Central α2-adrenergic mechanisms regulate human sympathetic neuronal discharge strategies

Abstract

The present study investigated the impact of central α₂-adrenergic mechanisms on sympathetic action potential (AP) discharge, recruitment and latency strategies. We used the microneurographic technique to record muscle sympathetic nerve activity and a continuous wavelet transform to investigate postganglionic sympathetic AP firing during a baseline condition and an infusion of a α₂-adrenergic receptor agonist, dexmedetomidine (10 min loading infusion of 0.225 µg kg^-1; maintenance infusion of 0.1-0.5 µg kg h^-1) in eight healthy individuals (28 ± 7 years, five females). Dexmedetomidine reduced mean pressure (92 ± 7 to 80 ± 8 mmHg, P < 0.001) but did not alter heart rate (61 ± 13 to 60 ± 14 bpm; P = 0.748). Dexmedetomidine reduced sympathetic AP discharge (126 ± 73 to 27 ± 24 AP 100 beats^-1, P = 0.003) most strongly for medium-sized APs (normalized cluster 2: 21 ± 10 to 5 ± 5 AP 100 beats^-1; P < 0.001). Dexmedetomidine progressively de-recruited sympathetic APs beginning with the largest AP clusters (12 ± 3 to 7 ± 2 clusters, P = 0.002). Despite de-recruiting large AP clusters with shorter latencies, dexmedetomidine reduced AP latency across remaining clusters (1.18 ± 0.12 to 1.13 ± 0.13 s, P = 0.002). A subset of six participants performed a Valsalva manoeuvre (20 s, 40 mmHg) during baseline and the dexmedetomidine infusion. Compared to baseline, AP discharge (Δ 361 ± 292 to Δ 113 ± 155 AP 100 beats^-1, P = 0.011) and AP cluster recruitment elicited by the Valsalva manoeuvre were lower during dexmedetomidine (Δ 2 ± 1 to Δ 0 ± 2 AP clusters, P = 0.041). The reduction in sympathetic AP latency elicited by the Valsalva manoeuvre was not affected by dexmedetomidine (Δ -0.09 ± 0.07 to Δ -0.07 ± 0.14 s, P = 0.606). Dexmedetomidine reduced baroreflex gain, most strongly for medium-sized APs (normalized cluster 2: -6.0 ± 5 to -1.6 ± 2 % mmHg^-1; P = 0.008). These data suggest that α₂-adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans. KEY POINTS: Sympathetic postganglionic neuronal subpopulations innervating the human circulation exhibit complex patterns of discharge, recruitment and latency. However, the central neural mechanisms governing sympathetic postganglionic discharge remain unclear. This microneurographic study investigated the impact of a dexmedetomidine infusion (α₂-adrenergic receptor agonist) on muscle sympathetic postganglionic action potential (AP) discharge, recruitment and latency patterns. Dexmedetomidine infusion inhibited the recruitment of large and fast conducting sympathetic APs and attenuated the discharge of medium sized sympathetic APs that fired during resting conditions and the Valsalva manoeuvre. Dexmedetomidine infusion elicited shorter sympathetic AP latencies during resting conditions but did not affect the reductions in latency that occurred during the Valsalva manoeuvre. These data suggest that α₂-adrenergic mechanisms within the central nervous system modulate sympathetic postganglionic neuronal discharge, recruitment and latency strategies in humans.

Keywords: action potential; dexmedetomidine; human; microneurography; muscle sympathetic nerve activity; valsalva manoeuvre; α2‐adrenergic receptors.

Figure 1.. Individual data illustrating the sympathoinhibitory effect of dexmedetomidine infusion on sympathetic neural discharge.

Data from a single participant illustrating ECG, blood pressure (BP), integrated muscle sympathetic nerve activity (MSNA), and filtered MSNA during baseline, the last two-minutes of the dexmedetomidine loading dose, and the last two-minute period of the dexmedetomidine maintenance dose. MSNA neurograms were temporally shifted to correct for the conduction delay. Notice the reduction in sympathetic action potential (AP) discharge and AP amplitude with dexmedetomidine infusion.

Figure 2.. The impact of dexmedetomidine on hemodynamic and integrated muscle sympathetic nerve activity (MSNA) indices.

The left panels illustrate data for 5 minutes of baseline (BSL), the 10-minute dexmedetomidine loading dose delineated into 2-minute periods, and two 2-minute periods of the dexmedetomidine maintenance dose. Heart rate (HR; A), mean arterial pressure (MAP; B), integrated MSNA burst frequency (C), burst incidence (D), burst amplitude (E), and total MSNA (F) are presented. The right panels illustrate BSL versus the last 2-minute period of the dexmedetomidine infusion (Dex Last). Symbols and error lines represent mean and standard deviation. The black lines represent trend lines and the grey lines represent individual data. Cohen’s d effect sizes are presented. Paired t-tests compared BSL to Dex Last. Data are presented for n = 8 participants. Two participants had strong sympathoinhibitory responses to dexmedetomidine and data are only reported until the last period with detectable integrated MSNA bursts. AU, arbitrary units.

Figure 3.. The impact of dexmedetomidine on sympathetic action potential (AP) discharge.

The left panels illustrate data for the 5-minute baseline condition (BSL), the 10-minute dexmedetomidine loading dose delineated into 2-minute periods, and two 2-minute periods of the dexmedetomidine maintenance dose. AP frequency (A), AP incidence (B), APs per burst (C), AP clusters per burst (D), and total AP clusters (E) are presented. The right panels illustrate 5 minutes of BSL data versus the last 2-minute period of the dexmedetomidine infusion (Dex Last). Symbols and error lines represent mean and standard deviation. The black lines represent trend lines and the grey lines represent individual data. Cohen’s d effect sizes are presented. Paired t-tests compared BSL to Dex Last. Data are presented for n = 8 participants. Two participants had strong sympathoinhibitory responses to dexmedetomidine and data are only reported until the last period with detectable integrated MSNA bursts.

Figure 4.. Individual data illustrating inhibition of sympathetic action potential (AP) discharge and sympathetic AP cluster de-recruitment throughout the dexmedetomidine infusion.

AP cluster firing over time is presented for baseline, the dexmedetomidine loading dose, and the dexmedetomidine maintenance dose. AP clusters represent APs of similar morphology and are arranged vertically based on mean AP cluster amplitude from smallest (AP cluster 1) to largest (AP cluster 11). Individual vertical spikes represent AP cluster firing over time. AP clusters were normalized across condition so that each AP cluster could be tracked over time (i.e., cluster 1 represents APs with the same morphology in all three conditions). Notice the progressive reduction in AP cluster discharge with dexmedetomidine infusion, most notable for clusters 3 to 6. Also, notice the progressive de-recruitment of AP clusters 8 to 11 which fired during baseline but were not active during the dexmedetomidine maintenance dose.

Figure 5.. Sympathoinhibition of sympathetic action potential (AP) cluster discharge by dexmedetomidine.

Sympathetic AP incidence for five normalized clusters during baseline (BSL), and the last two-minute period during the dexmedetomidine infusion (Dex Last). Symbols and error lines represent mean and standard deviation for each condition. Grey lines represent individual data. A mixed-effects model investigated the impact of dexmedetomidine and normalized AP cluster on AP incidence. Paired t-tests were performed to investigate the significant Condition by Cluster Interaction. Data are presented for n = 8 participants.

Figure 6.. The impact of dexmedetomidine on sympathetic action potential (AP) latency.

Panel A (left) illustrates data for 5 minutes of baseline (BSL), the 10-minute dexmedetomidine loading dose delineated into 2-minute periods, and two 2-minute periods of the dexmedetomidine maintenance dose. Panel A (right) illustrates BSL versus the last 2-minute period of the dexmedetomidine infusion (Dex Last). Symbols and error lines represent mean and standard deviation. The black line represents a trend line and the grey lines represent individual data. Cohen’s d effect sizes are presented. Paired t-tests compared BSL to Dex Last. *, denotes P < 0.05 versus BSL. Data are presented for n = 8 participants. Panel B illustrates the relationship (Pearson correlation) between AP latency and normalized AP cluster for baseline (r = −0.99, P < 0.001) and the last two-minute period analyzed during the dexmedetomidine infusion (r = −0.52, P = 0.365; Last). Symbols and error lines represent mean and standard deviation. Data are presented for n = 8 participants.

Figure 7.. Individual data illustrating the sympathoinhibitory effect of dexmedetomidine during Valsalva Manoeuvre.

Data from a single participant illustrating ECG, blood pressure (BP), integrated muscle sympathetic nerve activity (MSNA), and filtered MSNA during Valsalva Manoeuvre at baseline and the dexmedetomidine maintenance dose. MSNA neurograms were temporally shifted to correct for the conduction delay. Notice the reduction in sympathetic discharge with dexmedetomidine infusion. *, represents technical artifact.

Figure 8.. The impact of dexmedetomidine on integrated muscle sympathetic nerve activity (MSNA) responses to Valsalva Manoeuvre.

The change (Δ) in burst frequency (A), burst incidence (B), burst amplitude (C), and total MSNA (D) with Valsalva Manoeuvre during the baseline (BSL) condition and the dexmedetomidine maintenance dose (DEX) is illustrated. Symbols and error lines represent mean and standard deviation. Paired t-tests compared baseline and dexmedetomidine conditions. Grey lines represent individual data. Cohen’s d effect sizes are presented. Data are presented for n = 6 participants.

Figure 9.. Individual data illustrating dexmedetomidine-mediated inhibition of sympathetic action potential (AP) cluster discharge and recruitment imposed by Valsalva Manoeuvre.

AP cluster firing over time is presented for the Pre-Valsalva and Valsalva periods during baseline and the dexmedetomidine maintenance dose. AP clusters represent APs of similar morphology and are arranged vertically based on mean AP cluster amplitude from smallest (AP cluster 1) to largest (AP cluster 7). Individual vertical spikes represent AP cluster firing over time. AP clusters were normalized across condition so that each AP cluster could be tracked over time (i.e., cluster 1 represents APs with the same morphology in all four panels). Notice that during the baseline condition, AP clusters 5-7 did not fire during the Pre-Valsalva period but were recruited by Valsalva Manoeuvre and an increase in AP discharge occurred. Also, notice that during the dexmedetomidine condition no additional larger AP clusters were recruited by Valsalva Manoeuvre and no increase in AP discharge occurred.

Figure 10.. Sympathoinhibitory effect of dexmedetomidine on sympathetic action potential (AP) responses to Valsalva Manoeuvre.

The change (Δ) in AP frequency (A), AP incidence (B), AP per burst (C), AP clusters per burst (D), total AP clusters (E), and AP latency (F) with Valsalva Manoeuvre during the baseline condition (BSL) and the dexmedetomidine maintenance dose (DEX) is illustrated. Symbols and error lines represent mean and standard deviation. Grey lines represent individual data. Paired t-tests compared baseline and dexmedetomidine conditions. Cohen’s d effect sizes are presented. Data are presented for n = 6 participants.

Figure 11.. The impact of dexmedetomidine on sympathetic action potential (AP) cluster discharge responses to Valsalva Manoeuvre.

The change (Δ) in sympathetic AP cluster incidence across five normalized clusters elicited by Valsalva Manoeuvre during baseline (BSL) and the dexmedetomidine maintenance dose (DEX) is illustrated. Symbols and error lines represent mean and standard deviation. Grey lines represent individual data. A mixed-effects model investigated the impact of dexmedetomidine and normalized AP cluster on AP incidence. Paired t-tests were performed to investigate the significant Condition by Cluster Interaction. Data are presented for n = 6 participants.

Figure 12.. Inhibition of sympathetic action potential (AP) cluster baroreflex gain by dexmedetomidine.

Baroreflex gain across five normalized clusters during baseline (BSL) and the dexmedetomidine maintenance dose (DEX) is illustrated. Symbols and error lines represent mean and standard deviation. Grey lines represent individual data. A mixed-effects model investigated the impact of dexmedetomidine and normalized AP cluster on AP baroreflex gain. Paired t-tests were performed to investigate the significant Condition by Cluster Interaction. Data are presented for n = 6 participants.