovascular transduction, despite the systemic nature of BP regulation. The present analysis tested whether the peak change in signal-averaged sympathetic transduction of BP was correlated to the change in regional sympathetic vascular transduction at rest. Fourteen adults (5 females, 23±3 years) arrived at the laboratory, ate a standardized meal, and rested for 90-120 minutes. MSNA (fibular nerve microneurography), heart rate (electrocardiography), beat-to-beat BP (finger photoplethysmography), and superficial femoral artery blood flow (Doppler ultrasound) were obtained continuously for 10 minutes in the supine position. Femoral vascular conductance was calculated as blood flow divided by mean arterial BP. The peak change in diastolic BP following a burst of MSNA was correlated to the corresponding nadir change in femoral vascular conductance (r=-0.58 [-0.07 to -0.85], P=0.03) and superficial femoral artery blood flow (r=-0.54 [-0.17 to -0.83], P=0.04). The nadir change in diastolic BP in cardiac cycles not following a MSNA burst was correlated to the peak change in femoral vascular conductance (r=-0.42 [-0.83 to 0.00], p=0.05) but not superficial femoral artery blood flow (r=0.41 [-0.77 to 0.15], p=0.14). In conclusion, more commonly assessed sympathetic transduction of BP provides moderate insight into regional sympathetic neurovascular transduction.

O'Brien M.W., Schwartz B.D., Petterson J.L., Courish M.K., Shivgulam M.E., Kimmerly D.S.

The nadir pressure responses to cardiac cycles absent of muscle sympathetic nerve activity (MSNA) bursts (or non-bursts) are typically reported in studies quantifying sympathetic transduction, but the information gained by studying non-bursts is unclear. We tested the hypothesis that longer sequences of non-bursts (≥8 cardiac cycles) would be associated with a greater nadir diastolic blood pressure (DBP) and that better popliteal artery function would be associated with an augmented reduction in DBP.

D'Souza A.W., Moore J.P., Manabe K., Lawley J.S., Washio T., Hissen S.L., Sanchez B., Fu Q.

Body posture and biological sex exhibit independent effects on the sympathetic neural responses to dynamic exercise. However, the neural mechanisms (e.g., baroreflex) by which posture impacts sympathetic outflow during rhythmic muscular contractions and whether biological sex affects posture-mediated changes in efferent sympathetic nerve traffic during exercise remains unknown. Thus, we tested the hypotheses that increases in muscle sympathetic nerve activity (MSNA) would be greater during upright compared to supine rhythmic handgrip (RHG) exercise, and that females would demonstrate smaller increases in MSNA during upright RHG exercise than males. Twenty young (30 [6] years; mean [SD]) individuals (9 males, 11 females) underwent 6-minutes of supine and upright (head-up tilt 45°) RHG exercise at 40% maximal voluntary contraction with continuous measurements of MSNA (microneurography), blood pressure (photoplethysmography) and heart rate (electrocardiogram). In the pooled group, absolute MSNA burst frequency ( P<0.001), amplitude ( P=0.009), and total MSNA ( P<0.001) were higher during upright compared to supine RHG exercise. However, body posture did not impact the peak change in MSNA during RHG exercise (range: P=0.063-0.495). Spontaneous sympathetic baroreflex gain decreased from rest to RHG exercise ( P=0.006) and was not impacted by posture ( P=0.347). During upright RHG exercise, males demonstrated larger increases in MSNA burst amplitude ( P=0.002) and total MSNA ( P=0.001) compared to females, that coincided with greater reductions in sympathetic baroreflex gain ( P=0.004). Collectively, these data indicate that acute attenuation of baroreflex-mediated sympathoinhibition permits increases in MSNA during RHG exercise, and that males exhibit a greater reserve for efferent sympathetic neural recruitment during orthostasis than females.

Plunkett M.J., Holwerda S., Young B.E., Fadel P.J., Fisher J.P.

AbstractType 2 diabetes (T2D) is often accompanied by hypertension, exaggerated blood pressure (BP) responses to sympatho‐excitatory stressors, and raised cardiovascular disease risk. Appropriate respiratory–sympathetic coupling and sympathetic transduction to BP are important for short‐ and longer‐term BP control. We tested the hypotheses that respiratory modulation of muscle sympathetic nerve activity (MSNA) and its transduction to BP would be impaired in T2D and associated with higher BP and respiratory‐coupled BP variability. Resting MSNA, respiration and beat‐to‐beat BP were recorded in 20 T2D (49.1 ± 7.4 years; mean ± SD) and 13 healthy control (46.3 ± 9.4 years) participants. MSNA and the transduction of sympathetic bursts (signal‐averaging) to mean arterial pressure (MAP) were compared at low and high lung volume phases. The peak MAP response following a sympathetic burst was lower during the high lung volume than low lung volume phase in controls (P = 0.005), whereas it was unchanged with phase in T2D participants (P = 0.522). Respiratory modulation of MSNA was impaired in T2D participants, who had an attenuated reduction in burst incidence from low to the high lung volume phase, versus controls (27.8 ± 38.4% vs. 49.4 ± 24.6%, respectively; P = 0.043). The T2D participants were grouped into unimpaired respiratory modulators (burst incidence modulation median or above) or impaired respiratory modulators (below median). Impaired modulators had higher systolic BP (133 ± 14 vs. 121 ± 11 mmHg, P = 0.046), greater Traube–Hering wave amplitudes (6.3 ± 2.4 vs. 4.6 ± 1.1 mmHg; P = 0.028) and higher BP variability (MAP average real variability, 2.0 ± 0.7 vs. 1.4 ± 0.3, P = 0.033). Respiratory modulation of MSNA and sympathetic transduction to BP are altered in T2D patients and may contribute to their increased hypertension and cardiovascular risk. imageKey points Respiratory–sympathetic coupling and sympathetic transduction to blood pressure (BP) contribute to short‐ and longer‐term BP control. Our understanding of these processes in health and type 2 diabetes (T2D), a condition with high prevalence of hypertension and cardiovascular risk, is incomplete. We found that respiration and sympathetic transduction to BP are coupled in healthy individuals. The mean arterial pressure response to a sympathetic burst was reduced during the high lung volume compared to the low lung volume phase. This coupling was absent in T2D. Respiratory modulation of muscle sympathetic nerve activity (MSNA) is impaired in T2D, with a blunted reduction of MSNA observed during the high lung volume phase. T2D patients with impaired respiratory MSNA modulation had augmented systolic BP, respiratory‐related BP excursions (Traube–Hering waves) and BP variability. Abnormal respiratory modulation of MSNA and sympathetic transduction to BP in T2D may contribute to altered blood pressure control and cardiovascular risk in this population.

Teixeira A.L., Nardone M., Fernandes I.A., Millar P.J., Vianna L.C.

Microneurographic recordings of muscle sympathetic nerve activity (MSNA) and the succeeding changes in beat-to-beat blood pressure (i.e., sympathetic transduction) provide important insights into the neural control of the circulation in humans. Despite its widespread use, the reliability of this technique remains unknown. Herein, we assessed the intra- and inter-day test-retest reliability of signal-averaging sympathetic transduction to blood pressure. Data were analyzed from 15 (9M/6F) young, healthy participants who completed two baseline recordings of fibular nerve MSNA separated by 60 minutes (intra-day). The inter-day reliability was obtained in a subset of participants ( n=13, 9M/4F) who completed a follow-up MSNA study. Signal-averaging sympathetic transduction was quantified as peak change in diastolic (DBP) and mean arterial pressure (MAP) following a burst of MSNA. Analyses were also computed considering different MSNA burst sizes (quartiles of normalized MSNA), and burst patterns (singlets, couplets, triplets, and quadruplets+), as well as non-burst responses. Intraclass-correlation coefficients (ICC) were used as the main reliability measure. Peak changes in MAP [intra-day: ICC=0.76(0.30-0.92), P=0.006; inter-day: ICC=0.91(0.63-0.97), P<0.001] demonstrated very good to excellent reliability. Sympathetic transduction of MSNA burst size displayed moderate to very good reliability, though the reliability of MSNA burst pattern was poor to very good. Non-burst responses revealed poor intra-day [ICC=0.37(-1.05-0.80), P=0.21], but very good inter-day [ICC=0.76(0.18-0.93), P=0.01] reliability. Intra-day reliability measures were consistently lower than inter-day. Similar results were obtained using DBP. Collectively, these findings provide evidence that the burst-triggering signal-averaging technique is a reliable measure of sympathetic transduction to blood pressure in young, healthy adults.

Gimhani D., Shanks J., Pachen M., Chang J.W., Ramchandra R.

AbstractSympathetic transduction is the study of how impulses of sympathetic nerve activity (SNA) affect end‐organ function. Recently, the transduction of resting bursts of muscle SNA (MSNA) has been investigated and shown to have a role in the maintenance of blood pressure through changes in vascular tone in humans. In the present study, we investigate whether directly recorded resting cardiac SNA (CSNA) regulates heart rate (HR), coronary blood flow (CoBF), coronary vascular conductance (CVC), cardiac output (CO) and mean arterial pressure. Instrumentation was undertaken to record CSNA and relevant vascular variables in conscious sheep. Recordings were performed at baseline, as well as after the infusion of a β‐adrenoceptor blocker (propranolol) to determine the role of β‐adrenergic signalling in sympathetic transduction in the heart. The results show that after every burst of CSNA, there was a significant effect of time on HR (n = 10, ∆: +2.1 ± 1.4 beats min–1, P = 0.002) and CO (n = 8, ∆: +100 ± 150 mL min–1, P = 0.002) was elevated, followed by an increase in CoBF (n = 9, ∆: +0.76 mL min–1, P = 0.001) and CVC (n = 8, ∆: +0.0038 mL min–1 mmHg–1, P = 0.0028). The changes in HR were graded depending on the size and pattern of CSNA bursts. The HR response was significantly attenuated after the infusion of propranolol. Our study is the first to explore resting sympathetic transduction in the heart, suggesting that CSNA can dynamically change HR mediated by an action on β‐adrenoceptors. imageKey points Sympathetic transduction is the study of how impulses of sympathetic nerve activity (SNA) affect end‐organ function. Previous studies have examined sympathetic transduction primarily in the skeletal muscle and shown that bursts of muscle SNA alter blood flow to skeletal muscle and mean arterial pressure, although this has not been examined in the heart. We investigated sympathetic transduction in the heart and show that, in the conscious condition, the size of bursts of SNA to the heart can result in incremental increases in heart rate and coronary blood flow mediated by β‐adrenoceptors. The pattern of bursts of SNA to the heart also resulted in incremental increases in heart rate mediated by β‐adrenoceptors. This is the first study to explore the transduction of bursts of SNA to the heart.

D'Souza A.W., Hissen S.L., Manabe K., Takeda R., Washio T., Coombs G.B., Sanchez B., Fu Q., Shoemaker J.K.

Bursts of muscle sympathetic nerve activity (MSNA) and the ensuing vasoconstriction are pivotal determinants of beat-by-beat blood pressure regulation. Although age and sex impact blood pressure regulation, how these factors affect the central and peripheral arcs of the baroreflex remains unclear. In 27 young (25[3] years) males (YM; n=14) and females (YF; n=13) and 23 older (71[5] years) males (OM; n=11) and females (OF; n=12) femoral artery blood flow, blood pressure and MSNA were recorded for 10 minutes of supine rest. Sympathetic baroreflex sensitivity (i.e., central arc) was quantified as the relationship between diastolic blood pressure and MSNA burst incidence. Signal averaging was used to determine sympathetic vascular transduction into leg vascular conductance (LVC) for 12 cardiac cycles following MSNA bursts (i.e., peripheral arc). Older adults demonstrated attenuated sympathetic transduction into LVC (both P<0.001) following MSNA bursts, and smaller increases in sympathetic transduction as a function of MSNA burst size and firing pattern compared to young adults (range: P=0.004-0.032). YM (r2=0.36; P=0.032) and OM (r2=0.51; P=0.014) exhibited an inverse relationship between the central and peripheral arcs of the baroreflex, whereas females did not (YF: r2=0.03; P=0.621, OF: r2=0.06; P=0.445). MSNA burst incidence was inversely related with sympathetic transduction in YM and OF (range: P=0.03-0.046), but not in YF or OM (range: P=0.360-0.603). These data indicate that age is associated with attenuated sympathetic vascular transduction whereas age- and sex-specific changes are present in the relationship between the central and peripheral arcs of the baroreflex regulation of blood pressure.

O’Brien M.W., Nardone M., Foster M., Coovadia Y., Usselman C.W., Taylor C.E., Millar P.J., Kimmerly D.S.

Nardone M., Notarius C.F., Badrov M.B., Millar P.J., Floras J.S.

Background: Heart failure with reduced ejection fraction (HFrEF) is associated with reduced cardiac β-adrenergic signal transduction in response to chronic elevations in neurally released and circulating norepinephrine. Whether elevations in muscle sympathetic nerve activity (MSNA) are accompanied by attenuated α-adrenoceptor–mediated vasoconstriction remains unclear. Therefore, the objective of the current work was to compare transduction of sympathetic firing into blood pressure (BP) in treated patients with HFrEF and healthy controls. Methods: Twenty-three treated patients with HFrEF (4 females, left ventricular ejection fraction: 28±2%) and 22 healthy controls (6 females) underwent a 7-minute resting measurement of continuous beat-to-beat BP (finger photoplethysmography), heart rate (electrocardiography), and MSNA (microneurography). Sympathetic-BP transduction was quantified using both signal averaging, whereby the BP response to each MSNA burst was serially tracked over 15 cardiac cycles and averaged to derive the peak change in BP, and cross-spectral analysis of low-frequency (0.04–0.15 Hz) MSNA and BP oscillations. Results: Compared with controls, patients with HFrEF had less sympathetic-BP transduction (0.7±0.3 versus 0.2±0.3 mm Hg; P <0.01), and lower low-frequency oscillations in MSNA (120±56 versus 64±32 arbitrary units 2 ; P <0.01) and BP (3.1±1.6 versus 2.0±1.7 mm Hg 2 ; P <0.01). In subgroup analysis, resting sympathetic-BP transduction was lower in patients with HFrEF with normal resting MSNA compared to healthy controls (0.7±0.3 versus 0.4±0.3 mm Hg; P =0.01) and further attenuated (0.1±0.1 mm Hg; P =0.03) in patients with HFrEF with elevated resting MSNA. Conclusions: Treated HFrEF is associated with lower sympathetic-BP transduction, even when MSNA is not elevated, and diminishes further with disease progression. These adaptations may serve to limit the adverse consequences of oscillatory surges in sympathetic vasoconstrictor discharge on stroke volume.

Fisher J.P., Zera T., Paton J.F.

Much of biology is rhythmical and comprises oscillators that can couple. These have optimized energy efficiency and have been preserved during evolution. The respiratory and cardiovascular systems contain numerous oscillators, and importantly, they couple. This coupling is dynamic but essential for an efficient transmission of neural information critical for the precise linking of breathing and oxygen delivery while permitting adaptive responses to changes in state. The respiratory pattern generator and the neural network responsible for sympathetic and cardiovagal (parasympathetic) tone generation interact at many levels ensuring that cardiac output and regional blood flow match oxygen delivery to the lungs and tissues efficiently. The most classic manifestations of these interactions are respiratory sinus arrhythmia and the respiratory modulation of sympathetic nerve activity. These interactions derive from shared somatic and cardiopulmonary afferent inputs, reciprocal interactions between brainstem networks and inputs from supra-pontine regions. Disrupted respiratory-cardiovascular coupling can result in disease, where it may further the pathophysiological sequelae and be a harbinger of poor outcomes. This has been well documented by diminished respiratory sinus arrhythmia and altered respiratory sympathetic coupling in animal models and/or patients with myocardial infarction, heart failure, diabetes mellitus, and neurological disorders as stroke, brain trauma, Parkinson disease, or epilepsy. Future research needs to assess the therapeutic potential for ameliorating respiratory-cardiovascular coupling in disease.

O’Brien M.W., Schwartz B.D., Petterson J.L., Kimmerly D.S.

Spontaneous sympathetic transduction reflects the vascular and/or pressor responses to bursts of muscle sympathetic nerve activity (MSNA). Separately, signal-averaging and regression-based approaches have been implemented to quantify resting sympathetic transduction. It is unknown whether the outcomes of these analytical approaches provide (dis)similar information, which is imperative for between-study comparisons and the amalgamation of results for synthesis of multiple studies (i.e., meta-analyses). We explored the diastolic blood pressure (DBP) responses to spontaneous bursts of MSNA between these two methods of analysis. Resting beat-by-beat DBP (via finger photoplethysmography) and common peroneal nerve MSNA (via microneurography) were recorded in 52 healthy, normotensive adults (age 38 ± 20 years; 19 females). For the signal-averaged method, transduction was quantified as the mean peak increase in DBP (ΔDBP) during the 12 cardiac cycles following each MSNA burst. In addition, DBP was regressed to a moving two-cardiac-cycle window of normalized relative burst height (mmHg/relative %) to provide the regression-based transduction outcome. The signal-averaged (1.2 ± 0.7 mmHg) and regression-based approaches (0.009 ± 0.016 mmHg/%) were unrelated (ρ = 0.03, p = 0.86). Adding to the discrepancy, only the signal-averaging approach demonstrated a lower transduction in middle-aged-older males versus younger males. The decision of which method to use when calculating sympathetic transduction influences study outcomes, with the two most common methods of determining transduction being unrelated. There are challenges of making sweeping conclusions across studies if different analysis strategies are implemented. An understanding of when to use each method is needed to adopt a harmonized approach to quantifying sympathetic transduction.

Nardone M., Katerberg C., Teixeira A.L., Lee J.B., Bommarito J.C., Millar P.J.

Sympathetic transduction of blood pressure (BP) is correlated negatively with resting muscle sympathetic nerve activity (MSNA) in cross-sectional data, but the acute effects of increasing MSNA are unclear. Sixteen (4 female) healthy adults (26 ± 3 years) underwent continuous measurement of heart rate, BP, and MSNA at rest and during graded lower body negative pressure (LBNP) at −10, −20, and −30 mmHg. Sympathetic transduction of BP was quantified in the time (signal averaging) and frequency (MSNA-BP gain) domains. The proportions of MSNA bursts firing within each tertile of BP were calculated. As expected, LBNP increased MSNA burst frequency ( P < 0.01) and burst amplitude ( P < 0.02), although the proportions of MSNA bursts firing across each BP tertile remained stable (all P > 0.44). The MSNA-diastolic BP low-frequency transfer function gain ( P = 0.25) was unchanged during LBNP; the spectral coherence was increased ( P = 0.03). Signal-averaged sympathetic transduction of diastolic BP was unchanged (from 2.1 ± 1.0 at rest to 2.4 ± 1.5, 2.2 ± 1.3, and 2.3 ± 1.4 mmHg; P = 0.43) during LBNP, but diastolic BP responses following nonburst cardiac cycles progressively decreased (from −0.8 ± 0.4 at rest to −1.0 ± 0.6, −1.2 ± 0.6, and −1.6 ± 0.9 mmHg; P < 0.01). As a result, the difference between MSNA burst and nonburst diastolic BP responses was increased (from 2.9 ± 1.4 at rest to 3.4 ± 1.9, 3.4 ± 1.9, and 3.9 ± 2.1 mmHg; P < 0.01). In conclusion, acute increases in MSNA using LBNP did not alter traditional signal-averaged or frequency-domain measures of sympathetic transduction of BP or the proportion of MSNA bursts firing at different BP levels. The factors that determine changes in the firing of MSNA bursts relative to oscillations in BP require further investigation.

Nardone M., Katerberg C., Incognito A.V., Teixeira A.L., Vianna L.C., Millar P.J.

The current signal-averaging technique for calculating sympathetic transduction of blood pressure does not consider the arterial pressure at which each muscle sympathetic burst occurs. A burst firing when mean arterial pressure is above the operating pressure was associated with a decrease in blood pressure. Thus, individuals with higher muscle sympathetic nerve activity demonstrate a reduced sympathetic transduction owing to the weighted contribution of more sympathetic bursts at higher levels of arterial pressure.