Impairment of sympathetic activation during static exercise in patients with muscle phosphorylase deficiency (McArdle''s disease).

Static exercise in normal humans causes reflex increases in muscle sympathetic nerve activity (MSNA) that are closely coupled to the contraction-induced decrease in muscle cell pH, an index of glycogen degradation and glycolytic flux. To determine if sympathetic activation is attenuated when muscle glycogenolysis is blocked due to myophosphorylase deficiency (McArdle's disease), an inborn enzymatic defect localized to skeletal muscle, we now have performed microelectrode recordings of MSNA in four patients with McArdle's disease during static handgrip contraction. A level of static handgrip that more than doubled MSNA in normal humans had no effect on MSNA and caused an attenuated rise in blood pressure in the patients with myophosphorylase deficiency. In contrast, two nonexercise sympathetic stimuli, Valsalva's maneuver and cold pressor stimulation, evoked comparably large increases in MSNA in patients and normals. The principal new conclusion is that defective glycogen degradation in human skeletal muscle is associated with a specific reflex impairment in sympathetic activation during static exercise.     

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.     

Reflex Inhibition of Renal Sympathetic Nerve Activity during Myocardial Ischemia Mediated by Left Ventricular Receptors with Vagal Afferents in Dogs

The major goal of this investigation was to determine if activation of cardiac receptors during coronary artery occlusion could inhibit efferent renal sympathetic nerve activity. In nine chloralose anesthetized dogs with only carotid (n = 3) or with sinoaortic (n = 6) baroreceptors operative, anterior descending coronary artery (LAD) occlusion resulted in a small decrease in mean arterial pressure (-9.8+/-5.1 mm Hg, NS) and in a significant (P < 0.05) increase in renal nerve activity (24.0+/-4.1%). In these dogs, circumflex coronary artery (Cx) occlusion resulted in greater hypotension (-18.4+/-4.0 mm Hg), and yet no change (1.1+/-9%) in renal nerve activity was noted. Changes in left atrial pressure during LAD and Cx occlusion were not different. In seven dogs with carotid sinus denervation, coronary occlusions resulted in decreases both in arterial pressure and in renal nerve activity which were consistently greater during Cx occlusion. The responses to coronary occlusion in six dogs after sinoaortic deafferentation were similar to those observed with only carotid sinuses denervated. In all experiments, vagotomy abolished the difference in the blood pressure responses and the decreases in renal sympathetic nerve activity during Cx occlusion. Vagotomy also abolished the decrease in nerve activity during LAD occlusion in dogs with carotid or sinoaortic denervation. These data show that Cx occlusion and, to a lesser degree, LAD occlusion resulted in reflex withdrawal of renal sympathetic nerve activity mediated by left ventricular receptors with vagal afferents. The reflex withdrawal of renal nerve activity during Cx occlusion occurred in spite of hypotension and the presence of functioning sinoaortic baroreceptors.     

Interaction of baroreceptor and chemoreceptor reflex control of sympathetic nerve activity in normal humans.

Animal studies have demonstrated that activation of the baroreflex by increases in arterial pressure inhibits cardiovascular and ventilatory responses to activation of peripheral chemoreceptors (PC) with hypoxia. In this study, we examined the influences of baroreflex activation on the sympathetic response to stimulation of PC and central chemoreceptors in humans. PC were stimulated by hypoxia (10% O2/90% N2) (n = 6) and central chemoreceptors by hypercapnia (7% CO2/93% O2) (n = 6). Responses to a cold pressor stimulus were also obtained as an internal reflex control to determine the selectivity of the interactive influence of baroreflex activation. Baroreflex activation was achieved by raising mean blood pressure by greater than 10 mmHg with intravenous infusion of phenylephrine (PE). Sympathetic nerve activity (SNA) to muscle was recorded from a peroneal nerve (microneurography). During hypoxia alone, SNA increased from 255 +/- 92 to 354 +/- 107 U/min (P less than 0.05). During PE alone, mean blood pressure increased and SNA decreased to 87 +/- 45 U/min (P less than 0.05). With hypoxia during baroreflex activation with PE, SNA did not increase (50 +/- 23 U/min). During hypercapnia alone, SNA increased from 116 +/- 39 to 234 +/- 72 U/min (P less than 0.01). Hypercapnia during baroreflex activation with PE increased SNA from 32 +/- 25 U/min during PE alone to 61 +/- 26 U/min during hypercapnia and PE (P less than 0.05). Like hypercapnia (but unlike hypoxia) the cold pressor test also increased SNA during PE. We conclude that baroreflex activation selectively abolishes the SNA response to hypoxia but not to hypercapnia or the cold pressor test. The inhibitory interaction of the baroreflex and the peripheral chemoreflex may be explained by convergence of baroreceptor and peripheral chemoreceptor afferents on neurons in the medulla.     

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.     

Forearm elevation augments sympathetic activation during handgrip exercise in humans

Although angina pectoris in patients with coronary heart disease often occurs when their forearms are in an elevated position for a prolonged period, and sympathetic activation is a major cause of this condition, little is known about the physiological effects of forearm elevation on sympathetic activity during forearm exercise. We hypothesized that forearm elevation augments sympathetic activation during the static handgrip exercise in humans. A total of 10 healthy male volunteers performed 2 min of static handgrip exercise at 30% of maximal voluntary contraction followed by 2 min of post-exercise muscle ischaemia (PEMI; specific activation of the muscle metaboreflex) with two forearm positions: the exercising forearm was elevated 50 cm above the heart (forearm-elevated trial) or fixed at the level of the heart (heart-level trial). Muscle sympathetic nerve activity (MSNA), blood pressure and heart rate were monitored. MSNA increased during handgrip exercise in both forearm positions (P<0.001); the increase was 51% greater in the forearm-elevated trial (516+/-99 arbitrary units) than in the heart-level trial (346+/-44 units; P<0.05). The increase in mean blood pressure was 8.4 mmHg greater during exercise in the forearm-elevated trial (P<0.05), while changes in heart rate were similar in both forearm positions. The increase in MSNA during PEMI was 71% greater in the forearm-elevated trial (393+/-71 arbitrary units/min) than in the heart-level trial (229+/-29 units/min; P<0.05). These results support the hypothesis that forearm elevation augments sympathetic activation during handgrip exercise. The excitatory effect of forearm elevation on exercising MSNA may be mediated primarily by increased activation of the muscle metaboreflex.     

Differential control of heart rate and sympathetic nerve activity during dynamic exercise. Insight from intraneural recordings in humans.

We used microelectrode recordings of muscle sympathetic nerve activity (MSNA) from the peroneal nerve in the leg during arm exercise in conscious humans to test the concept that central command and muscle afferent reflexes produce mass sympathetic discharge at the onset of exercise. Nonischemic rhythmic handgrip and mild arm cycling produced graded increases in heart rate and arterial pressure but did not increase MSNA, whereas ischemic handgrip and moderate arm cycling dramatically increased MSNA. There was a slow onset and offset of the MSNA responses, which suggested metaboreceptor mediation. When forearm ischemia was continued after ischemic handgrip, MSNA remained elevated (muscle chemoreflex stimulation) but heart rate returned to control (elimination of central command). The major new conclusions are that: the onset of dynamic exercise does not produce mass, uniform sympathetic discharge in humans, and muscle chemoreflexes and central command appear to produce differential effects on sympathetic and parasympathetic responses.     

Differential sympathetic neural control of oxygenation in resting and exercising human skeletal muscle.

Metabolic products of skeletal muscle contraction activate metaboreceptor muscle afferents that reflexively increase sympathetic nerve activity (SNA) targeted to both resting and exercising skeletal muscle. To determine effects of the increased sympathetic vasoconstrictor drive on muscle oxygenation, we measured changes in tissue oxygen stores and mitochondrial cytochrome a,a3 redox state in rhythmically contracting human forearm muscles with near infrared spectroscopy while simultaneously measuring muscle SNA with microelectrodes. The major new finding is that the ability of reflex-sympathetic activation to decrease muscle oxygenation is abolished when the muscle is exercised at an intensity > 10% of maximal voluntary contraction (MVC). During high intensity handgrip, (45% MVC), contraction-induced decreases in muscle oxygenation remained stable despite progressive metaboreceptor-mediated reflex increases in SNA. During mild to moderate handgrips (20-33% MVC) that do not evoke reflex-sympathetic activation, experimentally induced increases in muscle SNA had no effect on oxygenation in exercising muscles but produced robust decreases in oxygenation in resting muscles. The latter decreases were evident even during maximal metabolic vasodilation accompanying reactive hyperemia. We conclude that in humans sympathetic neural control of skeletal muscle oxygenation is sensitive to modulation by metabolic events in the contracting muscles. These events are different from those involved in either metaboreceptor muscle afferent activation or reactive hyperemia.     

Effects of intranasal cocaine on sympathetic nerve discharge in humans.

Cocaine-induced cardiovascular emergencies are mediated by excessive adrenergic stimulation. Animal studies suggest that cocaine not only blocks norepinephrine reuptake peripherally but also inhibits the baroreceptors, thereby reflexively increasing sympathetic nerve discharge. However, the effect of cocaine on sympathetic nerve discharge in humans is unknown. In 12 healthy volunteers, we recorded blood pressure and sympathetic nerve discharge to the skeletal muscle vasculature using intraneural microelectrodes (peroneal nerve) during intranasal cocaine (2 mg/kg, n = 8) or lidocaine (2%, n = 4), an internal local anesthetic control, or intravenous phenylephrine (0.5-2.0 microg/kg, n = 4), an internal sympathomimetic control. Experiments were repeated while minimizing the cocaine-induced rise in blood pressure with intravenous nitroprusside to negate sinoaortic baroreceptor stimulation. After lidocaine, blood pressure and sympathetic nerve discharge were unchanged. After cocaine, blood pressure increased abruptly and remained elevated for 60 min while sympathetic nerve discharge initially was unchanged and then decreased progressively over 60 min to a nadir that was only 2+/-1% of baseline (P < 0.05); however, plasma venous norepinephrine concentrations (n = 5) were unchanged up to 60 min after cocaine. Sympathetic nerve discharge fell more rapidly but to the same nadir when blood pressure was increased similarly with phenylephrine. When the cocaine-induced increase in blood pressure was minimized (nitroprusside), sympathetic nerve discharge did not decrease but rather increased by 2.9 times over baseline (P < 0.05). Baroreflex gain was comparable before and after cocaine. We conclude that in conscious humans the primary effect of intranasal cocaine is to increase sympathetic nerve discharge to the skeletal muscle bed. Furthermore, sinoaortic baroreflexes play a pivotal role in modulating the cocaine-induced sympathetic excitation. The interplay between these excitatory and inhibitory neural influences determines the net effect of cocaine on sympathetic discharge targeted to the human skeletal muscle circulation.     

The role of carotid chemoreceptors in the sympathetic activation by adenosine in humans

The direct vasodilatory and negative chronotropic effects of adenosine in humans are counterbalanced by a reflex increase in sympathetic nerve traffic. A suggested mechanism for this reflex includes peripheral chemoreceptor activation. We, therefore, assessed the contribution of carotid chemoreceptors to sympatho-excitation by adenosine. Muscle sympathetic nerve activity was recorded during adenosine infusion (140 microg.kg(-1).min(-1) for 5 min) in five patients lacking carotid chemoreceptors after bilateral carotid body tumour resection (one male and four female, mean age 51 +/- 11 years) and in six healthy controls (two male and four female, mean age 50 +/- 7 years). Sympathetic responses to sodium nitroprusside injections were assessed to measure baroreceptor-mediated sympathetic activation. In response to adenosine, controls showed no change in blood pressure, an increase in heart rate (+48.2 +/- 13.2%; P<0.003) and an increase in sympathetic nerve activity (+195 +/- 103%; P<0.022). In contrast, patients showed a decrease in blood pressure (-14.6 +/- 4.9/-17.6 +/- 6.0%; P<0.05), an increase in heart rate (+25.3 +/- 8.4%; P<0.032) and no significant change in sympathetic activity. Adenosine-induced hypotension in individual patients elicited less sympathetic activation than equihypotensive sodium nitroprusside injections. In humans lacking carotid chemoreceptors, adenosine infusion elicits hypotension due to the absence of significant sympatho-excitation. Chemoreceptor activation is essential for counterbalancing the direct vasodilation by adenosine. In addition, blunting of the baroreflex sympathetic response to adenosine-induced hypotension may indicate a direct sympatho-inhibitory effect of adenosine.     

Differential effects of hyperinsulinemia and carbohydrate metabolism on sympathetic nerve activity and muscle blood flow in humans.

Euglycemic hyperinsulinemia evokes both sympathetic activation and vasodilation in skeletal muscle, but the mechanism remains unknown. To determine whether insulin per se or insulin-induced stimulation of carbohydrate metabolism is the main excitatory stimulus, we performed, in six healthy lean subjects, simultaneous microneurographic recordings of muscle sympathetic nerve activity, plethysmographic measurements of calf blood flow, and calorimetric determinations of carbohydrate oxidation rate. Measurements were made during 2 h of: (a) insulin/glucose infusion (hyperinsulinemic [6 pmol/kg per min] euglycemic clamp), (b) exogenous glucose infusion at a rate matched to that attained during protocol a, and (c) exogenous fructose infusion at the same rate as for glucose infusion in protocol b. For a comparable rise in carbohydrate oxidation, insulin/glucose infusion that resulted in twofold greater increases in plasma insulin concentrations than did glucose infusion alone, evoked twofold greater increases in both muscle sympathetic nerve activity and calf blood flow. Fructose infusion, which increased carbohydrate oxidation comparably, but had only a minor effect on insulinemia, did not stimulate either muscle sympathetic nerve activity or calf blood flow. These observations suggest that in humans hyperinsulinemia per se, rather than insulin-induced stimulation of carbohydrate metabolism, is the main mechanism that triggers both sympathetic activation and vasodilation in skeletal muscle.     

Baroreflex impairment precedes hypertension during chronic cerebroventricular infusion of hypertonic sodium chloride in rats

Osmotic minipumps were implanted chronically for continuous 11-d infusion of hypertonic sodium chloride (NaCl) into the third cerebral ventricle (ICV) of awake rats to determine whether baroreflex sensitivity would be altered. Systolic and mean pressures, recorded from aortic catheters on day 11 while the rats were anesthetized with alpha-chloralose, were significantly higher in rats infused with artificial cerebrospinal fluid (CSF) containing hypertonic NaCl than in controls similarly infused with artificial CSF alone. Reflex changes in heart rate produced by subsequent intravenous infusions of either phenylephrine or sodium nitroprusside were inhibited, but reflex changes in renal nerve activity were unaltered. Magnitude of reflex bradycardia during pressor responses to phenylephrine, as well as of reflex tachycardia during depressor responses to sodium nitroprusside, was consistently smaller in NaCl-infused than in control rats. By contrast, group differences in attendant renal nerve firing were not significant. After sinoaortic denervation, drug-induced blood pressure effects persisted, but reflex responses in heart rate and renal nerve firing were abolished or markedly diminished. Peripheral effects produced by hypertonic NaCl leakage from the infusion site were considered unlikely because after 11 d of ICV infusion, sodium concentration, though appreciably elevated in CSF samples collected from the cisterna magna, was unaffected in corresponding serum samples. When cardiovascular responses to phenylephrine were recorded while chronic ICV infusions were in progress, awake rats receiving hypertonic NaCl were still normotensive on day 2 yet reflex bradycardia was already attenuated. In showing that baroreflex impairment preceded the development of hypertension, our results suggest that by depressing the anterior hypothalamus, chronic ICV infusion of hypertonic NaCl reduces sympatho-inhibition, and the ensuing baroreflex impairment then elevates blood pressure. However, other mechanisms could also be involved.     

Sympathetic nerve discharge is coupled to muscle cell pH during exercise in humans.

We used phosphorus nuclear magnetic resonance spectroscopy (31P-NMR) to probe the cellular events in contracting muscle that initiate the reflex stimulation of sympathetic outflow during exercise. In conscious humans, we performed 31P-NMR on exercising forearm muscle and simultaneously recorded muscle sympathetic nerve activity (MSNA) with microelectrodes in the peroneal nerve to determine if the activation of MSNA is coupled to muscle pH, an index of glycolysis, or to the concentrations (II) of inorganic phosphate (Pi) and adenosine diphosphate (ADP) which are modulators of mitochondrial respiration. During both static and rhythmic handgrip, the onset of sympathetic activation in resting muscle coincided with the development of cellular acidification in active muscle. Furthermore, increases in MSNA were correlated closely with decreases in intracellular pH but dissociated from changes in phosphocreatine [( PCr]), [Pi], and [ADP]. The principal new conclusion is that activation of muscle sympathetic outflow during exercise in humans is coupled to the cellular accumulation of protons in contracting muscle.     

How sympathetic tone maintains or alters arterial pressure

Summary— After chronic sympathectomy or sinoaortic denervation (SAD), arterial pressure (AP) becomes extremely unstable, especially because of movement-related depressor episodes. The simultaneous measurement of AP and regional blood flows in sympathectomized and SAD rats indicates that these depressor episodes are accompanied by strong regional vasodilations, possibly involving an autoregulatory component. The sympathetic nervous system, mainly through baroreflex modulation of its activity, overrides these responses and thereby, considerably limits the AP variability. In the conscious unrestrained rat, AP fluctuates in a narrow range (variation coefficients calculated over 1-hour beat-to-beat recordings are typically −5%). This variability of AP involves sympathetically-mediated pressor episodes that are coupled to behavior and alerting environmental stimuli. Regarding the latter, studies in SAD rats point to an opposing interaction between centrally-induced sympathoexcitation and baroreflex activation. Another component of normal AP variability appears as an oscillation centered around 0.4 Hz. Spectral analysis of AP and regional hemodynamic variables indicates that this oscillation is secondary to rhythmic fluctuations in the vasomotor sympathetic tone that are synchronized by the arterial baroreceptor reflex. It is concluded that both stability and normal variability of AP critically depend on the baroreflex control of the sympathetic vascular tone.     

Spontaneous 'baroreflex sequences' occur as deterministic functions of breathing phase

Parallel increases or decreases of systolic pressures and R-R intervals occur spontaneously in healthy resting humans, and are thought to be expressions of vagal baroreflex physiology. We studied ten healthy supine young adults, and tested the null hypothesis that spontaneous baroreflex sequences are distributed uniformly throughout the breathing cycle. We recorded the electrocardiogram, photoplethysmographic arterial pressure, respiration (pneumobelt), and peroneal nerve muscle sympathetic activity in supine subjects who breathed spontaneously, or held their breaths in inspiration after 2 min of hyperventilation with 100% oxygen. We analysed pairs of three or more increasing or decreasing systolic pressures and R-R intervals with linear regression, and related the gain and timing of the onset of such sequences to the phase of respiration, and to preceding muscle sympathetic nerve activity. We found that baroreflex sequences occur erratically, at a frequency about one-third that of breathing. However, when baroreflex sequences do occur, the timing of their onset is dictated by the phase of respiration. Parallel increases of systolic pressures and R-R intervals ('up' sequences) begin just before and after the beginning of expiration, and parallel decreases of systolic pressures and R-R intervals ('down' sequences) begin during late expiration and inspiration. Average gains of up and down baroreflex sequences triggered by muscle sympathetic bursts are comparable during breathing and apnoea. However, the latencies between sympathetic bursts and baroreflex sequences are less during breathing than during apnoea. We propose that parallel systolic pressure--R-R interval sequences are expressions of arterial baroreflex physiology, and that the nearly fixed timing of such sequences within breaths reflects simply respiratory gating of muscle sympathetic bursts.     

Sympathetic and baroreceptor reflex function in neurally mediated syncope evoked by tilt.

The pathophysiology of neurally mediated syncope is poorly understood. It has been widely assumed that excessive sympathetic activation in a setting of left ventricular hypovolemia stimulates ventricular afferents that trigger hypotension and bradycardia. We tested this hypothesis by determining if excessive sympathetic activation precedes development of neurally mediated syncope, and if this correlates with alterations in baroreflex function. We studied the changes in intraarterial blood pressure (BP), heart rate (HR), central venous pressure (CVP), muscle sympathetic nerve activity (MSNA), and plasma catecholamines evoked by upright tilt in recurrent neurally mediated syncope patients (SYN, 5+/-1 episodes/mo, n = 14), age- and sex-matched controls (CON, n = 23), and in healthy subjects who consistently experienced syncope during tilt (FS+, n = 20). Baroreflex responses were evaluated from changes in HR, BP, and MSNA that were obtained after infusions of phenylephrine and sodium nitroprusside. Compared to CON, patients with SYN had blunted increases in MSNA at low tilt levels, followed by a progressive decrease and ultimately complete disappearance of MSNA with syncope. SYN patients also had attenuation of norepinephrine increases and lower baroreflex slope sensitivity, both during tilt and after pharmacologic testing. FS+ subjects had the largest decrease in CVP with tilt and had significant increases in MSNA and heart rate baroreflex slopes. These data challenge the view that excessive generalized sympathetic activation is the precursor of the hemodynamic abnormality underlying recurrent neurally mediated syncope.     

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).     

The effects of rilmenidine on tests of autonomic function in humans.

The effects of rilmenidine, a new centrally acting antihypertensive agent, on a number of tests of autonomic function were investigated in six healthy male volunteers. Baroreflex function (delta RR interval [in milliseconds] with each millimeter of mercury change in systolic blood pressure) was determined in response to changes in pressure after injections of phenylephrine and nitroglycerin. Reflex cardiovascular responses to handgrip and standing, as well as during deep breathing and the Valsalva maneuver, were also investigated. Rilmenidine produced a dose-dependent decrease in blood pressure that was not accompanied by an increase in heart rate. Under conditions of low basal sympathetic activity, rilmenidine enhanced parasympathetic tone during the early reflex heart rate changes that occur immediately after standing and during deep breathing, as well as baroreflex heart rate responses to phenylephrine. During a test of sympathetic function, standing blood pressure, and heart rate after 3 minutes, rilmenidine reduced sympathetic tone.     

Role of norepinephrine in the lack of reflex tachycardia after angiotensin converting enzyme inhibitor treatment.

Angiotensin converting enzyme inhibitors decrease blood pressure without causing reflex tachycardia in hypertensives, but do not always do so in normotensives. To investigate this phenomenon, hemodynamic changes in normotensive rabbits receiving a subpressor dose of norepinephrine were studied following captopril or diltiazem treatment. We also investigated the effect of captopril on baroreceptor reflex in relation to norepinephrine infusion; the baroreflex sensitivity was determined by the relationship between mean arterial pressure and pulse interval receiving graded doses of phenylephrine. Captopril infusion decreased mean arterial pressure and pulse interval from 84 +/- 4 to 74 +/- 5 mmHg and 244 +/- 7.4 to 216 +/- 7.6 msec, respectively. In contrast, in rabbits receiving a norepinephrine infusion captopril lowered mean arterial pressure to the same extent (92 +/- 5 to 76 +/- 3 mmHg, p less than 0.05) without producing reflex tachycardia. When diltiazem was administered, reflex tachycardia occurred in rabbits both with and without a norepinephrine infusion. There was no difference in the baroreflex sensitivity between rabbits receiving norepinephrine with and without captopril treatment. However, the baroreflex curve showed a slight shift to lower pressures after norepinephrine infusion in the rabbits receiving captopril. These results suggest that elevating circulating norepinephrine might be involved in preventing reflex tachycardia after captopril.     

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.