Rise In Muscle Sympathetic Nerve Activity Research Articles

Endothelin-1 receptor blockade does not alter the sympathetic and hemodynamic response to acute intermittent hypoxia in men.

Repeat exposures to low oxygen (intermittent hypoxia, IH), like that observed in sleep apnea, elicit increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in men. Endothelin (ET) receptor antagonists can attenuate the sympathetic and BP response to IH in rodents; whether these data translate to humans are unclear. We hypothesized that ET-receptor antagonism would ameliorate any rise in MSNA and BP following acute IH in humans. Twelve healthy men (31 ± 1 yr) completed two visits (control, bosentan) separated by at least 1 wk. MSNA, BP, and baroreflex sensitivity (modified Oxford) were assessed during normoxic rest before and following 30 min of IH. The midpoint (T50) for each individual's baroreflex curve was calculated. Acute IH increased plasma ET-1 (P < 0.01), MSNA burst frequency (P = 0.03), and mean BP (P < 0.01). There was no effect of IH on baroreflex sensitivity (P = 0.46), although an increase in T50 was observed (P < 0.01). MSNA burst frequency was higher (P = 0.04) and mean BP (P < 0.01) was lower following bosentan treatment compared with control. There was no effect of bosentan on baroreflex sensitivity (P = 0.53), although a lower T50 was observed on the bosentan visit (P < 0.01). There was no effect of bosentan on increases in MSNA (P = 0.81) or mean BP (P = 0.12) following acute IH. Acute IH results in an increase in ET-1, MSNA, and BP in healthy young men. The effect of IH on MSNA and BP is not attenuated following ET-receptor inhibition. Present data suggest that acute IH does not increase MSNA or BP through activation of ET-receptors in healthy young men.NEW & NOTEWORTHY Repeat exposures to low oxygen (intermittent hypoxia, IH) elicit increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in men. Endothelin (ET) receptor antagonists can attenuate the sympathetic and BP response to IH in rodents; whether these data translate to humans were unclear. We show acute IH results in an increase in ET-1, MSNA, and BP in healthy young men; however, the effect of IH on MSNA and BP does not occur through activation of ET-receptors in healthy young men.

Prenatal Exercise and Cardiovascular Health (PEACH) Study: Impact on Muscle Sympathetic Nerve (Re)Activity.

Women who develop gestational hypertension have evidence of elevated muscle sympathetic nerve activity (MSNA) in early pregnancy, which continues to rise after diagnosis. Exercise has been shown to play a preventative role in the development of gestational hypertension and has been shown to reduce resting and reflex MSNA in nonpregnant populations. We sought to investigate whether aerobic exercise affected the sympathetic regulation of blood pressure between the second and third trimesters of pregnancy. We conducted a randomized controlled trial of structured aerobic exercise (n = 31) compared with no intervention (control, n = 28) beginning at 16-20 wk and continuing until 34-36 wk of gestation (NCT02948439). Women in the exercise group were prescribed aerobic activity at 50%-70% of their heart rate reserve, on 3-4 d·wk-1 for 25-40 min with a 5-min warm-up and 5-min cool-down (i.e., up to 160 min total activity per week). At preintervention and postintervention assessments, data from ~10 min of quiet rest and a 3-min cold pressor test were analyzed to determine sympathetic nervous system activity and reactivity. MSNA was obtained in 51% of assessments. Resting MSNA burst frequency and burst incidence increased across gestation (main effect of gestational age, P = 0.002). Neurovascular transduction was blunted in the control group (P = 0.024) but not in exercisers (P = 0.873) at the postintervention time point. Lastly, MSNA reactivity during the cold pressor test was not affected by gestational age or exercise (P = 0.790, interaction). These data show that exercise attenuates both the rise in MSNA and the blunting of neurovascular transduction. This may partially explain the lower risk of developing gestational hypertension in women who are active during their pregnancies.

Endothelin contributes to the blood pressure rise triggered by hypoxia in severe obstructive sleep apnea.

Obstructive sleep apnea (OSA) is strongly correlated with an increased risk of systemic hypertension. However, the link between systemic hypertension and nocturnal apneas remains incompletely understood. Animal studies suggest an implication of the endothelin system. The aim of the present study is to determine if endogenous endothelin plays a role in the increase in blood pressure observed during hypoxic episodes in OSA patients, in addition to peripheral chemoreflex and neural sympathetic activation. We assessed the effects of the nonspecific endothelin antagonist bosentan (500 mg; Tracleer; Actelion; Basel, Switzerland) on ventilation, hemodynamics, and muscle sympathetic nerve activity (MSNA) during normoxia and isocapnic hypoxia using a randomized, crossover, double-blinded, placebo-controlled study design, and in 13 severely untreated sleep apneic patients (age 50 ± 9 years, apnea-hypopnea index 35 ± 21/h). Hypoxia increased blood pressure, MSNA, and minute ventilation as oxygen saturation decreased. Bosentan suppressed completely the increase in SBP during a 5-min hypoxic challenge (143 ± 5 mmHg during hypoxia vs. 133 ± 5 mmHg during normoxia with placebo and 127 ± 3 mmHg during hypoxia vs. 125 ± 3 mmHg during normoxia under bosentan, P = 0.023). DBP as well as the rise in MSNA and ventilation during isocapnic hypoxia did not differ between bosentan and placebo. Endothelin contributes to the rise in SBP in response to acute hypoxia in patients with severely untreated OSA. This was not due to lower chemoreflex activation with bosentan.

Sympathetic Vasoconstriction is Attenuated in Young Women During Hypoxia and Cold Pressor Test

Recent studies suggest that muscle sympathetic nerve activity (MSNA) at rest is correlated to vascular resistance in young men but not in young women. We hypothesized that increases in MSNA during acute physiological stressors induce less vasoconstriction in young women compared to young men. Nineteen healthy humans participated in this study (5 young women, 5 young men, 5 older men, 4 older women). Subjects underwent poikilocapnic hypoxia (5 min, 10% O2, 90% N2) and the cold pressor test (hand in ice water at 0° C for 2 min). MSNA, femoral blood velocity, heart rate, and blood pressure were acquired continuously. Femoral artery diameter was obtained every minute and used to calculate femoral blood flow (FBF) and vascular resistance (FVR). In response to hypoxia, young women had a similar increase in MSNA compared to young men (Δ 6 ± 1 vs. Δ 7 ± 2, bursts/min, P = 0.632) but an exaggerated increase in FBF (Δ 67 ± 10 vs. Δ 32 ± 14 mL/min, P = 0.031) and a greater reduction in FVR (45 ± 4% vs. 24 ± 9%, P = 0.050). In response to cold pressor test, young women had an attenuated rise in MSNA (Δ 5 ± 1 vs. Δ 26 ± 3, bursts/min, P = 0.008) and a smaller increase in FVR (8 ± 17% vs. 173 ± 48%, P = 0.037) compared to young men. Physiological responses to hypoxia and cold pressor test were comparable between older men and women (P &gt; 0.1). These data suggest that young women have decreased sympathetic vasoconstrictor drive during physiological stress, which may explain decreased cardiovascular risk.Support or Funding InformationUL1 TR000127, KL2 TR000126, P01 HL096570, 15PRE24470033

Effect of contraction intensity on sympathetic nerve activity to active human skeletal muscle.

The effect of contraction intensity on muscle sympathetic nerve activity (MSNA) to active human limbs has not been established. To address this, MSNA was recorded from the left peroneal nerve during and after dorsiflexion contractions sustained for 2 min by the left leg at ~10, 25, and 40% MVC. To explore the involvement of the muscle metaboreflex, limb ischemia was imposed midway during three additional contractions and maintained during recovery. Compared with total MSNA at rest (11.5 ± 4.1 mv.min−1), MSNA in the active leg increased significantly at the low (21.9 ± 13.6 mv.min−1), medium (30.5 ± 20.8 mv.min−1), and high (50.0 ± 24.5 mv.min−1) intensities. This intensity-dependent effect was more strongly associated with increases in MSNA burst amplitude than burst frequency. Total MSNA then returned to resting levels within the first minute of recovery. Limb ischemia had no significant influence on the intensity-dependent rise in MSNA or its decline during recovery in the active leg. These findings reveal intensity-dependent increases in total MSNA and burst amplitude to contracting human skeletal muscle that do not appear to involve the muscle metaboreflex.

Is insulin the new intermittent hypoxia?

The sympathoexcitatory effects of insulin are well-established, although the exact mechanisms by which insulin stimulates the sympathetic nervous system are not completely understood. The majority of research supports a primary role for the central nervous system in the gradual and sustained rise in muscle sympathetic nerve activity (MSNA) in response to hyperinsulinemia; in addition, recent studies in animals suggests carotid body chemoreceptors respond to increases in systemic insulin levels. Intermittent activation of the carotid chemoreceptors, similar to that seen in patients with sleep apnea, can result in sensory long term facilitation and may contribute to the observed rise in baseline MSNA in this population. Consistent with this idea, insulin exposure results in sustained increases in MSNA that persist even when plasma insulin levels return to baseline. We propose the carotid chemoreceptors contribute to insulin-mediated sympathoexcitation and the persistent rise in MSNA in patients with sustained hyperinsulinemia. If the carotid chemoreceptors sense and respond to changes in systemic insulin levels, these organs may provide a viable target for the treatment of disorders known to exhibit sustained hyperinsulinemia and sympathoexcitation including, but not limited to, obesity, hypertension, sleep apnea, metabolic syndrome, cardiovascular disease, and diabetes.

Sympathetic and cardiovascular responses to glossopharyngeal insufflation in trained apnea divers

Glossopharyngeal insufflation (lung packing) is a common maneuver among experienced apnea divers by which additional air is pumped into the lungs. It has been shown that packing may compromise cardiovascular homeostasis. We tested the hypothesis that the packing-mediated increase in intrathoracic pressure enhances the baroreflex-mediated increase in muscle sympathetic nerve activity (MSNA) in response to an exaggerated drop in cardiac output (CO). We compared changes in hemodynamics and MSNA (peroneal microneurography) during maximal breath-holds without and with prior moderate packing (0.79 ± 0.40 liters) in 14 trained divers (12 men, 2 women, 26.7 ± 4.5 yr, body mass index 24.8 ± 2.4 kg/m(2)). Packing did not change apnea time (3.8 ± 1.0 vs. 3.8 ± 1.2 min), hemoglobin oxygen desaturation (-17.6 ± 12.3 vs. -18.7 ± 12.8%), or the reduction in CO (1 min: -3.65 ± 1.83 vs. -3.39 ± 1.96 l/min; end of apnea: -2.44 ± 1.33 vs. -2.16 ± 1.44 l/min). On the other hand, packing dampened the early, i.e., 1-min increase in mean arterial pressure (MAP, 1 min: 9.2 ± 8.3 vs. 2.4 ± 11.0 mmHg, P < 0.01) and in total peripheral resistance (relative TPR, 1 min: 2.1 ± 0.5 vs. 1.9 ± 0.5, P < 0.05) but it augmented the concomitant rise in MSNA (1 min: 28.0 ± 11.7 vs. 39.4 ± 12.7 bursts/min, P < 0.001; 32.8 ± 16.4 vs. 43.9 ± 14.8 bursts/100 heart beats, P < 0.01; 3.3 ± 2.1 vs. 4.8 ± 3.2 au/min, P < 0.05). We conclude that the early sympathoactivation 1 min into apnea after moderate packing is due to mechanisms other than excessive reduction in CO. We speculate that lower MAP despite increased MSNA after packing might be explained by vasodilator substances released by the lungs. This idea should be addressed in future studies.

Myogenic activity in autoregulation during low frequency oscillations

Lower body negative pressure (LBNP) was applied in eight human subjects to trigger low frequency oscillations in order to study the nature of functional coupling between the hemodynamic and autonomic nervous systems, with particular focus on how the myogenic response fits within this coupling. To this end muscle sympathetic nerve activity (MSNA), mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), and total peripheral resistance (TPR) were measured at baseline and during LBNP and were then examined in both the time and frequency domains. At the height of low frequency oscillations (~ 0.1 Hz) there was a strong coupling between all the five indices, marked by perfect alignment of their oscillatory frequencies. Results in the time domain show that a fall in MAP is followed by a fall in TPR at 1.58 s SD 0.69), a rise in heart rate at 2.64 s (SD 0.98), a rise in cardiac output at 3.72 s (SD 0.60), a peak in MSNA at 5.71 s (SD 1.27) and, finally, a rise in TPR at 7.13 s (SD 1.02). A possible interpretation of the latter is that a drop in MAP first triggers a drop in TPR via a myogenic response before the expected rise in TPR via a rise in MSNA. In other words, following a drop in arterial pressure, myogenic response controls vessel diameter before this control is taken over by MSNA. These findings provide a possible resolution of a longstanding conceptual argument against attributing a significant role for the myogenic response in blood flow autoregulation.

Strong potential for baroreflex-governed sympathetic outflow revealed during nausea

Muscle sympathetic nerve activity (MSNA) was recorded in two patients with amyotrophic lateral sclerosis. As expected, they exhibited a high level of MSNA at rest, with an inverse weak response to different maneuvers normally eliciting strong increase in MSNA. About 30min after the intake of a glucose solution, they developed nausea with an extreme rise in MSNA and blood pressure. In one patient, a quantified analysis of this reaction could be done: the outflow was close to 200% above the already high resting level and >100% stronger than the response to any of the performed maneuvers. We regard this observation of importance, because it seems to unveil resources utilized only rarely, and strongly overcoming the "ceiling effect" that seemingly is a hindrance for sympathetic activation in subjects with high lever of MSNA at rest. An inhibitory "safety limit" might exist, the trespassing of which would damage the organism and thus occurs only during extraordinary circumstances.

Influence of endurance training on central sympathetic outflow to skeletal muscle in response to a mixed meal

Nutrient intake is accompanied by increases in central sympathetic outflow, a response that has been mainly attributed to insulin. Insulin-mediated sympathoexcitation appears to be blunted in insulin-resistant conditions, suggesting that aside from peripheral insulin insensitivity, such conditions may also impair the central action of insulin in mediating sympathetic activation. What remains unclear is whether an insulin-sensitive state, such as that induced by chronic endurance training, alters the central sympathetic effects of insulin during postprandial conditions. To examine this question plasma insulin and glucose, muscle sympathetic nerve activity (MSNA), heart rate, and arterial blood pressure were measured in 11 high-fit [HF; peak oxygen uptake (V(O(2peak))) 65.9 +/- 1.4 ml x kg(-1) x min(-1)] and 9 average-fit (AF; V(O(2peak)) 43.6 +/- 1.3 ml x kg(-1) x min(-1)) male subjects before and for 120 min after ingestion of a mixed meal drink. As expected, the insulin response to meal ingestion was lower in HF than AF participants (insulin area under the curve(0-120): 2,314 +/- 171 vs. 4,028 +/- 460 microIU x ml(-1) x 120(-1), HF vs. AF, P < 0.05), with similar plasma glucose responses between groups. Importantly, following consumption of the meal, the HF subjects demonstrated a greater rise in MSNA compared with the AF subjects (e.g., 120 min: Delta21 +/- 1 vs. 8 +/- 3 bursts/100 heart beats, HF vs. AF, P < 0.05). Furthermore, when expressed relative to plasma insulin, HF subjects exhibited a greater change in MSNA for any given change in insulin. Arterial blood pressure responses following meal intake were similar between groups. Collectively, these data suggest that, in addition to improved peripheral insulin sensitivity, endurance training may enhance the central sympathetic effect of insulin to increase MSNA following consumption of a mixed meal.

Dipyridamole increases interstitial adenosine during intermittent isometric exercise but does not augment the pressor reflex

Interstitial adenosine is increased during intermittent isometric exercise (handgrip) and may be an afferent signal for the pressor reflex. The effect of the nucleoside transport inhibitor dipyridamole on interstitial adenosine concentration has never been studied in humans. The aim of the study was to determine whether dipyridamole increases interstitial adenosine during handgrip and potentiates the exercise-induced pressor reflex. In nine healthy volunteers, isometric hand-contractions (50% of maximal force) were performed with and without dipyridamole (12 mg 100 ml−1 min−1, infused into the brachial artery). Interstitial adenosine was measured in the flexor digitorum superficialis muscle using microdialysis with h.p.l.c. detection. Blood pressure was measured at 2 min intervals (Dinamap). Peroneal nerve muscle sympathetic nerve activity (MSNA) was successfully recorded in four volunteers. Intermittent handgrip increased dialysate adenosine by 0.3 ± 0.1 and 0.5 ± 0.1 nmol ml−1 in the absence and presence of dipyridamole respectively (mean ± s.e. mean; P < 0.05 for effect of dipyridamole). Dipyridamole did not augment the handgrip-induced rise in MSNA in any of the volunteers. Handgrip increased blood pressure (SBP/DBP) by 9.6 ± 2.4/4.5 ± 2.0 and 10.4 ± 2.2/7.0 ± 1.3 mmHg in the absence and presence of dipyridamole respectively (P = NS for dipyridamole effect). In none of the volunteers, dipyridamole augmented the exercise-induced rise in MSNA. Dipyridamole increases interstitial adenosine during handgrip but does not potentiate the pressor reflex. Our data do not support a role for adenosine as a trigger of the exercise-induced pressor reflex in healthy volunteers.

Hypoxia augments apnea-induced peripheral vasoconstriction in humans.

Obstructive apnea and voluntary breath holding are associated with transient increases in muscle sympathetic nerve activity (MSNA) and arterial pressure. The contribution of changes in blood flow relative to the contribution of changes in vascular resistance to the apnea-induced transient rise in arterial pressure is unclear. We measured heart rate, mean arterial blood pressure (MAP), MSNA (peroneal microneurography), and femoral artery blood velocity (V(FA), Doppler) in humans during voluntary end-expiratory apnea while they were exposed to room air, hypoxia (10.5% inspiratory fraction of O2), and hyperoxia (100% inspiratory fraction of O2). Changes from baseline of leg blood flow (Q) and vascular resistance (R) were estimated from the following relationships: Q proportional to V(FA), corrected for the heart rate, and R proportional to MAP/Q. During apnea, MSNA rose; this rise in MSNA was followed by a rise in MAP, which peaked a few seconds after resumption of breathing. Responses of MSNA and MAP to apnea were greatest during hypoxia and smallest during hyperoxia (P < 0.05 for both compared with room air breathing). Similarly, apnea was associated with a decrease in Q and an increase in R. The decrease in Q was greatest during hypoxia and smallest during hyperoxia (-25 +/- 3 vs. -6 +/- 4%, P < 0.05), and the increase in R was the greatest during hypoxia and the least during hyperoxia (60 +/- 8 vs. 21 +/- 6%, P < 0.05). Thus voluntary apnea is associated with vasoconstriction, which is in part mediated by the sympathetic nervous system. Because apnea-induced vasoconstriction is most intense during hypoxia and attenuated during hyperoxia, it appears to depend at least in part on stimulation of arterial chemoreceptors.

Increased muscle perfusion reduces muscle sympathetic nerve activity during handgripping

This study sought to determine whether increasing blood flow to active muscles can blunt the normal rise in muscle sympathetic nerve activity (MSNA) during heavy rhythmic forearm exercise in humans. Subjects performed 5- to 6-min exercise bouts of handgripping (30/min) at 40-50% of maximum voluntary contraction (MVC). Blood flow was increased by application of suction (50 mmHg) around the forearm. Suction increased deep venous oxygen saturation in blood draining the forearm from 34 +/- 4 to 45 +/- 4%, indicating that muscle blood flow had risen by approximately 20%. Suction had no impact on the heart rate, perceived exertion, or electromyographic responses to the handgripping. During 6 min of exercise at 50% of MVC, MSNA rose from 376 +/- 67 to 970 +/- 125 units during the control trial vs. 396 +/- 69 to 729 +/- 94 units during the suction trial, and the difference was maintained during 2 min of postexercise ischemia (P < 0.05; suction < control). Mean arterial pressure (MAP) rose from 99 +/- 4 to 129 +/- 6 mmHg during control vs. 99 +/- 4 to 126 +/- 6 mmHg during the suction trial, and these responses were only different (P < 0.05; suction < control) during the final minute of the exercise bouts. During postexercise ichemia, MAP was 122 +/- 6 mmHg after the control trial but was only 112 +/- 4 mmHg after the suction trial. These results indicate that forearm suction augmented muscle blood flow, limited the activation of chemosensitive muscle afferents, and blunted the rise in MSNA during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)