SUMMARY. The purpose of this study was to determine the contribution of muscle afferents and central command in regulating sympathetic nerve activity during static exercise in humans. In 20 healthy subjects, we recorded heart rate, arterial pressure, and efferent sympathetic nerve activity in the leg during arm exercise. Microelectrodes were inserted percutaneously into a fascicle of the peroneal nerve to measure sympathetic discharge to muscle. Measurements were obtained in nine subjects during sustained handgrip (30% maximal voluntary contraction) followed by relaxation or by arrested circulation of the forearm. Heart rate and arterial pressure increased during the first and second minutes of handgrip. Muscle sympathetic nerve activity increased from 261 ± 46 to 504 ± 97 units (mean ± SE; units = burst frequency x amplitude; P < 0.05) during the second minute of handgrip. During forearm ischemia following handgrip, heart rate returned promptly to control, whereas arterial pressure and muscle sympathetic nerve activity (631 ±115 units) remained elevated. In contrast, muscle sympathetic nerve activity returned toward control during relaxation without arrested circulation. These data indicate that muscle sympathetic nerve activity is increased by stimulation of chemically sensitive muscle afferents. To determine the influence of central command on muscle sympathetic nerve activity, we compared responses during ar. involuntary and a voluntary biceps contraction, each at 20% maximal voluntary contraction. Both maneuvers raised arterial pressure, but heart rate increased only during voluntary contraction. More importantly, muscle sympathetic nerve activity rose during involuntary contraction, but fell during voluntary effort. These studies demonstrate that during sustained handgrip in humans, stimulation of chemically sensitive muscle afferents increases muscle sympathetic nerve activity in the leg, and central command causes tachycardia, but inhibits muscle sympathetic outflow in the leg. (Circ Res 57: 461-469, 1985)

SUMMARY The purpose of this study was to determine the effects of the cold pressor test on sympathetic outflow with direct measurements of nerve traffic in conscious humans and to test the strength of correlation between sympathetic nerve discharge and the changes in arterial pressure, heart rate, and plasma norepinephrine. In 25 healthy subjects, arterial pressure, heart rate, and muscle sympathetic nerve activity were measured with microelectrodes inserted percutaneously into a peroneal muscle nerve fascicle in the leg during immersion of the hand in ice water for 2 minutes. Arterial pressure rose steadily during the first and second minutes of the cold pressor test. Muscle sympathetic activity (burst frequency x amplitude) did not increase in the first 30 seconds of the test but increased from 230 ± 27 to 386 ± 52 units (mean ± SE, p< 0.05) by the end of the first minute of the test and to 574 ±73 (p<0.01) during the second minute. In contrast, heart rate increased maximally during the first 30 seconds of the cold pressor test and returned to control during the second minute. The increases in heart rate were abolished by /3-adrenergic blockade. The increases in muscle sympathetic activity during the cold pressor test were correlated with the increases in both mean arterial pressure (r=0.86, p<0.01) and peripheral venous norepinephrine (r=0.72, p<0.05); however, large changes in nerve traffic were associated with small changes in plasma norepinephrine. The major new conclusions from this study are that 1) stimulation of sympathetic neural outflow to skeletal muscle is an important component of the sympathetic response to the cold pressor test, 2) the cold pressor test appears to produce differentia] effects on sympathetic outflow to the heart and to the skeletal muscles, and 3) the arterial pressure response to the cold pressor test provides an approximate index of muscle sympathetic activity in this setting. (Hypertension 9: 429-436, 1987) KEY WORDS • cold pressor test norepinephrine sympathetic nerve activity • heart rate • plasma I N most healthy human subjects, cutaneous application of ice water, the cold pressor test (CPT), increases arterial pressure, heart rate, and vascular resistance.' For many years, the CPT has been Used From the Department of Medicine, the Cardiovascular Center, and the Veterans Administration Medical Center, University of Iowa College of Medicine, Iowa City, Iowa, and the Department of Clinical Neurophysiology, Sahlgrenska Hospital, Goteborg, Sweden.Supported by Clinical Investigator Award (HL01362) to Dr. Victor from the National Heart, Lung, and Blood Institute (NHLBI), by research grants HL24962 and HL14388 from the NHLBI, and by research funds from the Veterans Administration.A preliminary report of this work was presented at the annual meeting of the American College of Cardiology in Anaheim, California, March, 1985 (abstract published in J Am Coll Cardiol 19855:415).Address for reprints: Ronald G. Victor, M.D., Cardiology Division, Rm. H8.116, Department of Internal Medicin...

Patients with heart failure have increased vascular resistance and evidence for increased neurohumoral drive. High levels of circulating norepinephrine are found in patients with heart failure, but it is not known whether they reflect increased sympathetic neural activity or result from altered synthesis, release, or metabolism of norepinephrine. We used microneurography (peroneal nerve) to directly record sympathetic nerve activity to muscle (mSNA) and also measured plasma norepinephrine levels in patients with heart failure and in normal control subjects. Our goal was to determine whether sympathetic nerve activity is increased in patients with heart failure and whether plasma norepinephrine levels correlate with levels of mSNA in heart failure. Resting muscle sympathetic nerve activity in 16 patients with moderate to severe heart failure (54 + 5 bursts/min, mean + SE) was significantly higher (p < .01) than the levels of activity in either nine age-matched normal control subjects (25 ± 4 bursts/min) or 19 "young" normal control subjects (24 + 2 bursts/min). We found a significant correlation between plasma norepinephrine levels and mSNA (r = .73, p < .05). Neither mSNA nor plasma norepinephrine levels correlated with total systemic vascular resistance, cardiac index, left ventricular ejection fraction, or heart rate. However, both mSNA and plasma norepinephrine levels showed significant positive correlations (p < .05) with left ventricular filling pressures (r = .80, mSNA vs filling pressures; r = .82, norepinephrine levels vs filling pressures) and mean right atrial pressure. The results of the study provide the first direct evidence of increased central sympathetic nerve outflow in patients with heart failure and the first direct evidence that plasma norepinephrine levels show a reasonable correlation with sympathetic nerve activity to muscle in these patients. Furthermore, the data suggest that preload is an important determinant of SNA in these patients. Circulation 73, No. 5, 913-919, 1986. A HALLMARK of advanced heart failure is high peripheral vascular resistance.' Several neurohumoral factors may contribute to the increased vascular resistance, including increased activity of the renin-angiotensin system,24 elevated levels of arginine vasopressin,5 and increased activity of the sympathetic nervous

Muscle nerve sympathetic activity (MSA), the interval between two R-waves in the ECG, or the interbeat interval (RR-interval), and blood pressure (BP) were recorded in 10 awake patients with obstructive sleep apnea (OSA) and in nine sex- and age-matched controls. Changes in RR-interval and MSA, evoked by sodium nitroprusside-induced reduction of BP, were used to quantitate baroreflex sensitivity. Both the cardiac (expressed as the RR-interval versus mean arterial BP slope) and the muscle sympathetic (mean MSA area versus diastolic BP slope) baroreflex sensitivity were depressed in patients as compared with controls. Cardiac baroreflex slope sensitivity (expressed as a regression coefficient) was 5.5 +/- 1.2 (mean +/- SEM) in patients and 9.6 +/- 0.96 in controls (p < 0.05). The corresponding figures for the sympathetic slope sensitivity were -4.9 +/- 0.9 and -13.1 +/- 2.3, respectively (p < 0.05). Differences remained after stepwise correction for age, body mass index (BMI), and to some extent BP. Resting MSA correlated with cardiac (r = 0.67, p < 0.003) and sympathetic (r = 0.56, p < 0.025) baroreflex sensitivity in the entire study group. We conclude that OSA patients exhibit an impaired baroreflex sensitivity to a hypotensive stimulus, which may represent an adaptive response to changes in BP or hypoxemia occurring in association with nocturnal apneas. Baroreflex adaptation may also contribute to the augmentation of resting MSA observed in OSA patients in this as well as in a previous study.

Bilateral lidocaine blocks of glossopharyngeal and vagus nerves in the neck were made in two healthy subjects to achieve deafferentation of arterial and cardiopulmonary baroreceptors. Microelectrode recordings of muscle nerve sympathetic activity (MSA) were made in one peroneal nerve; in one subject skin sympathetic activity (SSA) was recorded simultaneously in the other peroneal nerve. Following the nerve block in the neck there was a strong increase of MSA accompanied by temporary hypertension and tachycardia. The normal cardiac rhythmicity of MSA disappeared and the outflow appeared as bursts of impulses of variable duration occurring in a slow, irregular rhythm. Thus MSA became similar to SSA, but the activities never became synchronous. During the nerve block arousal stimuli evoked single bursts of MSA, a reflex response which normally occurs in SSA but not in MSA. It is concluded that (1) cardiac rhythmicity of MSA is due to baroreceptor influence; (2) a low level of MSA at rest depends on strong baroreceptor inhibition and not on a weak central drive; (3) central sympathetic outflows to skin and muscle are similar though not identical and the different characteristics normally observed are due to a large extent to different modulatory influences from afferent activity (presumably of baroreceptor origin) in glossopharyngeal and vagus nerves; and (4) baroreceptor deafferentation resulting in resting tachycardia and hypertension may explain sympathetic hyperactivity in the Guillain-Barré syndrome.