Nitric oxide-dependent modulation of sympathetic neural control of oxygenation in exercising human skeletal muscle

Abstract

Nitric oxide (NO) attenuates alpha-adrenergic vasoconstriction in contracting rodent skeletal muscle, but it is unclear if NO plays a similar role in human muscle. We therefore hypothesized that in humans, NO produced in exercising skeletal muscle blunts the vasoconstrictor response to sympathetic activation. We assessed vasoconstrictor responses in the microcirculation of human forearm muscle using near-infrared spectroscopy to measure decreases in muscle oxygenation during reflex sympathetic activation evoked by lower body negative pressure (LBNP). Experiments were performed before and after NO synthase inhibition produced by systemic infusion of N(G)-nitro-L-arginine methyl ester (L-NAME). Before L-NAME, LBNP at -20 mmHg decreased muscle oxygenation by 20 +/- 2 % in resting forearm and by 2 +/- 3 % in exercising forearm (n = 20), demonstrating metabolic modulation of sympathetic vasoconstriction. As expected, L-NAME increased mean arterial pressure by 17 +/- 3 mmHg, leading to baroreflex-mediated suppression of baseline muscle sympathetic nerve activity (SNA). The increment in muscle SNA in response to LBNP at -20 mmHg also was attenuated after L-NAME (before, +14 +/- 2; after, +8 +/- 1 bursts min(-1); n = 6), but this effect of L-NAME was counteracted by increasing LBNP to -40 mmHg (+19 +/- 2 bursts min(-1)). After L-NAME, LBNP at -20 mmHg decreased muscle oxygenation similarly in resting (-11 +/- 3 %) and exercising (-10 +/- 2 %) forearm (n = 12). Likewise, LBNP at -40 mmHg decreased muscle oxygenation both in resting (-19 +/- 4 %) and exercising (-21 +/- 5 %) forearm (n = 8). These data advance the hypothesis that NO plays an important role in modulating sympathetic vasoconstriction in the microcirculation of exercising muscle, because such modulation is abrogated by NO synthase inhibition with L-NAME.

Figures

Figure 1. Effect of NOS inhibition on the relationship between sympathetically mediated decreases in blood flow and muscle oxygenation in resting hindlimb of anaesthetized rats

A, segments of an original record showing the arterial blood pressure (BP), femoral blood flow and gastrocnemius muscle oxygenation (HbO2 + MbO2) responses to sympathetic nerve stimulation (SNS) before and after l-NAME. Terminal aortic occlusion (Occl.) was used to determine the total labile signal (TLS). OD, optical density. B, summary data (n = 5) showing that sympathetically mediated decreases in hindlimb blood flow and muscle oxygenation are described by a linear relationship that is not significantly altered by l-NAME.

Figure 2. Effect of NOS inhibition on the muscle sympathetic nerve activity (SNA) and forearm vascular conductance responses to lower body negative pressure (LBNP) in humans

Before l-NAME, LBNP at −20 mmHg produced robust increases in muscle SNA and decreases in forearm vascular conductance. After l-NAME, the responses to this same level of LBNP were attenuated significantly, probably because of baroreflex-mediated suppression of baseline muscle SNA. However, responses were fully restored when LBNP was increased to −40 mmHg. Muscle SNA, n = 6; forearm vascular conductance, n = 4.

Figure 3. Effect of NOS inhibition on muscle oxygenation responses to reflex sympathetic activation in resting and exercising forearm

A, before l-NAME, the decrease in muscle oxygenation (HbO2 + MbO2) in resting forearm elicited by lower body negative pressure (LBNP) at −20 mmHg was greatly attenuated during rhythmic handgrip at 20 % of maximal voluntary contraction. B, in this same subject after l-NAME, LBNP at −40 mmHg elicited similar decreases in muscle oxygenation in resting and exercising forearm. Shaded areas, provided to aid visual comparison, indicate the total decreases in muscle oxygenation in response to LBNP beginning with the onset of the stimulus and ending with the return of muscle oxygenation to its pre-LBNP baseline. OD, optical density; TLS, total labile signal.

Figure 4. Effect of NOS inhibition on sympathetically mediated decreases in muscle oxygenation in resting and exercising forearm

Before l-NAME (open bars), the decreases in muscle oxygenation (HbO2 + MbO2) evoked by lower body negative pressure (LBNP) at −20 mmHg in resting forearm were attenuated during handgrip (HG) exercise (n = 20). After l-NAME (filled bars), LBNP at −20 mmHg (n = 12) or −40 mmHg (n = 8) evoked decreases in oxygenation that were similar in resting and exercising forearm. TLS, total labile signal.