Arterial pressure and muscle sympathetic nerve activity are increased after two hours of sustained but not cyclic hypoxia in healthy humans.

Sustained and episodic hypoxic exposures lead, by two different mechanisms, to an increase in ventilation after the exposure is terminated. Our aim was to investigate whether the pattern of hypoxia, cyclic or sustained, influences sympathetic activity and hemodynamics in the postexposure period. We measured sympathetic activity (peroneal microneurography), hemodynamics [plethysmographic forearm blood flow (FBF), arterial pressure, heart rate], and peripheral chemosensitivity in normal volunteers on two occasions during and after 2 h of either exposure. By design, mean arterial oxygen saturation was lower during sustained relative to cyclic hypoxia. Baseline to recovery muscle sympathetic nerve activity and blood pressure went from 15.7 +/- 1.2 to 22.6 +/- 1.9 bursts/min (P < 0.01) and from 85.6 +/- 3.2 to 96.1 +/- 3.3 mmHg (P < 0.05) after sustained hypoxia, respectively, but did not exhibit significant change from 13.6 +/- 1.5 to 17.3 +/- 2.5 bursts/min and 84.9 +/- 2.8 to 89.8 +/- 2.5 mmHg after cyclic hypoxia. A significant increase in FBF occurred after sustained, but not cyclic, hypoxia, from 2.3 +/- 0.2 to 3.29 +/- 0.4 and from 2.2 +/- 0.1 to 3.1 +/- 0.5 ml.min(-1).100 g of tissue(-1), respectively. Neither exposure altered the ventilatory response to progressive isocapnic hypoxia. Two hours of sustained hypoxia increased not only muscle sympathetic nerve activity but also arterial blood pressure. In contrast, cyclic hypoxia produced slight but not significant changes in hemodynamics and sympathetic activity. These findings suggest the cardiovascular response to acute hypoxia may depend on the intensity, rather than the pattern, of the hypoxic exposure.     

Responses in muscle sympathetic nerve activity to sustained hand-grips of different tensions in humans

To clarify whether sympathetic nerve activity increases in relation to the tension of a sustained muscle contraction, muscle sympathetic nerve activity (MSA) was recorded directly from the peroneal nerve fascicle at the popliteal fossa by means of tungsten microelectrodes in five healthy male subjects. A sustained muscle contraction was performed by handgrip for two minutes in a supine position at tensions of 10, 30 and 45% of maximal grip strength (MGS). MSA, electrocardiogram (ECG) using bipolar electrodes from the chest and surface electromyogram (EMG) from the extensor pollicis longus were recorded simultaneously before and during the sustained handgrip. Arterial blood pressure was measured at the resting upper arm by auscultation. During handgrip with tensions of 10, 30 and 45% MGS, average MSA burst rate (bursts X min-1) increased to 122, 152 and 230% of the resting value, respectively. During the same experimental procedures with tensions of 10, 30 and 45% MGS, average heart rate increased to 105, 110 and 111% of the resting value. These results confirm that sympathetic outflow to a resting muscle is increased with elevation of tension in an active muscle. This process would promote perfusion pressure in the active muscle.     

Responses in muscle sympathetic activity to acute hypoxia in humans

Responses in muscle sympathetic activity (MSA) to acute hypoxia were studied in 13 healthy male subjects under hypobaric hypoxic conditions at a simulated altitude of 4,000, 5,000, and 6,000 m. Efferent postganglionic MSA was recorded directly with a tungsten microelectrode inserted percutaneously into the tibial nerve. Heart rate (HR) and respiratory rate (RR) were counted respectively from the R wave of an electrocardiogram and from the respiratory tracing recorded by the strain-gauge method. The average values of the MSA burst rate and total activity of MSA (burst rate x mean burst amplitude) at 4,000, 5,000, and 6,000 m were 36.4 +/- 2.6, 39.1 +/- 3.1, and 40.2 +/- 4.2 (SE) bursts/min and 616 +/- 138, 794 +/- 190, and 764 +/- 227 arbitrary units, respectively. These values were significantly higher than the values of 27.1 +/- 2.9 bursts/min and 446 +/- 28 at sea level. HR increased significantly at altitudes, but RR did not show significant change. Under severe hypoxic conditions beyond 5,000 m, there were large interindividual differences in the MSA responsiveness to hypoxia. The results indicate that MSA is activated under hypoxia by stimulating the chemoreceptors. However, the central controlling mechanisms that would be affected by hypoxia may also influence the MSA responsiveness under severe hypoxia.     

Spectral analysis of muscle sympathetic nerve activity in heat-stressed humans

Whole body heating increases muscle sympathetic nerve activity (MSNA); however, the effect of heat stress on spectral characteristics of MSNA is unknown. Such information may provide insight into mechanisms of heat stress-induced MSNA activation. The purpose of the present study was to test the hypothesis that heat stress-induced changes in systolic blood pressure variability parallel changes in MSNA variability. In 13 healthy subjects, MSNA, electrocardiogram, arterial blood pressure (via Finapres), and respiratory activity were recorded under both normothermic and heat stress conditions. Spectral characteristics of integrated MSNA, R-R interval, systolic blood pressure, and respiratory excursions were assessed in the low (LF; 0.03-0.15 Hz) and high (HF; 0.15-0.45 Hz) frequency components. Whole body heating significantly increased skin and core body temperature, MSNA burst rate, and heart rate, but not mean arterial blood pressure. Systolic blood pressure and R-R interval variability were significantly reduced in both the LF and HF ranges. Compared with normothermic conditions, heat stress significantly increased the HF component of MSNA, while the LF component of MSNA was not altered. Thus the LF-to-HF ratio of MSNA oscillatory components was significantly reduced. These data indicate that the spectral characteristics of MSNA are altered by whole body heating; however, heat stress-induced changes in MSNA do not parallel changes in systolic blood pressure variability. Moreover, the reduction in LF component of systolic blood pressure during heat stress is unlikely related to spectral changes in MSNA.     

Effect of hypoxia on arterial baroreflex control of heart rate and muscle sympathetic nerve activity in humans.

We tested the hypothesis that acute hypoxia would alter the sensitivity of arterial baroreflex control of both heart rate and sympathetic vasoconstrictor outflow. In 16 healthy, nonsmoking, normotensive subjects (8 women, 8 men, age 20-33 yr), we assessed baroreflex control of heart rate and muscle sympathetic nerve activity by using the modified Oxford technique during both normoxia and hypoxia (12% O(2)). Compared with normoxia, hypoxia reduced arterial O(2) saturation levels from 96.8 +/- 0.3 to 80.7 +/- 1.4% (P < 0.001), increased heart rate from 59.8 +/- 2.4 to 79.4 +/- 2.9 beats/min (P < 0.001), increased mean arterial pressure from 96.7 +/- 2.5 to 105.0 +/- 3.3 mmHg (P = 0.002), and increased sympathetic activity 126 +/- 58% (P < 0.05). The sensitivity for baroreflex control of both heart rate and sympathetic activity was not altered by hypoxia (heart rate: -1.02 +/- 0.09 vs. -1.02 +/- 0.11 beats. min(-1). mmHg(-1); nerve activity: -5.6 +/- 0.9 vs. -6.2 +/- 0.9 integrated activity. beat(-1). mmHg(-1); both P > 0.05). Acute exposure to hypoxia reset baroreflex control of both heart rate and sympathetic activity to higher pressures without changes in baroreflex sensitivity.     

Dissociation of muscle sympathetic nerve activity and leg vascular resistance in humans

We examined the hypothesis that the increase in inactive leg vascular resistance during forearm metaboreflex activation is dissociated from muscle sympathetic nerve activity (MSNA). MSNA (microneurography), femoral artery mean blood velocity (FAMBV, Doppler), mean arterial pressure (MAP), and heart rate (HR) were assessed during fatiguing static handgrip exercise (SHG, 2 min) followed by posthandgrip ischemia (PHI, 2 min). Whereas both MAP and MSNA increase during SHG, the transition from SHG to PHI is characterized by a transient reduction in MAP but sustained elevation in MSNA, facilitating separation of these factors in vivo. Femoral artery vascular resistance (FAVR) was calculated (MAP/MBV). MSNA increased by 59 +/- 20% above baseline during SHG (P < 0.05) and was 58 +/- 18 and 78 +/- 18% above baseline at 10 and 20 s of PHI, respectively (P < 0.05 vs. baseline). Compared with baseline, FAVR increased 51 +/- 22% during SHG (P < 0.0001) but returned to baseline levels during the first 30 s of PHI, reflecting the changes in MAP (P < 0.005) and not MSNA. It was concluded that control of leg muscle vascular resistance is sensitive to changes in arterial pressure and can be dissociated from sympathetic factors.     

Baroreflex control of muscle sympathetic nerve activity as a mechanism for persistent sympathoexcitation following acute hypoxia in humans

This study tested the hypothesis that acute isocapnic hypoxia results in persistent resetting of the baroreflex to higher levels of muscle sympathetic nerve activity (MSNA), which outlasts the hypoxic stimulus. Cardiorespiratory measures were recorded in humans (26 ± 1 yr; n = 14; 3 women) during baseline, exposure to 20 min of isocapnic hypoxia, and for 5 min following termination of hypoxia. The spontaneous baroreflex threshold technique was used to determine the change in baroreflex function during and following 20 min of isocapnic hypoxia (oxyhemoglobin saturation = 80%). From the spontaneous baroreflex analysis, the linear regression between diastolic blood pressure (DBP) and sympathetic burst occurrence, the T50 (DBP with a 50% likelihood of a burst occurring), and DBP error signal (DBP minus the T50) provide indexes of baroreflex function. MSNA and DBP increased in hypoxia and remained elevated during posthypoxia relative to baseline (P < 0.05). The DBP error signal became progressively less negative (i.e., smaller difference between DBP and T50) in the hypoxia and posthypoxia periods (baseline: -3.9 ± 0.8 mmHg; hypoxia: -1.4 ± 0.6 mmHg; posthypoxia: 0.2 ± 0.6 mmHg; P < 0.05). Hypoxia caused no change in the slope of the baroreflex stimulus-response curve; however, there was a shift toward higher pressures that favored elevations in MSNA, which persisted posthypoxia. Our results indicate that there is a resetting of the baroreflex in hypoxia that outlasts the stimulus and provide further explanation for the complex control of MSNA following acute hypoxia.     

Effects of muscle metabolites on responses of muscle sympathetic nerve activity to mechanoreceptor(s) stimulation in healthy humans

Based on animal studies, it has been speculated that muscle metabolites sensitize muscle mechanoreceptors and increase mechanoreceptor-mediated muscle sympathetic nerve activity (MSNA). However, this hypothesis has not been directly tested in humans. In this study, we tested the hypothesis that in healthy individuals passive stretch of forearm muscles would evoke significant increases in mean MSNA when muscle metabolite concentrations were increased. In 12 young healthy subjects, MSNA, ECG, and blood pressure were recorded. Subjects performed static fatiguing isometric handgrip at 30% maximum voluntary contraction followed by 4 min of postexercise muscle ischemia (PEMI). After 2 min of PEMI, wrist extension (i.e., wrist dorsiflexion) was performed. The static stretch protocol was also performed during 1) a freely perfused condition, 2) ischemia alone, and 3) PEMI after nonfatiguing exercise. Finally, repetitive short bouts of wrist extension were also performed under freely perfused conditions. This last paradigm evoked transient increases in MSNA but had no significant effect on mean MSNA over the whole protocol. During the PEMI after fatiguing handgrip, static stretch induced significant increases in MSNA (552 +/- 74 to 673 +/- 90 U/min, P < 0.01) and mean blood pressure (102 +/- 2 to 106 +/- 2 mmHg, P < 0.001). Static stretch performed under the other three conditions had no significant effects on mean MSNA and blood pressure. The present data verified that in healthy humans mechanoreceptor(s) stimulation evokes significant increases in mean MSNA and blood pressure when muscle metabolite concentrations are increased above a certain threshold.     

Baroreflex modulation of muscle sympathetic nerve activity during posthandgrip muscle ischemia in humans.

To identify whether muscle metaboreceptor stimulation alters baroreflex control of muscle sympathetic nerve activity (MSNA), MSNA, beat-by-beat arterial blood pressure (Finapres), and electrocardiogram were recorded in 11 healthy subjects in the supine position. Subjects performed 2 min of isometric handgrip exercise at 40% of maximal voluntary contraction followed by 2.5 min of posthandgrip muscle ischemia. During muscle ischemia, blood pressure was lowered and then raised by intravenous bolus infusions of sodium nitroprusside and phenylephrine HCl, respectively. The slope of the relationship between MSNA and diastolic blood pressure was more negative (P < 0.001) during posthandgrip muscle ischemia (-201.9 +/- 20.4 units. beat(-1). mmHg(-1)) when compared with control conditions (-142.7 +/- 17.3 units. beat(-1). mmHg(-1)). No significant change in the slope of the relationship between heart rate and systolic blood pressure was observed. However, both curves shifted during postexercise ischemia to accommodate the elevation in blood pressure and MSNA that occurs with this condition. These data suggest that the sensitivity of baroreflex modulation of MSNA is elevated by muscle metaboreceptor stimulation, whereas the sensitivity of baroreflex of modulate heart rate is unchanged during posthandgrip muscle ischemia.     

Basis for the cardiac-related rhythm in muscle sympathetic nerve activity of humans

We tested the hypothesis that the cardiac-related rhythm in muscle sympathetic nerve activity (MSNA) of humans reflects entrainment of a central oscillator by pulse-synchronous baroreceptor nerve activity. Partial autospectral analysis was used to mathematically remove the portion of cardiac-related power in MSNA autospectra that was attributable to its linear relationship to the ECG. In 54 of 98 cases, > or =15% of cardiac-related power remained after partialization with the ECG; peak residual cardiac-related power was often at a frequency different than heart rate. When assessed on a cardiac-related burst-by-burst basis, there was a progressive and cyclic change in the ECG-MSNA interval (delay from R wave to peak of cardiac-related burst) on the time scale of respiration in four subjects. In these subjects, as well as in some in which the interval appeared to change randomly, there was an inverse relationship between the ECG-MSNA interval and cardiac-related burst amplitude. However, in 45% of the cases, these parameters were not related. These results support the view that the cardiac-related rhythm in MSNA reflects forcing of a nonlinear oscillator rather than periodic inhibition of unstructured, random activity.     

Modulation of arterial baroreflex control of muscle sympathetic nerve activity by muscle metaboreflex in humans

We aimed to investigate the interaction [with respect to the regulation of muscle sympathetic nerve activity (MSNA) and blood pressure] between the arterial baroreflex and muscle metaboreflex in humans. In 10 healthy subjects who performed a 1-min sustained handgrip exercise at 50% maximal voluntary contraction followed by forearm occlusion, arterial baroreflex control of MSNA (burst incidence and strength and total activity) was evaluated by analyzing the relationship between beat-by-beat spontaneous variations in diastolic arterial blood pressure (DAP) and MSNA both during supine rest (control) and during postexercise muscle ischemia (PEMI). During PEMI (vs. control), 1) the linear relationship between burst incidence and DAP was shifted rightward with no alteration in sensitivity, 2) the linear relationship between burst strength and DAP was shifted rightward and upward with no change in sensitivity, and 3) the linear relationship between total activity and DAP was shifted to a higher blood pressure and its sensitivity was increased. The modification of the control of total activity that occurs in PEMI could be a consequence of alterations in the baroreflex control of both MSNA burst incidence and burst strength. These results suggest that the arterial baroreflex and muscle metaboreflex interact to control both the occurrence and strength of MSNA bursts.     

Modulation of control of muscle sympathetic nerve activity during orthostatic stress in humans

We tested the hypothesis that orthostatic stress would modulate the arterial baroreflex (ABR)-mediated beat-by-beat control of muscle sympathetic nerve activity (MSNA) in humans. In 12 healthy subjects, ABR control of MSNA (burst incidence, burst strength, and total activity) was evaluated by analysis of the relation between beat-by-beat spontaneous variations in diastolic blood pressure (DAP) and MSNA during supine rest (CON) and at two levels of lower body negative pressure (LBNP: -15 and -35 mmHg). At -15 mmHg LBNP, the relation between burst incidence (bursts per 100 heartbeats) and DAP showed an upward shift from that observed during CON, but the further shift seen at -35 mmHg LBNP was only marginal. The relation between burst strength and DAP was shifted upward at -15 mmHg LBNP (vs. CON) and further shifted upward at -35 mmHg LBNP. At -15 mmHg LBNP, the relation between total activity and DAP was shifted upward from that obtained during CON and further shifted upward at -35 mmHg LBNP. These results suggest that ABR control of MSNA is modulated during orthostatic stress and that the modulation is different between a mild (nonhypotensive) and a moderate (hypotensive) level of orthostatic stress.     

Baroreflex modulation of muscle sympathetic nerve activity during cold pressor test in humans

The purpose of this project was to test the hypothesis that baroreceptor modulation of muscle sympathetic nerve activity (MSNA) and heart rate is altered during the cold pressor test. Ten subjects were exposed to a cold pressor test by immersing a hand in ice water for 3 min while arterial blood pressure, heart rate, and MSNA were recorded. During the second and third minute of the cold pressor test, blood pressure was lowered and then raised by intravenous bolus infusions of sodium nitroprusside and phenylephrine HCl, respectively. The slope of the relationship between MSNA and diastolic blood pressure was more negative (P < 0.005) during the cold pressor test (-244.9 +/- 26.3 units x beat(-1) x mmHg(-1)) when compared with control conditions (-138.8 +/- 18.6 units x beat(-1) x mmHg(-1)), whereas no significant change in the slope of the relationship between heart rate and systolic blood pressure was observed. These data suggest that baroreceptors remain capable of modulating MSNA and heart rate during a cold pressor test; however, the sensitivity of baroreflex modulation of MSNA is elevated without altering the sensitivity of baroreflex control of heart rate.     

Regulation of muscle sympathetic nerve activity after bed rest deconditioning

Cardiovascular deconditioning reduces orthostatic tolerance. To determine whether changes in autonomic function might produce this effect, we developed stimulus-response curves relating limb vascular resistance, muscle sympathetic nerve activity (MSNA), and pulmonary capillary wedge pressure (PCWP) with seven subjects before and after 18 days of -6 degrees head-down bed rest. Both lower body negative pressure (LBNP; -15 and -30 mmHg) and rapid saline infusion (15 and 30 ml/kg body wt) were used to produce a wide variation in PCWP. Orthostatic tolerance was assessed with graded LBNP to presyncope. Bed rest reduced LBNP tolerance from 23.9 +/- 2.1 to 21.2 +/- 1.5 min, respectively (means +/- SE, P = 0.02). The MSNA-PCWP relationship was unchanged after bed rest, though at any stage of the LBNP protocol PCWP was lower, and MSNA was greater. Thus bed rest deconditioning produced hypovolemia, causing a shift in operating point on the stimulus-response curve. The relationship between limb vascular resistance and MSNA was not significantly altered after bed rest. We conclude that bed rest deconditioning does not alter reflex control of MSNA, but may produce orthostatic intolerance through a combination of hypovolemia and cardiac atrophy.     

Postexercise responses of muscle sympathetic nerve activity and blood flow to hyperinsulinemia in humans.

Although insulin and exercise cause dramatic changes in physiological parameters, the impact of exercise on neural and hemodynamic responses to insulin administration has not been described. In a study of the effects of a single bout of exercise on blood pressure (BP), muscle sympathetic nerve activity (MSNA), and forearm blood flow (FBF) responses to insulin infusion during the postexercise period, 11 healthy men underwent, in a random order, two hyperinsulinemic euglycemic clamps performed after 45 min of 1) bicycle exercise (50% peak O(2) uptake, Exercise session) and 2) seated rest (Control session). Data were analyzed during baseline and steady-state periods. Although insulin levels and insulin sensitivity were similar, baseline plasma glucose levels were significantly lower in the Exercise than in the Control session. Mean BP was significantly lower (3%) and FBF was higher (27%) in the Exercise session. Exercise increased insulin-induced MSNA enhancement (84%) without changing FBF and BP responses to hyperinsulinemia. In conclusion, a single bout of exercise that does not alter insulin sensitivity exacerbates insulin-induced increase in MSNA without changing FBF and BP responses to hyperinsulinemia.     

Relationship between blood pressure,sleep K-complexes,and muscle sympathetic nerve activity in humans

Stage 2 sleep is characterized by the EEG appearance of "K-complexes" and blood pressure oscillations. K-complexes may be directly related to blood pressure changes or they may reflect central sympathetic activation. We analyzed the temporal relationship among K-complexes, heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) during sleep in eight healthy volunteers (3 men and 5 women, age 22-41 yr). Most K-complexes presented as single large complexes (56 +/- 20%), followed by single small complexes (15 +/- 14%) and as couplets or triplets (13 +/- 6%). Single large K-complexes were preceded by a baroreflex-mediated increase of MSNA in approximately one-half (55%) of the cases. Detailed analysis of HR, BP, and MSNA was possible in 63 (45%) large single K-complexes not disturbed by preceding baroreflex-related changes. Systolic and diastolic BP and MSNA increased significantly after single events (22.5 +/- 13, 5.2 +/- 2.1, and 6.5 +/- 3.0%). Mean sympathetic baroreflex latency was similar after the single large K-complexes compared with the mean value during stage 2 sleep (1,290 +/- 126 vs. 1,279 +/- 61 ms). The area under the burst was significantly increased after single large K-complexes (median 3.9 vs. 9.0 arbitrary units, P < 0.03). The results support the hypothesis that K-complexes express cortical activation leading to temporary facilitation of sympathetic outflow in a graded fashion. Their functional effects appear to be independent of baroreflex modulation of MSNA in approximately 50% of the cases.