Increase In Muscle Sympathetic Nerve Activity Research Articles

Cyclooxygenase inhibition attenuates sympathetic responses to muscle stretch in humans

Passive muscle stretch performed during a period of post-exercise muscle ischemia (PEMI) increases muscle sympathetic nerve activity (MSNA), and this suggests that the muscle metabolites may sensitize mechanoreceptors in healthy humans. However, the responsible substance(s) has not been studied thoroughly in humans. Human and animal studies suggest that cyclooxygenase products sensitize muscle mechanoreceptors. Thus we hypothesized that local cyclooxygenase inhibition in exercising muscles could attenuate MSNA responses to passive muscle stretch during PEMI. Blood pressure (Finapres), heart rate, and MSNA (microneurography) responses to passive muscle stretch were assessed in 13 young healthy subjects during PEMI before and after cyclooxygenase inhibition, which was accomplished by a local infusion of 6 mg ketorolac tromethamine in saline via Bier block. In the second experiment, the same amount of saline was infused via the Bier block. Ketorolac Bier block decreased prostaglandin synthesis to approximately 34% of the baseline. Before ketorolac Bier block, passive muscle stretch evoked significant increases in MSNA (P < 0.005) and mean arterial blood pressure (P < 0.02). After ketorolac Bier block, passive muscle stretch did not evoke significant responses in MSNA (P = 0.11) or mean arterial blood pressure (P = 0.83). Saline Bier block had no effect on the MSNA or blood pressure response to ischemic stretch. These observations indicate that cyclooxygenase inhibition attenuates MSNA responses seen during PEMI and suggest that cyclooxygenase products sensitize the muscle mechanoreceptors.

Does infusion of ANG II increase muscle sympathetic nerve activity in patients with primary aldosteronism?

Patients with primary aldosteronism (PA) were shown to have suppressed muscle sympathetic nerve activity (MSNA) in our previous study. Although baroreflex inhibition probably accounts in part for this reduced MSNA in PA, we hypothesized that the lowered activity of the renin-angiotensin system in PA may also contribute to the suppressed SNA. We recorded MSNA in 9 PA and 16 age-matched normotensive controls (NC). In PA, the resting mean blood pressure (MBP) and serum sodium concentrations were increased, and MSNA was reduced. We examined the effects of infusion of a high physiological dose of ANG II (5.0 ng.kg(-1).min(-1)) on MSNA in 6 of 9 PA and 9 of 16 NC. Infusion of ANG II caused a greater pressor response in PA than NC, but, in spite of the greater increase in pressure, MSNA increased in PA, whereas it decreased in NC. Simultaneous infusion of nitroprusside and ANG II, to maintain central venous pressure at the baseline level and reduce the elevation in MBP induced by ANG II, caused significantly greater increases in MSNA in PA than in NC. Baroreflex sensitivity of heart rate, estimated during phenylephrine infusions, was reduced in PA, but baroreflex sensitivity of MSNA was unchanged in PA compared with NC. All the abnormalities in PA were eliminated following unilateral adrenalectomy. In conclusion, the suppressed SNA in PA depends in part on the low level of ANG II in these patients.

Cyclooxygenase products sensitize muscle mechanoreceptors in humans with heart failure

Prior work in animals and humans suggests that muscle mechanoreceptor control of sympathetic activation [muscle sympathetic nerve activity (MSNA)] during exercise in heart failure (HF) patients is heightened compared with that of healthy humans and that muscle mechanoreceptors are sensitized by metabolic by-products. We sought to determine whether cyclooxygenase products and/or endogenous adenosine, two metabolites of ischemic exercise, sensitize muscle mechanoreceptors during rhythmic handgrip (RHG) exercise in HF patients. Indomethacin, which inhibits the production of prostaglandins, and saline control were infused in 12 HF patients. In a different protocol, aminophylline, which inhibits adenosine receptors, and saline control were infused in 12 different HF patients. MSNA was recorded (microneurography). During exercise following saline, MSNA increased in the first minute of exercise, consistent with baseline heightened mechanoreceptor sensitivity. MSNA continued to increase during 3 min of RHG, indicative that muscle mechanoreceptors are sensitized by ischemia metabolites. Indomethacin, but not aminophylline, markedly attenuated the increase in MSNA during the entire 3 min of low-level rhythmic exercise, consistent with the sensitization of muscle mechanoreceptors by cyclooxygenase products. Interestingly, even the early increase in MSNA was abolished by indomethacin infusion, indicative of the very early generation of cyclooxygenase products after the onset of exercise in HF patients. In conclusion, muscle mechanoreceptors mediate the increase in MSNA during low-level RHG exercise in HF. Cyclooxygenase products, but not endogenous adenosine, play a central role in muscle mechanoreceptor sensitization. Finally, muscle mechanoreceptors in patients with HF have heightened basal sensitivity to mechanical stimuli, which also appears to be mediated by the early generation of cyclooxygenase products, resulting in exaggerated early increases in MSNA.

The effect of intraduodenal glucose on muscle sympathetic nerve activity in healthy young and older subjects

The cardiovascular response to a meal is modulated by gastric distension and the interaction of nutrients, particularly carbohydrate, within the small intestine. We tested the hypothesis that the depressor effect of small intestinal glucose is greater in older than in young subjects, because the reflex increase in muscle sympathetic nerve activity (MSNA) is blunted by age. The effects of intraduodenal glucose infusion (IDGI) on blood pressure, heart rate and MSNA were evaluated in eight healthy young subjects (4 women; mean age +/- SEM: 28.8 +/- 3.4 years), eight healthy elderly (4 women; 75.3 +/- 1.6 years) and in two patients with symptomatic postprandial hypotension (PPH), one young (21 years), and one old (90 years). In both young and elderly healthy subjects, IDGI decreased blood pressure (P < 0.05), but the fall in systolic blood pressure was greater in the older subjects (-17.0 +/- 4.1 vs. -6.5 +/- 1.6 mmHg, P < 0.03). MSNA increased similarly, after infusion in both young (9.0 +/- 3.4 bursts/min) and elderly (7.8 +/- 1.0 bursts/min) subjects. Baroreflex sensitivity for number of sympathetic bursts was attenuated in the elderly (P < 0.03). The increase in burst area in the young patient with PPH was attenuated (18 vs. 63% in the healthy young group). The fall in BP induced by IDGI was greater in healthy elderly compared to healthy young subjects. The reason for this is unclear, as they have similar increases in MSNA.

Perturbed Autonomic Nervous System Function in Metabolic Syndrome

The metabolic syndrome is characterized by the clustering of various common metabolic abnormalities in an individual and it is associated with increased risk for the development of type 2 diabetes and cardiovascular diseases. Its prevalence in the general population is approximately 25%. Central fat accumulation and insulin resistance are considered as the common denominators of the abnormalities of the metabolic syndrome. Subjects with metabolic syndrome have autonomic nervous system dysfunction characterized by predominance of the sympathetic nervous system in many organs, i.e. heart, kidneys, vasculature, adipose tissue, and muscles. Sympathetic nervous system activation in metabolic syndrome is detected as increased heart rate and blood pressure, diminished heart rate variability, baroreceptor dysfunction, enhanced lipolysis in visceral fat, increased muscle sympathetic nerve activity, and high urine or plasma catecholamine concentrations as well as turnover rates. The augmented sympathetic activity in individuals with metabolic syndrome worsens prognosis of this high-risk population. The mechanisms linking metabolic syndrome with sympathetic activation are complex and not clearly understood. Whether sympathetic overactivity is involved in the development of the metabolic syndrome or is a consequence of it remains to be elucidated since data from prospective studies are missing. Intervention studies have demonstrated that the autonomic disturbances of the metabolic syndrome may be reversible.

Sympathetic Mechanisms of Hypoglycemic Counterregulation

In normal individuals hypoglycemic counterregulation is a multifactorial, redundant process that involves reduction of insulin secretion, increasing glucagon secretion, adrenergic activation, and increased growth hormone and cortisol secretion. Metabolically, these lead to increased glucose production, initially through glycogenolysis and later through gluconeogenesis, decreased muscle glucose oxidation and storage and increased release and use of alternative fuels, primarily free fatty acids. They also lead to hypoglycemic symptoms and hunger which increase food intake. These systems are designed to provide as much glucose as possible for brain glucose use. In patients with type 1 diabetes there are multiple impairments of these responses. Insulin does not decrease. Glucagon secretion is decreased or absent. Recovery from hypoglycemia is therefore dependent on the adrenergic response. Hypoglycemia increases plasma levels of both epinephrine and norepinephrine. These catechols are released primarily from the adrenal medulla. However, it is well documented that hypoglycemic increases muscle sympathetic nerve activity, and that both alpha and beta adrenergic activity increase. Increased beta-activity increases free fatty acid release which increase glucose production and decrease glucose utilization. The increased alpha-adrenergic activity's primary role is to counteract beta-adrenergic vasodilation. It may also reduce neurogenic and neuroglycopenic symptoms. Lastly, there is evidence that both cardiac and adrenergic sensitivity are altered in type 1 diabetes. It is hoped that this information can be used in the future to help develop ways to protect patients with type 1 diabetes from hypoglycemia and its adverse effects.

Effect of baroreflex loading on the responsiveness of the vestibulosympathetic reflex in humans

Activation of the vestibular otolith organs with head-down rotation (HDR) increases muscle sympathetic nerve activity (MSNA) in humans. Previously, we demonstrated this vestibulosympathetic reflex (VSR) elicits increases in MSNA during baroreflex unloading (i.e., lower body negative pressure) in humans. Whether such an effect persists during baroreflex loading is unknown. We tested the hypothesis that the ability of the VSR to increase MSNA is preserved during baroreflex unloading and inhibited during baroreflex loading. Ten subjects (26 +/- 1 yr) performed three trials of HDR to activate the VSR. These trials were performed after a period of sustained saline (control), nitroprusside (baroreflex unloading: 0.8-1.0 microg.kg(-1).min(-1)), and phenylephrine (baroreflex loading: 0.6-0.8 microg.kg(-1).min(-1)) infusion. Nitroprusside infusion decreased (Delta7 +/- 1 mmHg, where Delta is change; P < 0.001) and phenylephrine infusion increased mean arterial pressure (Delta8 +/- 1 mmHg; P < 0.001) at rest. HDR performed during the control [Delta3 +/- 2 bursts/min, Delta314 +/- 154 arbitrary units (au) total activity, Delta41 +/- 18% total activity; P < 0.05] and nitroprusside trials [Delta5 +/- 2 bursts/min, Delta713 +/- 241 au total activity, Delta49 +/- 20% total activity; P < 0.05] increased MSNA similarly despite significantly elevated levels at rest (13 +/- 2 to 26 +/- 3 bursts/min) in the latter. In contrast, HDR performed during the phenylephrine trial failed to increase MSNA (Delta0 +/- 1 bursts/min, Delta-15 +/- 33 au total activity, Delta-8 +/- 21% total activity). These results confirm previous findings that the ability of the VSR to increase MSNA is preserved during baroreflex unloading. In contrast, the ability of the VSR to increase MSNA is abolished during baroreflex loading. These results provide further support for the concept that the VSR may act primarily to defend against hypotension in humans.

The role of the cyclooxygenase products in evoking sympathetic activation in exercise

Animal studies suggest that prostaglandins in skeletal muscles stimulate afferents and contribute to the exercise pressor reflex. However, human data regarding a role for prostaglandins in this reflex are varied, in part because of systemic effects of pharmacological agents used to block prostaglandin synthesis. We hypothesized that local blockade of prostaglandin synthesis in exercising muscles could attenuate muscle sympathetic nerve activity (MSNA) responses to fatiguing exercise. Blood pressure (Finapres), heart rate, and MSNA (microneurography) were assessed in 12 young healthy subjects during static handgrip and postexercise muscle ischemia (PEMI) before and after local infusion of 6 mg of ketorolac tromethamine in saline via Bier block (regional intravenous anesthesia). In the second experiment (n = 10), the same amount of saline was infused via the Bier block. Ketorolac Bier block decreased the prostaglandins synthesis to approximately 33% of the baseline. After ketorolac Bier block, the increases in MSNA from the baseline during the fatiguing handgrip was significantly lower than that before the Bier block (before ketorolac: Delta502 +/- 111; post ketorolac: Delta348 +/- 62%, P = 0.016). Moreover, the increase in total MSNA during PEMI after ketorolac was significantly lower than that before the Bier block (P = 0.014). Saline Bier block had no similar effect. The observations indicate that blockade of prostaglandin synthesis attenuates MSNA responses seen during fatiguing handgrip and suggest that prostaglandins contribute to the exercise pressor reflex.

Atrial Septostomy Decreases Sympathetic Overactivity in Pulmonary Arterial Hypertension

We have reported previously that the sympathetic nervous system is activated in patients with pulmonary arterial hypertension (PAH), and that this is only partly explained by a decrease in arterial oxygenation. Possible causes for increased muscle sympathetic nerve activity (MSNA) in patients with PAH include right atrial distension and decreased cardiac output. Both may be improved by atrial septostomy, but this intervention also further decreases arterial oxygenation. In the present study, we wanted to investigate the effect of atrial septostomy on MSNA in patients with PAH. We recorded BP, heart rate (HR), arterial O2 saturation (SaO2), and MSNA before and after atrial septostomy in PAH patients (mean [+/- SE] age, 48 +/- 5 years) and in closely matched control subjects. Measurements were also performed after septostomy, while SaO2 was brought to the preprocedure level by supplemental O2 therapy. Compared to the control subjects (n = 10), the PAH patients (n = 11) had a lower mean BP (75 +/- 2 vs 96 +/- 3 mm Hg, respectively; p < 0.001), lower mean SaO2 (92 +/- 1% vs 97 +/- 0%, respectively; p < 0.001), increased mean HR (84 +/- 4 vs 68 +/- 3 beats/min; p < 0.01), and markedly increased mean MSNA (76 +/- 5 vs 29 +/- 2 bursts per minute; p < 0.001). Atrial septostomy decreased mean SaO2 (to 85 +/- 2%; p < 0.001) and mean MSNA (to 69 +/- 4 bursts per minute; p < 0.01), but did not affect HR or BP. Therapy with supplemental O2 did not affect MSNA, BP, or HR. The decrease in MSNA was correlated to the decrease in right atrial pressure (r = 0.62; p < 0.05). Atrial septostomy in PAH patients decreases sympathetic hyperactivity despite an associated decrease in arterial oxygenation, and this appears to be related to decreased right atrial distension.

Blunted muscle vasodilatation during chemoreceptor stimulation in patients with heart failure

Chemoreflex control of sympathetic nerve activity is exaggerated in heart failure (HF) patients. However, the vascular implications of the augmented sympathetic activity during chemoreceptor activation in patients with HF are unknown. We tested the hypothesis that the muscle blood flow responses during peripheral and central chemoreflex stimulation would be blunted in patients with HF. Sixteen patients with HF (49 +/- 3 years old, Functional Class II-III, New York Heart Association) and 11 age-paired normal controls were studied. The peripheral chemoreflex control was evaluated by inhalation of 10% O(2) and 90% N(2) for 3 min. The central chemoreflex control was evaluated by inhalation of 7% CO(2) and 93% O(2) for 3 min. Muscle sympathetic nerve activity (MSNA) was directly evaluated by microneurography. Forearm blood flow was evaluated by venous occlusion plethysmography. Baseline MSNA were significantly greater in HF patients (33 +/- 3 vs. 20 +/- 2 bursts/min, P = 0.001). Forearm vascular conductance (FVC) was not different between the groups. During hypoxia, the increase in MSNA was significantly greater in HF patients than in normal controls (9.0 +/- 1.6 vs. 0.8 +/- 2.0 bursts/min, P = 0.001). The increase in FVC was significantly lower in HF patients (0.00 +/- 0.10 vs. 0.76 +/- 0.25 units, P = 0.001). During hypercapnia, MSNA responses were significantly greater in HF patients than in normal controls (13.9 +/- 3.2 vs. 2.1 +/- 1.9 bursts/min, P = 0.001). FVC responses were significantly lower in HF patients (-0.29 +/- 0.10 vs. 0.37 +/- 0.18 units, P = 0.001). In conclusion, muscle vasodilatation during peripheral and central chemoreceptor stimulation is blunted in HF patients. This vascular response seems to be explained, at least in part, by the exaggerated MSNA responses during hypoxia and hypercapnia.

Muscle metabolites accentuate muscle sympathetic nerve activity responses to passive muscle stretch

It was speculated that muscle metabolites can sensitize muscle mechanoreceptors, and accentuate muscle sympathetic nerve activity (MSNA) responses to mechanoreceptors stimulation in exercise. However, this hypothesis has not been verified directly in healthy subjects. To test whether the MSNA response to passive stretch could be accentuated with increasing metabolites in the muscles, MSNA, ECG and blood pressure (BP) were recorded in 14 young healthy subjects. Subjects performed static isometric handgrip at 30% maximum voluntary contraction (MVC) until fatigue followed by 4 min post exercise ischemia (PEMI). After 2 min of PEMI, the hand was passively stretched (dorsiflexion). In 10 of the subjects, the stretch protocol was also performed without preceding handgrip or ischemia, ischemia alone, and following non-fatigue handgrip at 30% MVC followed by ischemia. During the PEMI after fatigue handgrip, stretch induced significant increase in MSNA (26.4±2.6 to 30.7±2.8 bursts/min, P=0.002) and mean BP (106±2 to 108±2 mmHg, P=0.01). Stretch performed under the other 3 conditions had no significant effect on MSNA. The present data suggest that muscle metabolites accentuate MSNA response to mechanoreceptors stimulation, probably via sensitizing the mechanoreceptors. Supported by NIH P01 HL077670 and M01 RR010732, and AHA 0565399U, 0635245N.

Anxiolytic therapy with alprazolam increases muscle sympathetic activity in patients with panic disorders

Anxiolytic therapy with the benzodiazepine alprazolam is an established therapy in patients with panic disorder. Normally, panic-like anxiety and its concomitant physical symptoms quickly disappear under such treatment. Therefore we investigated whether there is a difference in sympathetic nervous system in patients with panic disorder compared to healthy controls. Three groups of subjects were included: ten patients with panic disorder, who received alprazolam and 20 healthy control subjects who were given either alprazolam ( n = 10) or matching placebo ( n = 10). Muscle sympathetic nerve activity (MSNA) and heart rate did not differ at baseline but significantly increased both in patients and healthy controls after intake of alprazolam (1 mg). However, in both groups both MSNA and heart rate were significantly elevated when compared to both baseline and the placebo control group. This study demonstrates (1) that anxiolytic therapy with alprazolam increases muscle sympathetic nerve activity and heart rate not only in patients with panic disorder but also in healthy controls and (2) that a significant difference in sympathetic nervous system activity between patients and controls, at baseline and during the therapy with alprazolam could not be demonstrated.

Forebrain regions associated with postexercise differences in autonomic and cardiovascular function during baroreceptor unloading

The cortical regions representing peripheral autonomic reactions in humans are poorly understood. This study examined whether changes in forebrain activity were associated with the altered physiological responses to lower body negative pressure (LBNP) following a single bout of dynamic exercise (POST-EX). We hypothesized that, compared with the nonexercised condition (NO-EX), POST-EX would elicit greater reductions in stroke volume (SV) and larger increases in heart rate (HR) and muscle sympathetic nerve activity (MSNA) during LBNP (5, 15, and 35 mmHg). Forebrain neural activity (n = 11) was measured using blood oxygen level-dependent (BOLD) functional magnetic resonance imaging. HR, SV, arterial blood pressure (ABP), and MSNA were collected separately. Compared with NO-EX, baseline ABP was reduced, whereas HR and total vascular conductance (TVC) were elevated in POST-EX (P < 0.05). In both conditions, 5 mmHg LBNP did not elicit a change (from baseline) in any physiological parameter. Compared with NO-EX, 35 mmHg LBNP-mediated decreases in SV and TVC produced greater increases in HR and MSNA during POST-EX (P < 0.05). The right posterior insula and dorsal anterior cingulate cortex demonstrated a larger decrease in BOLD at 5 mmHg LBNP but greater BOLD increase at 15 and 35 mmHg LBNP POST-EX vs. NO-EX (P < 0.005). Conversely, the thalamus and ventral medial prefrontal cortex displayed the opposite BOLD activity pattern (i.e., larger increase at 5 mmHg LBNP but greater decrease at 15 and 35 mmHg LBNP POST-EX vs. NO-EX). Our findings suggest that discrete forebrain regions may be involved with the generation of baroreflex-mediated sympathetic and cardiovascular responses elicited by moderate LBNP.

Increased mechanoreceptor/metaboreceptor stimulation explains the exaggerated exercise pressor reflex seen in heart failure

The following letters are in response to the Point:Counterpoint series “Increased mechanoreceptor/metaboreceptor stimulation explains the exaggerated exercise pressor reflex seen in heart failure” that appears in this issue. To the Editor: The Point:Counterpoint concerning the issue of

Muscle sympathetic nerve activity responses to dynamic passive muscle stretch in humans

It is suggested that mechanoreceptors in muscle play an important role in the exercise pressor reflex. However, it has not been verified whether isolated stimulation of the mechanoreceptors can induce responses in muscle sympathetic nerve activity (MSNA) in young healthy individuals. We tested the hypothesis that passive stretch of muscle can evoke an increase in MSNA in healthy individuals. In 12 young subjects, leg calf muscles were passively stretched, or actively contracted for 5 s followed by a 15-25 s (random length) relaxation period. Stretch and contraction were each repeated 25 times. MSNA, heart rate and blood pressure were analysed, and averaged according to the onset of the force on a beat-by-beat basis. At the 1st to the 3rd heart beat from the onset of stretch, MSNA (199 +/- 30%, P < 0.05) as well as heart rate (102.5 +/- 0.7%, P < 0.05) increased transiently but significantly from the prior stretch baseline (100%), followed (from 3rd to 7th beat from the onset of stretch) by a transient increase in mean blood pressure (101.9 +/- 0.3%, P < 0.05) from the baseline. Similar response patterns were observed during active muscle contractions. The present data show that MSNA responses to isolated stimulation of mechanoreceptors are measurable. Because of baroreflex engagement, the magnitude of the response is small and transient, and the haemodynamic consequences using this protocol may be limited.

Mechanisms of Sympathetic Activation in Obesity-Related Hypertension

Obesity prevalence is soaring in industrialized countries and progressively increasing in the developing world. Altered patterns of nutrition and reduction in work-related energy expenditure have led to obesity becoming a truly global health issue. The central thermodynamic formulation for the origins of obesity, a mismatched energy balance equation, with an excess of dietary calorie intake over body energy expenditure, is a first step in the understanding of this phenomenon but leaves the diverse causal issues unexplored. Dietary calorie intake is modified by multiple social, economic, and cultural issues. Similarly, the reduction in energy expenditure in recent decades has complex origins, deriving from demographic and social change, which includes third-world transition from a labor-intensive agricultural economy to an industrial base, the introduction of household labor-saving devices, the popularity of transportation modes not reliant on physical effort, and from changed recreational habits, particularly in childhood (computer games instead of physical games). The prevalence of childhood obesity is escalating, having whimsically but not entirely unrealistically been attributed to “potato chips and computer chips.” Obesity and hypertension are intimately associated, and both very commonly coexist in individual patients with insulin resistance, hyperinsulinemia, and hyperlipidemia, this clustering of adverse health factors1 being designated the metabolic syndrome. The pathophysiological mechanisms by which obesity leads to hypertension remain uncertain. Understanding these processes might, perhaps, provide a more rational basis for drug treatment of obesity-related hypertension. Attempts at reduction in body weight, although pivotal in the treatment of obesity-related hypertension, more often than not fail, so that antihypertensive drug therapy is often needed. This review analyses the proposition that obesity is characterized by activation of the sympathetic nervous system and that obesity-related hypertension is, in fact, neurogenic, being initiated and sustained by neural mechanisms. At one time, this idea would have been held to fly in the …

Mechanoreceptors and central command

static exercise increases mean arterial pressure, heart rate, and ventilation. Central command and the exercise pressor reflex are the two neural mechanisms causing these responses to static exercise. Central command is defined as the parallel activation of the locomotor and autonomic circuits in

α‐Adrenergic Control of Skeletal Muscle Circulation at Rest and During Exercise in Aging Humans

Aging is associated with many changes in autonomic nervous system function that often lead to impairments in the normal ability to respond to physiological stressors commonly encountered in daily life. In addition, many of these chronic age-related changes in autonomic-circulatory function can potentially predispose the older adult to elevated risk for acute and chronic cardiovascular complications. One of the most pronounced and repeatable findings with respect to changes in the autonomic nervous system with human aging is the progressive increase in basal muscle sympathetic nerve activity (MSNA) directed to skeletal muscle vascular beds. Although the mechanism(s) underlying this sustained age-associated increase in MSNA are not completely understood, several changes in sympathetic a-adrenergic function occur with age. In this review, the authors discuss how aging affects (1) a-adrenergic control of skeletal muscle vascular tone under resting conditions and the differences that exist in this control of the upper and lower limbs (forearm vs leg circulation); (2) vasoconstrictor responsiveness to endogenous norepinephrine release, as well as the specific responsiveness of postjunctional a(1)- and a(2)-adrenergic receptors; and (3) sympathetic a-adrenergic control of muscle blood flow and vascular tone during exercise in humans. Further, they discuss how these changes in sympathetic a-adrenergic control of skeletal muscle blood vessels have important physiological and clinical implications for the aging human.

Modulation of muscle sympathetic bursts by sinusoidal galvanic vestibular stimulation in human subjects

There is controversy as to whether the vestibulosympathetic reflexes demonstrated in experimental animals actually exist in human subjects. While head-down neck flexion and off-vertical axis rotation can increase muscle sympathetic nerve activity (MSNA) in awake subjects, we recently showed that bipolar galvanic vestibular stimulation (GVS) does not. However, it is possible that our stimuli (2 mA, 1 s)-although capable of causing strong postural and occulomotor responses-were too brief. To address this issue we activated vestibular afferents using continuous sinusoidal (0.5-0.8 Hz, 60-100 cycles, +/-2 mA) bipolar binaural GVS in 11 seated subjects. Sinusoidal GVS evoked robust vestibular illusions of "rocking in a boat" or "swinging from side to side." Cross-correlation analysis revealed a cyclic modulation of MSNA ranging from 31 to 86% across subjects (mean +/- SE 58 +/- 5%), with total MSNA increasing by 156 +/- 19% (P = 0.001). Furthermore, we documented de novo synthesis of sympathetic bursts that were coupled to the sinusoidal input, such that two bursts-rather than the obligatory single burst-could be generated within a cardiac interval. This demonstrates that the human vestibular apparatus exerts a potent facilitatory influence on MSNA that potentially operates independently of the baroreceptor system.

Sympathetic nerve activity and ventilation exhibit similar activation patterns during graded arm cycling in humans

Studies have indicated that chemically-sensitive skeletal muscle afferents (i.e., metaboreflex) contribute to the muscle sympathetic nerve activity (MSNA) and ventilatory (VE) response to exercise. This information has mainly been derived from static exercise paradigms with post exercise circulatory occlusion to isolate the metaboreflex. Therefore, we sought to determine if any relationship exists between MSNA and VE during dynamic exercise. We reasoned that if the metaboreflex was a major stimulant for MSNA and VE, then both variables would follow a similar response pattern and temporal profile during graded exercise. Eight subjects performed continuous graded arm cycling to near maximal workloads while MSNA was directly measured from the peroneal nerve. In all subjects the MSNA and VE responses were closely related throughout exercise (r=0.91±0.02, p<0.01). Slight increases in MSNA and VE at the early stages of exercise were followed by clear thresholds at which time both variables concomitantly increased in a more abrupt fashion. The MSNA threshold occurred at an oxygen uptake (VO2) of 864±95 ml/min (52±3% VO2peak), while the VE threshold occurred at a comparable VO2 of 1,035±85 ml/min (62±2% VO2peak). These findings indicate that during graded dynamic arm exercise MSNA and VE follow similar patterns of activation whereby large increases are not found until a certain intensity of exercise is attained (~55% VO2peak). This profile of activation suggests that the metaboreflex plays an important role in mediating both the MSNA and VE response to dynamic exercise in humans. Supported by NIH Grant #HL-045547