Gender-related differences in the sympathetic vasoconstrictor drive of normal subjects

The risk of cardiovascular disease has been linked to sympathetic activation and its incidence is known to be lower in women than in men. However, the effect of gender on the sympathetic vasoconstrictor drive has not yet been established. In the present study, we investigated whether there is a gender difference in MSNA (muscle sympathetic nerve activity) and blood flow, and to determine the mechanisms involved. We examined 68 normal subjects, 34 women and 34 men, matched for age, BMI (body mass index) and waist circumference. MSNA was measured as the mean frequency of single units (s-MSNA) and as multi-unit bursts (m-MSNA) from the peroneal nerve simultaneously with its supplied muscle CBF (calf blood flow). Women had lower (P=0.0007) s-MSNA (24+/-2.0 impulses/100 cardiac beats) than men (34+/-2.3 impulses/100 cardiac beats), and a greater baroreceptor reflex sensitivity controlling efferent sympathetic nerve activity than men. The sympathetic activity was inversely and directly correlated respectively, with CBF (P=0.03) and CVR (calf vascular resistance; P=0.01) in men only. The responses of an increase in CVR to cold pressor and isometric handgrip tests were significantly smaller in women (P=0.002) than in men, despite similar increases in efferent sympathetic nerve activity. Women had a lower central sympathetic neural output to the periphery, the mechanism of which involved differences in central and reflex control, as well as a lower vasoconstrictor response to this neural output. It is suggested that this may partly explain the observed lower incidence of cardiovascular events in women compared with men.     

Sympathetic neural hyperactivity and its normalization following unstable angina and acute myocardial infarction

Impaired autonomic function occurs after AMI (acute myocardial infarction) and UA (unstable angina), which may be important prognostically. However, the pattern of sympathetic nerve hyperactivity has been investigated only after AMI. We aimed to quantify central sympathetic output to the periphery in patients with UA, investigate its progress over time relative to that after uncomplicated AMI and to explore the mechanisms involved. Muscle sympathetic nerve activity (MSNA) assessed from multiunit discharges and from single units (s-MSNA) was obtained in matched patients with UA ( n =9), AMI ( n =14) and stable CAD (coronary artery disease, n =11), patients with chest pain in which AMI was excluded (NMI, n =9) and normal controls (NCs, n =14). Measurements were obtained 2-4 days after UA or AMI, and repeated at 3 monthly intervals until they returned to normal levels. The respective MSNA and s-MSNA early after UA (72+/-4.0 bursts/100 beats and 78+/-4.2 impulses/100 beats respectively) were less than those after AMI (83+/-4.4 bursts/100 beats and 93+/-5.5 impulses/100 beats respectively). Relative to the control groups of NCs (51+/-2.7 bursts/100 beats and 58+/-3.4 impulses/100 beats respectively) and patients with CAD (54+/-3.7 bursts/100 beats and 58+/-3.9 impulses/100 beats respectively) and NMI (52+/-4.5 bursts/100 beats and 59+/-4.9 impulses/100 beats respectively), values returned to normal after 6 months in UA (55+/-5.0 bursts/100 beats and 62+/-5.5 impulses/100 beats respectively) and 9 months after AMI (60+/-3.8 bursts/100 beats and 66+/-4.2 impulses/100 beats respectively). In conclusion, both UA and AMI result in sympathetic hyper-activity, although this is of smaller magnitude in UA and is less protracted than in AMI. It is suggested that this hyperactivity is related to the degree of left ventricular dysfunction and reflexes.     

Cardiac vagal response to water ingestion in normal human subjects

In healthy young subjects there is direct evidence for sympathetic vasoconstrictor activation after drinking water, but this is not accompanied by an increase in arterial blood pressure. A marked pressor response to water ingestion has, however, been observed in elderly subjects and in patients with autonomic failure. We examined the effect of water ingestion on haemodynamic variables and heart rate variability (HRV) markers of cardiac vagal control in ten healthy young subjects and four cardiac transplant recipients with confirmed persistent cardiac vagal denervation. In a random order crossover protocol, changes in heart rate, blood pressure and measures of high frequency (HF) HRV were compared over time following the ingestion of 500 ml and 20 ml (control) of tap water. In healthy subjects, after drinking 500 ml of water the heart rate fell from 67.6+/-2.0 (mean+/-S.E.M.) to 60.7+/-2.4 beats/min (P<0.01), and the bradycardic response peaked between 20 and 25 min. There were no significant changes in arterial blood pressure. Over the same time course, water ingestion caused increases in measurements of HF HRV: root-mean-square of successive RR interval differences (RMSSD) increased by 13+/-2.7 ms after 500 ml versus 2+/-3.1 ms after 20 ml (P<0.05); HF power increased by 686+/-400 versus -63+/-322 (P<0.01). In transplant recipients water ingestion was followed by a pressor response (range 13 to 29 mmHg). These results provide evidence that water ingestion in normal subjects is followed by an increase in cardiac vagal control that may counteract the pressor effects of sympathetic activation. We suggest that in the elderly, in transplant recipients and in autonomic failure, loss of this buffering mechanism explains the pressor response to drinking water.     

Attenuated cardiac baroreflex in men with presyncope evoked by lower body negative pressure

Mechanisms responsible for presyncope during lower body negative pressure (LBNP) in otherwise healthy subjects are poorly understood. Muscle sympathetic nerve activity (MSNA), blood pressure, heart rate (HR), HR power spectra, central venous pressure (CVP) and stroke volume were determined in 14 healthy men subjected to incremental LBNP. Of these, seven experienced presyncope at LBNP >-15 mmHg. Subjects who tolerated LBNP >-15 mmHg had significantly lower CVP (2.6+/-1.0 versus 7.2+/-1.2 mmHg; means+/-S.E.M., P<0.02), HR (59+/-2 versus 66+/-3 beats/min, P<0.05) and MSNA burst frequency (29.0+/-2.4 versus 39.0+/-3.5 bursts/min, P<0.05) during supine rest. LBNP at -15 mmHg had no effect on blood pressure, but caused similar and significant reductions in stroke volume and cardiac output in both groups. Subjects who tolerated LBNP had significant reflex increases in HR, MSNA burst frequency and burst amplitude with LBNP of -15 mmHg. These responses were absent in those who experienced presyncope. The gain of the cardiac baroreflex regulation of MSNA was markedly attenuated in pre-syncopal subjects (1.2+/-0.6 versus 8.8+/-1.4 bursts/100 heart beats per mmHg; P<0.001). Healthy subjects who experience presyncope in response to LBNP appear more dependent, when supine, upon MSNA to maintain preload, and less able to increase sympathetic vasoconstrictor discharge to skeletal muscle reflexively in response to orthostatic stimuli.     

Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans.

Hyperinsulinemia may contribute to hypertension by increasing sympathetic activity and vascular resistance. We sought to determine if insulin increases central sympathetic neural outflow and vascular resistance in humans. We recorded muscle sympathetic nerve activity (MSNA; microneurography, peroneal nerve), forearm blood flow (plethysmography), heart rate, and blood pressure in 14 normotensive males during 1-h infusions of low (38 mU/m2/min) and high (76 mU/m2/min) doses of insulin while holding blood glucose constant. Plasma insulin rose from 8 +/- 1 microU/ml during control, to 72 +/- 8 and 144 +/- 13 microU/ml during the low and high insulin doses, respectively, and fell to 15 +/- 6 microU/ml 1 h after insulin infusion was stopped. MSNA, which averaged 21.5 +/- 1.5 bursts/min in control, increased significantly (P less than 0.001) during both the low and high doses of insulin (+/- 5.4 and +/- 9.3 bursts/min, respectively) and further increased during 1-h recovery (+15.2 bursts/min). Plasma norepinephrine levels (119 +/- 19 pg/ml during control) rose during both low (258 +/- 25; P less than 0.02) and high (285 +/- 95; P less than 0.01) doses of insulin and recovery (316 +/- 23; P less than 0.01). Plasma epinephrine levels did not change during insulin infusion. Despite the increased MSNA and plasma norepinephrine, there were significant (P less than 0.001) increases in forearm blood flow and decreases in forearm vascular resistance during both doses of insulin. Systolic pressure did not change significantly during infusion of insulin and diastolic pressure fell approximately 4-5 mmHg (P less than 0.01). This study suggests that acute increases in plasma insulin within the physiological range elevate sympathetic neural outflow but produce forearm vasodilation and do not elevate arterial pressure in normal humans.     

Haemodynamics of the pressor effect of oral water in human sympathetic denervation due to autonomic failure

Oral water ingestion increases blood pressure in normal elderly subjects and in patients suffering from autonomic failure, but the time course of the haemodynamic changes is not known. We therefore studied 14 subjects with documented sympathetic denervation due to pure autonomic failure, with continuous haemodynamic recordings obtained before and after ingestion of 500 ml of distilled water at room temperature. The time course of changes in values of systolic and diastolic beat-by-beat finger blood pressure, heart rate, stroke volume, cardiac output, ejection fraction and total peripheral resistance were analysed. Systolic blood pressure rose from 115+/-8 mmHg (mean+/-S.E.M.) to 133+/-8 mmHg (P<0.001), and diastolic blood pressure from 64+/-4 to 73+/-4 mmHg (P<0.001), with the pressor response beginning a few minutes after water ingestion, plateauing between 10 and 35 min (peak at 14 min), and returning to baseline at 50 min. Heart rate fell from 71+/-2.5 to 67+/-2 beats/min (P<0.001), and total peripheral resistance increased from 1.31+/-0.19 to 1.61+/-0.24 m-units (P<0.001). There were no significant changes in ejection fraction, stroke volume or cardiac output. This study confirmed a pressor response to oral water in subjects with sympathetic denervation. The temporal profile of the response did not favour reflexly mediated sympathetic activation. As subjects with autonomic failure are prone to salt and water depletion, and since blood pressure is exquisitely sensitive to such changes, it may be that the observed response is due to repletion or restoration of intravascular and extravascular fluid volume.     

Influence of sibutramine treatment on sympathetic vasomotor tone in obese subjects

BACKGROUND: Sibutramine, a serotonin and norepinephrine transporter blocker, is used as adjunctive obesity treatment. Studies in healthy subjects suggested that sibutramine might have opposing effects on peripheral and central sympathetic activity; an increase in blood pressure has been claimed. Direct measurements of muscle sympathetic nerve activity (MSNA) in sibutramine-treated patients have not been conducted. METHODS AND RESULTS: Twenty nondiabetic obese men and women completed the study (mean body mass index, 35 +/- 3 kg/m2; mean age, 42 +/- 8 years). They were treated for 5 days with 15 mg sibutramine per day or matching placebo in a randomized, double-blind, crossover fashion. At the end of each intervention, heart rate, blood pressure, and MSNA were recorded. Patients underwent cold pressor testing and phenylephrine and nitroprusside infusions. RESULTS: The mean blood pressure (systolic/diastolic) was 118 +/- 13 mm Hg/70 +/- 9 mm Hg with placebo and 120 +/- 13 mm Hg/69 +/- 8 mm Hg with sibutramine (P = .29). The mean resting MSNA was 28 +/- 14 bursts/min with placebo and 12 +/- 10 bursts/min with sibutramine (P < .0001). Sibutramine attenuated the rise in blood pressure (25 +/- 9 mm Hg/9 +/- 9 mm Hg versus 31 +/- 12 mm Hg/14 +/- 9 mm Hg, P < .01) and MSNA (0.3 +/- 0.5 arbitrary units/min versus 1.0 +/- 1.1 arbitrary units/min, P = .01) in response to cold pressor testing. Baroreflex heart rate control was similar with sibutramine and with placebo. The sympathetic baroreflex was shifted such that at a given blood pressure, MSNA was substantially decreased (top, 44 +/- 1.23 bursts/min versus 58 +/- 2.99 bursts/min [P < .001]; center point, 65 +/- 0.32 mm Hg versus 67 +/- 0.81 mm Hg [P < .05]). CONCLUSIONS: Sibutramine treatment profoundly and selectively reduces sympathetic nerve traffic at rest and attenuates the responsiveness to sympathetic stimuli. Our data support the idea that sibutramine's peripheral sympathomimetic effect is counteracted by a central sympatholytic mechanism.     

Carbohydrate ingestion, with transient endogenous insulinaemia, produces both sympathetic activation and vasodilatation in normal humans

It has been shown that sustained insulin infusion causes an increase in sympathetic vasoconstrictor discharge but, despite this, also causes peripheral vasodilatation. The present study was designed to determine in healthy subjects the effect of ingestion of a carbohydrate meal, with its attendant physiological insulinaemia, on vascular resistance in and sympathetic vasoconstrictor discharge to the same vascular bed, and the relationship between these parameters. Fifteen healthy subjects were studied for 2 h following ingestion of a carbohydrate meal. Calf vascular resistance was measured by venous occlusion plethysmography, and muscle sympathetic nerve activity was assessed by peroneal microneurography. Five of the subjects also ingested water on a separate occasion, as a control. Following the carbohydrate meal, the serum insulin concentration increased to 588+/-72 pmol/l. This was associated with a 47% increase in skeletal muscle blood flow (P<0.001), a 39% fall in vascular resistance (P<0.001) and a 57% increase in sympathetic activity (P<0.001). There was a significant correlation between the increase in insulin and the changes in blood flow, vascular resistance and sympathetic activity. In conclusion, we have shown that ingestion of a carbohydrate meal, with its attendant physiological insulinaemia, was associated with overriding skeletal muscle vasodilatation, despite an increase in sympathetic vasoconstrictor discharge to the same vascular bed. These mechanisms may be important in ensuring optimal glucose uptake and maintenance of blood pressure postprandially.     

Impaired insulin-induced sympathetic neural activation and vasodilation in skeletal muscle in obese humans.

The sympathetic nervous system is an important regulatory mechanism of both metabolic and cardiovascular function, and altered sympathetic activity may play a role in the etiology and/or complications of obesity. In lean subjects, insulin evokes sympathetic activation and vasodilation in skeletal muscle. In obese subjects such vasodilation is impaired and, in turn, may contribute to insulin resistance. To examine the relationship between sympathetic and vasodilatory responses in skeletal muscle to hyperinsulinemia, we simultaneously measured muscle sympathetic nerve activity (MSNA) and calf blood flow at basal and during a 2-h hyperinsulinemic (6 pmol/kg per min) euglycemic clamp in eight lean and eight obese subjects. The major findings of this study are twofold: obese subjects had a 2.2 times higher fasting rate of MSNA, and euglycemic hyperinsulinemia, which more than doubled MSNA and increased calf blood flow by roughly 30% in lean subjects, had only a minor vasodilatory and sympathoexcitatory effect in obese subjects. In contrast, two non-insulin-sympathetic stimuli evoked comparably large increases in MSNA in lean and obese subjects. We conclude that insulin resistance in obese subjects is associated with increased fasting MSNA and a specific impairment of sympathetic neural responsiveness to physiological hyperinsulinemia in skeletal muscle tissue.     

Dissociation between microneurographic and heart rate variability estimates of sympathetic tone in normal subjects and patients with heart failure.

The concept that spectral analysis of heart rate variability (HRV) can estimate cardiac sympathetic nerve traffic in subjects with both normal and impaired left ventricular systolic function has not been validated against muscle sympathetic nerve activity (MSNA). We used coarse-graining spectral analysis to quantify the harmonic and non-harmonic, or fractal, components of HRV and to determine low-frequency (0.0-0.15 Hz; PL) and high-frequency (0.15-0.5Hz; PH) harmonic power. To test the hypothesis that MSNA and HRV representations of sympathetic nerve activity (PL and PL/PH) increase in parallel in heart failure, we recorded heart rate and MSNA during supine rest in 35 patients (age 52.4+/-2 years; mean+/-S. E.M.), with a mean left ventricular ejection fraction of 22+/-2%, and in 34 age-matched normal subjects. Power density was log10 transformed. Mean MSNA was 52.9+/-2.6 bursts/min in heart failure patients and 34.9+/-1.9 bursts/min in normal subjects (P<0.0001). In normal subjects, but not in heart failure patients, total power (PT) (r=-0.41; P=0.02) and fractal power (PF) (r=-0.36; P=0.04) were inversely related to age. In heart failure patients, total and fractal power were reduced (P<0.009 for both), and were inversely related to MSNA burst frequency (r=-0.55, P=0.001 and r=-0.60, P=0. 0003 respectively). In normal subjects, there was no relationship between MSNA and either PL or PH. In heart failure patients, as anticipated, PH was inversely related to MSNA (r=-0.41; P<0.02). However, PL was also inversely rather than directly related to MSNA (r=0.44 for 1/log10 PL; P<0.01). There was no relationship between other sympathetic (PL/PH) or parasympathetic (PH/PT) indices and MSNA in either heart failure patients or normal subjects. The lack of concordance between these direct and indirect estimates of sympathetic nervous system activity indicates that this component of HRV cannot be used for between-subject comparisons of central sympathetic nervous outflow. It is the absence of low-frequency power that relates most closely to sympathetic activation in heart failure.     

Sympathetic response to oral carbohydrate administration. Evidence from microelectrode nerve recordings.

Microneurography was used to measure sympathetic outflow in human muscle nerves (MSA) for up to 90 min after the ingestion of 100 g D-glucose, 75.8 g D-xylose, intravenous D-glucose (0.35 g/kg), and 300 ml water. 19 healthy subjects were examined using a microelectrode positioned in the right peroneal nerve. MSA increased from 21 +/- 0.9 bursts/min at rest to 36.9 +/- 4.3 bursts/min 30 min after ingestion of D-glucose and from 18.9 +/- 2.9 to 26.3 +/- 3.4 bursts/min 30 min after D-xylose. The increase in MSA was already significant by 15 min. MSA had not returned to the basal level after 90 min. Neither intravenous D-glucose nor water intake enhanced MSA. MSA increased in parallel with plasma norepinephrine, and a significant correlation (r = 0.55; P less than 0.001) was observed between the plasma insulin concentration and MSA after D-glucose ingestion. In three subjects the outflow of sympathetic nerve activity to the skin was examined after oral D-glucose and no change was observed, emphasizing the differentiated nature of the sympathetic nerve response to carbohydrate. Multiple factors such as insulin alone, hemodynamic adjustment to splanchnic vasodilation, and gastrointestinal distension are probably involved in the increased muscle nerve sympathetic outflow after carbohydrate ingestion.     

Forearm vasoconstrictor response in uncomplicated type 1 diabetes mellitus

BACKGROUND: According to the 'haemodynamic hypothesis', increased tissue perfusion predisposes to microangiopathy in diabetic patients. We hypothesized that the typical haemodynamic changes underlying the increased tissue perfusion can be explained by a decreased sympathetic nerve activity caused by chronic hyperglycaemia. In this study we investigated sympathetic activity in patients with uncomplicated type 1 diabetes mellitus (DM). MATERIALS AND METHODS: In 15 DM patients (DM duration 6.3 +/- 3.8 year; HbA1c 7.9 +/- 1.3%) and 16 age- and sex-matched healthy volunteers (Control), sympathetic nervous system activity was measured at rest (baseline) and during sympathoneural stimulation (lower body negative pressure (LBNP)) by means of interstitial and plasma noradrenaline (NA) sampling and power spectral analysis. Muscle sympathetic nerve activity (MSNA) was measured before (baseline) and during a cold pressure test. Forearm blood flow was measured during forearm vascular alpha- and beta-adrenergic receptor blockade. RESULTS: At baseline, forearm vascular resistance (FVR), plasma NA concentrations, MSNA and heart rate variability were similar in both groups. LBNP-induced vasoconstriction was significantly attenuated in the DM group compared with the Control group (DeltaFVR: 12 +/- 4 vs. 19 +/- 3 arbitrary units, P < 0.05). The responses of plasma NA and heart rate variability did not differ. CONCLUSIONS: Baseline FVR and sympathetic nerve activity are normal in patients with uncomplicated type 1 diabetes. However, the forearm vasoconstrictor response to sympathetic stimulation is attenuated, which cannot be attributed to an impaired sympathetic responsiveness.     

Pregnancy-induced sympathetic overactivity: a precursor of preeclampsia

BACKGROUND: Preeclampsia has been shown to constitute a state of sympathetic overactivity. However, it remains unclear if the sympathetic activity precedes preeclampsia or represents only a secondary phenomenon. To further investigate this issue, we performed a prospective study in pregnant women considered to be at increased risk for preeclampsia owing to preeclampsia during a preceding pregnancy. MATERIALS AND METHODS: Twenty-two women with a history of preeclampsia were longitudinally studied on three occasions: twice during pregnancy (M1: 22 +/- 4, M2: 33 +/- 5 weeks) and once postpartum (M3: 26 +/- 6 weeks postpartum). We measured muscle sympathetic nerve activity (MSNA), forearm blood flow, and blood pressure at rest and during reactive hyperaemia after forearm occlusion. RESULTS: At M1 and M2, none of the subjects was hypertensive, however, muscle sympathetic nerve activity levels were significantly augmented, compared with their postpartum values (M1: 21 +/- 9, M2: 29 +/- 14, M3: 9 +/- 5 bursts min(-1); P < 0.05). Forearm vascular resistance did not significantly change from M1 through M3 (M1: 16 +/- 9, M2: 15 +/- 7, M3: 16 +/- 7 U; P = NS). Gestational muscle sympathetic nerve activity values did not differ significantly among the subjects with subsequent preeclampsia compared with those who remained normotensive [with preeclampsia (n = 6): M1: 21 +/- 5, M2: 27 +/- 6, M3: 7 +/- 4 bursts min(-1); without preeclampsia (n = 16): M1: 21 +/- 11, M2: 30 +/- 16, M3: 9 +/- 6 bursts min(-1); P = NS]. CONCLUSION: Invariably, all women at risk for preeclampisa showed a pregnancy-induced increase in MSNA (pregnancy-induced sympathetic overactivity, PISO), which normalized after delivery. Most importantly, PISO is not necessarily associated with peripheral vasoconstriction and hypertension. Furthermore, only a subset of patients developed preeclampsia later on. Therefore, we hypothesize that PISO constitutes a precursor of preeclampsia which is physiologically compensated for by vasodilating mechanisms, leading to preeclampsia only when they fail.     

Sympathetic reflex control of subcutaneous blood flow in patients with congestive heart failure

Central and local regulation of forearm subcutaneous vascular resistance (FSVR) during postural changes were studied in congestive heart failure (CHF). Blood flow was measured by the local 133Xe-washout technique. Nine patients with severe CHF (baseline angiographic ejection fraction, 23 +/- 2%, mean +/- SEM; cardiac index, 2.2 +/- 0.2 litres min-1 m-2; increased left ventricular pressures and dimensions) were compared with seven control subjects who had normal cardiac performance. Baseline FSVR and plasma concentrations of noradrenaline and adrenaline were substantially higher in patients with CHF than control subjects. However, the patients, like control subjects, increased FSVR by 46 +/- 3% in response to increase in local venous transmural pressure and disclosed a normal response to decrease in forearm perfusion pressure. Both responses to changes in vascular transmural pressure were preserved after either proximal nervous blockade or local beta-receptor blockade. Central sympathetic stimulation was induced with use of 45 degrees upright tilt. Control subjects developed vasoconstriction (FSVR increased by 59 +/- 5%), which was completely abolished after proximal nerve blockade. Patients with CHF developed vasodilatation (FSVR decreased by 24 +/- 8%), which was not only abolished but reversed after proximal nerve blockade (FSVR increased by 22 +/- 7%), probably owing to the increased humoral vasoconstrictor activity. The paradoxical vasodilator response to central sympathetic stimulation in these patients was reversed after local beta-receptor blockade (FSVR increased by 19 +/- 9%). The local vasoconstrictor reflex responsiveness and intrinsic vascular reactivity were not affected by the augmented baseline sympathetic vasoconstrictor activity in patients with CHF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sympathetic activation in exercise is not dependent on muscle acidosis. Direct evidence from studies in metabolic myopathies.

Muscle acidosis has been implicated as a major determinant of reflex sympathetic activation during exercise. To test this hypothesis we studied sympathetic exercise responses in metabolic myopathies in which muscle acidosis is impaired or augmented during exercise. As an index of reflex sympathetic activation to muscle, microneurographic measurements of muscle sympathetic nerve activity (MSNA) were obtained from the peroneal nerve. MSNA was measured during static handgrip exercise at 30% of maximal voluntary contraction force to exhaustion in patients in whom exercise-induced muscle acidosis is absent (seven myophosphorylase deficient patients; MD [McArdle's disease], and one patient with muscle phosphofructokinase deficiency [PFKD]), augmented (one patient with mitochondrial myopathy [MM]), or normal (five healthy controls). Muscle pH was monitored by 31P-magnetic resonance spectroscopy during handgrip exercise in the five control subjects, four MD patients, and the MM and PFKD patients. With handgrip to exhaustion, the increase in MSNA over baseline (bursts per minute [bpm] and total activity [%]) was not impaired in patients with MD (17+/-2 bpm, 124+/-42%) or PFKD (65 bpm, 307%), and was not enhanced in the MM patient (24 bpm, 131%) compared with controls (17+/-4 bpm, 115+/-17%). Post-handgrip ischemia studied in one McArdle patient, caused sustained elevation of MSNA above basal suggesting a chemoreflex activation of MSNA. Handgrip exercise elicited an enhanced drop in muscle pH of 0.51 U in the MM patient compared with the decrease in controls of 0.13+/-0.02 U. In contrast, muscle pH increased with exercise in MD by 0.12+/-0.05 U and in PFKD by 0.01 U. In conclusion, patients with glycogenolytic, glycolytic, and oxidative phosphorylation defects show normal muscle sympathetic nerve responses to static exercise. These findings indicate that muscle acidosis is not a prerequisite for sympathetic activation in exercise.     

Muscle sympathetic nerve activity during isometric exercise in patients with cerebrovascular accidents

OBJECTIVES: To define isometric exercise-induced pressor responses in patients with cerebrovascular accidents (CVAs) and to assess potential cardiovascular and sympathetic nervous system abnormalities during isometric exercise in CVA. DESIGN: Nonrandomized study. SETTING: University laboratory setting. PARTICIPANTS: Eight men with CVA who had documented damage of subcortical structures and 8 sex-matched controls. INTERVENTIONS: A 2-minute sustained contraction of elbow flexor muscles in the unaffected side at 35% of maximal voluntary contraction (MVC; isometric exercise). MAIN OUTCOME MEASURES: Heart rate, arterial blood pressure, and muscle sympathetic nerve activity (MSNA), recorded from the peroneal nerve on the affected side. RESULTS: The percent changes in total MSNA, heart rate, and mean blood pressure in patients with CVA increased during isometric exercise but were attenuated compared with the controls. Total MSNA (mean burst amplitude per minute times burst rate) increased significantly in CVA and control subjects during isometric exercise by 18.7%+/-6.3% and 95.8%+/-25.2%, respectively. CONCLUSIONS: The attenuated pressor responses during isometric exercise in subjects with CVA relative to the controls indicated damage to subcortical structures; such damage lowered sympathetic nervous response to isometric exercise. Our findings suggest that isometric exercise at 35% of MVC does not put patients with CVA at risk for serious tachycardia or hypertension.     

Effect of burst-mode transcutaneous electrical nerve stimulation on peripheral vascular resistance

BACKGROUND AND PURPOSE: Based on changes in skin temperature alone, some authors have proposed that postganglionic sympathetic vasoconstrictor fibers can be stimulated transcutaneously. Our goal was to determine the effects of low-frequency (2 bursts per second), burst-mode transcutaneous electrical nerve stimulation (TENS) on calf vascular resistance, a more direct marker of sympathetic vasoconstrictor outflow than skin temperature, in subjects with no known pathology. SUBJECTS: Fourteen women and 6 men (mean age=31 years, SD=13, range=18-58) participated in this study. METHODS: Calf blood flow, arterial pressure, and skin temperature were measured while TENS was applied over the common peroneal and tibial nerves. RESULTS: Blood flow immediately following stimulation was not affected by TENS applied just under or just above the threshold for muscle contraction. Transcutaneous electrical nerve stimulation applied at 25% above the motor threshold caused a transient increase in calf blood flow. Regardless of stimulation intensity, TENS had no effect on arterial pressure; therefore, calf vascular resistance decreased only during the trial that was 25% above the motor threshold. Regardless of stimulation intensity, TENS failed to alter dorsal or plantar skin temperature. DISCUSSION AND CONCLUSION: These results demonstrate that the effects of TENS on circulation depend on stimulation intensity. When the intensity was sufficient to cause a moderate muscle contraction, a transient, local increase in blood flow occurred. Cooling of the dorsal and plantar skin occurred in both the stimulated and control legs, most likely because skin temperature acclimatized to ambient room temperature, rather than because of any effect of TENS on circulation. The data, therefore, call into question the idea that postganglionic sympathetic efferent fibers are stimulated when TENS is applied at clinically relevant intensities to people without symptoms of cardiovascular or neuromuscular pathology.     

Limb congestion and sympathoexcitation during exercise. Implications for congestive heart failure.

During static exercise, heart failure (HF) subjects activate the sympathetic nervous system differently than normal controls. HF causes metaboreceptor desensitization with either enhanced mechanoreceptor activity or central command. In this report, we examined whether increased muscle interstitial pressure, as seen in HF, augments other neural systems. We measured muscle sympathetic nerve activity (MSNA; peroneal nerve) in 10 normals during static exercise (40% maximal voluntary grip) and posthandgrip circulatory arrest (PHG-CA). This was repeated after venous congestion (VC; cuff inflation to 90 mmHg). VC increased forearm volume (plethysmography) by 4.7%. MSNA responses to exercise were greater after VC (150.5 +/- 41.8 vs. 317.3 +/- 69.9 arbitrary units; P < 0.01). However, MSNA responses during PHG-CA were not affected by VC, and 31P nuclear magnetic resonance (n = 5) demonstrated no effect of VC on pH or H2PO4-. Similar effects of VC on MSNA were noted after ischemic exercise (n = 7), excluding flow alterations as the explantation. VC probably sensitized mechanically sensitive afferents since MSNA during involuntary biceps contractions increased after VC (n = 6), and skin sympathetic nerve responses during handgrip, an index of central command, were not increased by VC (n = 6).     

Role of adenosine in the sympathetic activation produced by isometric exercise in humans.

Isometric exercise increases sympathetic nerve activity and blood pressure. This exercise pressor reflex is partly mediated by metabolic products activating muscle afferents (metaboreceptors). Whereas adenosine is a known inhibitory neuromodulator, there is increasing evidence that it activates afferent nerves. We, therefore, examined the hypothesis that adenosine stimulates muscle afferents and participates in the exercise pressor reflex in healthy volunteers. Intraarterial administration of adenosine into the forearm, during venous occlusion to prevent systemic effects, mimicked the response to exercise, increasing muscle sympathetic nerve activity (MSNA, lower limb microneurography) and mean arterial blood pressure (MABP) at all doses studied (2, 3, and 4 mg). Heart rate increased only with the highest dose. Intrabrachial adenosine (4 mg) increased MSNA by 96 +/- 25% (n = 6, P < 0.01) and MABP by 12 +/- 3 mmHg (P < 0.01). Adenosine produced forearm discomfort, but equivalent painful stimuli (forearm ischemia and cold exposure) increased MSNA significantly less than adenosine. Furthermore, adenosine receptor antagonism with intrabrachial theophylline (1 microgram/ml forearm per min) blocked the increase in MSNA (92 +/- 15% vs. 28 +/- 6%, n = 7, P < 0.01) and MABP (38 +/- 6 vs. 27 +/- 4 mmHg, P = 0.01) produced by isometric handgrip (30% of maximal voluntary contraction) in the infused arm, but not the contralateral arm. Theophylline did not prevent the increase in heart rate produced by handgrip, a response mediated more by central command than muscle afferent activation. We propose that endogenous adenosine contributes to the activation of muscle afferents involved in the exercise pressor reflex in humans.     

The increase in sympathetic nerve activity after glucose ingestion is reduced in type I diabetes

Food intake is followed by an increase in baroreflex-governed sympathetic outflow to muscle vessels. It is established that insulin contributes to this stimulation; however, the increase occurs (to a lesser degree) even in the absence of enhanced insulin secretion. To further elucidate the role of insulin, muscle nerve sympathetic activity was recorded by microneurography, and the increase after an oral 100-g glucose load in eight C-peptide-negative patients with type I diabetes without any signs of neuropathy was compared with that in 16 healthy control subjects. The level of sympathetic activity at rest was similar in the two groups (type I diabetes patients, 19.5+/-2.4 bursts/min; controls, 20.4+/-4.8 bursts/min; means+/-S.D.). Following glucose intake there was a significant increase in activity in both groups, with maximum values at 30 min of 24.3+/-3.7 bursts/min for type I diabetes patients and 34.4+/-9.1 bursts/min for controls. The summarized response (during 90 min) of the diabetic patients was less than half that of the control subjects (P=0.0003). It is concluded that the response of muscle nerve sympathetic activity to glucose ingestion is reduced to about half of its normal strength in the absence of insulin, and that there is no difference in sympathetic outflow at rest between healthy subjects and diabetic patients without polyneuropathy.