Effects of three days of dry immersion on muscle sympathetic nerve activity and arterial blood pressure in humans

The present study was performed to determine how sympathetic function is altered by simulated microgravity, dry immersion for 3 days, and to elucidate the mechanism of post-spaceflight orthostatic intolerance in humans. Six healthy men aged 21-36 years old participated in the study. Before and after the dry immersion, subjects performed head-up tilt (HUT) test to 30 degrees and 60 degrees (5 min each) with recordings of muscle sympathetic nerve activity (MSNA, by microneurography), electrocardiogram, and arterial blood pressure (Finapres). Resting MSNA was increased after dry immersion from 23.7+/-3.2 to 40.9+/-3.0 bursts/min (p<0.005) without significant changes in resting heart rate (HR). MSNA responsiveness to orthostasis showed no significant difference but HR response was significantly augmented after dry immersion (p<0. 005). A significant diastolic blood pressure fall at 5th min of 60 degrees HUT was observed in five orthostatic tolerant subjects despite enough MSNA discharge after dry immersion. A subject suffered from presyncope at 2 min after 60 degrees HUT. He showed gradual blood pressure fall 10 s after 60 degrees HUT with initially well-maintained MSNA response and then with a gradually attenuated MSNA, followed by a sudden MSNA withdrawal and abrupt blood pressure drop. In conclusion, dry immersion increased MSNA without changing MSNA response to orthostasis, and resting HR, while increasing the HR response to orthostasis. Analyses of MSNA and blood pressure changes in orthostatic tolerant subjects and a subject with presyncope suggested that not only insufficient vasoconstriction to sympathetic stimuli, but also a central mechanism to induce a sympathetic withdrawal might play a role in the development of orthostatic intolerance after microgravity exposure.     

Effects of stimulation of the hypothalamic paraventricular nucleus on blood pressure and renal sympathetic nerve activity

Effects of electrical and chemical stimulation of the paraventricular nucleus (PVN) of the hypothalamus on blood pressure were examined in rats anesthetized with urethane-chloralose. Focal electrical stimulation (10-25 microA, 50 Hz, 0.5 msec) within the PVN consistently decreased blood pressure. Microinjection of L-glutamate (0.5 M, 80 n1) into the PVN led to a decrease in blood pressure, while the same amount of saline injection had no effect. The depressor response was not affected by cervical vagotomy. In order to obtain direct evidence for involvement of sympathetic nerve activity in the PVN-induced depressor response, effects of PVN stimulation on renal sympathetic nerve activity were examined. Low intensity electrical stimulation of the PVN inhibited renal sympathetic nerve activity, whereas the high intensity stimulation evoked a transient excitation followed by long lasting inhibition in renal sympathetic nerve activity. Latencies of the inhibitory and the excitatory responses were about 200 msec and 50-100 msec, respectively, judged by peristimulus time histograms. The result suggests that activation of PVN neurons produces a decrease in blood pressure due to inhibition of sympathetic outflows.     

Effects of prolactin-releasing peptide microinjection into the ventrolateral medulla on arterial pressure and sympathetic activity in rats

Prolactin-releasing peptide (PrRP), originally isolated from the hypothalamus, is highly localized in the cardiovascular regions of the medulla, and intracerebroventricular administration of PrRP causes a pressor response. In the present study we investigated the cardiovascular effects of PrRP applied to functionally different areas of the ventrolateral medulla (VLM), and to the nucleus tractus solitarius (NTS) and the area postrema (AP). In urethane-anesthetized rats, microinjection of PrRP into the pressor area of the most caudal VLM, recognized as the caudal pressor area in the rat, elicited dose-dependent increases in mean arterial pressure, heart rate, and renal sympathetic nerve activity. In the same injection area, neither thyrotropin-releasing hormone, corticotropin-releasing hormone nor angiotensin II affected these baseline cardiovascular variables. On the other hand, microinjection of PrRP into more rostral parts of the VLM, i.e. the depressor area of the caudal VLM and the pressor area of the rostral VLM, as well as the NTS and the AP, had no effect on these cardiovascular variables. Immunohistochemical analysis in the medulla revealed that the cardiovascularly PrRP-responsive region contained PrRP-immunoreactive cell bodies and nerve fibers. These results suggest that the most caudal VLM is an action site of PrRP to induce a pressor response, which is mediated, at least partly, by the increase in sympathetic outflow.     

Effects of hypoxia on muscle response to tendon vibration in humans

Previous animal studies have shown that hypoxia markedly reduces the activation of muscle spindles. The present study was undertaken to determine whether a reduced oxygen supply to muscle affects the tonic vibration reflex (TVR) in humans. In resting healthy volunteers, the effects of inhalation of hypoxic gas, apnea, and total forearm ischemia produced by cuff inflation were studied on separate days. The TVR was recorded in flexor digitorum superficialis and the neuromuscular conduction time (CT) was measured from the compound muscle action potential; the latency and amplitude of the H reflex were also determined. TVR depression began during inhalation of the hypoxic gas, at the end of apnea, and during cuff inflation, and persisted during the recovery period. The H-reflex amplitude concomitantly increased or remained unchanged. Thus, hypoxia seems to directly alter muscle spindle reactivity. Such alterations of sensorimotor control may occur in patients suffering from respiratory or circulatory insufficiency and may contribute to their exercise limitation.     

Effect of L-threo-3,4-dihydroxyphenylserine on muscle sympathetic nerve activity in humans.

To clarify the effect of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS), a precursor of norepinephrine (NE), the effect of this drug on microneurographically recorded muscle sympathetic nerve activity (MSA) from the tibial nerve was analyzed in ten healthy male volunteers. A single dose of 600 mg of L-threo-DOPS was orally administered and the effect of this norepinephrine precursor on MSA at resting and at upright standing positions, as well as the MSA responsiveness to head-up tilting was examined by comparing the data obtained after administration of the drug with those obtained under control conditions. The plasma NE levels were determined in two subjects. The results were as follows: (1) resting MSA increased significantly 80 min after administration of L-threo-DOPS and was accompanied by an increase in plasma NE levels; (2) standing MSA when treated with the drug was not significantly different from values obtained under control conditions; and (3) MSA responsiveness to orthostasis was reduced after L-threo-DOPS. We conclude from the activation of MSA by L-threo-DOPS that this drug raised blood pressure not only through an increase in metabolized plasma NE levels, but also through the enhancement of MSA by activation of descending noradrenergic or adrenergic pathways proximal to the recording site of the sympathetic discharge.     

Changes in muscle sympathetic nerve activity during sleep in humans.

We microneurographically recorded muscle sympathetic nerve activity (MSA) during sleep in 12 healthy volunteers while simultaneously recording EEG, EOG, ECG, respiration, and blood pressure and determined the number of pulse-synchronous MSA bursts per minute (burst rate) for non-rapid eye movement (nonREM) sleep and rapid eye movement (REM) sleep. MSA decreased during nonREM sleep with progressively deeper sleep stages. During REM sleep, the burst rate of MSA increased and was associated with marked fluctuations in arterial blood pressure. During sleep stage 2, MSA bursts occurred approximately 1 second after spontaneous K-complexes. We conclude that (1) the decreases in MSA during nonREM sleep stages may indicate sleep-stage dependent central suppression of MSA activity; (2) increases in MSA during REM sleep suggest instability of the autonomic nervous system; and (3) a common pathway may exist for MSA bursts and K-complexes.     

Effects of glucagon-like peptide-1 and sympathetic stimulation on gastric accommodation in humans.

In humans, glucagon-like peptide-1 (GLP-1) delays gastric emptying by inhibiting vagal activity and also increases gastric volumes, by unclear mechanisms. Because GLP-1 inhibits intestinal motility by stimulating the sympathetic nervous system in rats, we assessed the effects of a GLP-1 agonist and yohimbine, an alpha(2)-adrenergic antagonist, on gastric volumes in humans. In this double-blind study, 32 healthy volunteers were randomized to placebo, a GLP-1 agonist, yohimbine or GLP-1 and yohimbine. Gastric volumes (fasting predrug and postdrug, and postprandial postdrug) were measured by (99m)Tc single photon emission computed tomography imaging. Plasma catecholamines and haemodynamic parameters were assessed. Compared with placebo, GLP-1 increased (P = 0.03) but yohimbine did not affect fasting gastric volume. However, GLP-1 plus yohimbine increased (P < 0.001) postprandial gastric accommodation vs placebo and vs GLP-1 alone [postprandial volume change = 542 +/- 29 mL (mean +/- SEM, placebo), 605 +/- 31 mL (GLP-1), 652 +/- 54 mL (yohimbine) and 810 +/- 37 mL (GLP-1 and yohimbine)]. Plasma noradrenaline and dihydroxyphenylglycol concentrations were higher for yohimbine vs placebo and for GLP-1 and yohimbine vs GLP-1. Yohimbine stimulates central sympathetic activity and in combination with GLP-1, augments postprandial accommodation in humans.     

Awareness of high blood pressure influences on psychological and sympathetic responses.

The aim of the present study was to examine the effects of awareness of hypertension on psychological factors and whether there was an association between psychological and sympathetic responses. To avoid self-selection bias 32 19-yr old white men, all with mean blood pressure of 116 mm Hg were randomized into two groups. One group was informed that the blood pressure was elevated and asked to come to a second examination while the other was invited to take part in a coronary heart disease prevention program. A cold pressor test was undertaken and the subjects completed the Karolinska Scale of Personality (KSP). Assessed by the KSP, the informed group showed lower verbal aggression (p less than 0.01), irritability (p less than 0.05), monotony avoidance (p less than 0.05) and impulsiveness (p less than 0.05), higher detachment (p less than 0.05) but no significant differences in the other subscales like anxiety, psychasthenia or factors of hostility. Information significantly increased resting blood pressure and increments in heart rate and plasma adrenaline responses to cold pressor test. Thus, both psychological and sympathetic responses were influenced by awareness of high blood pressure. There were significant correlations between less assertive behaviour and increased plasma catecholamines.     

Psychosocial conflict in the tree shrew: Effects on sympathoadrenal activity and blood pressure

We investigated the influence of psychosocial conflict (PSC) on systolic blood pressure (BP) and on sympathoadrenal activity in male tree shrews. BP was recorded and urinary epinephrine and norepinephrine were determined daily during a 10-day control period and a subsequent 10-day period of PSC. At the end of the experiments, levels of adrenal tyrosine hydroxylase (TH), phenylethanolamine-N-methyl transferase (PNMT), epinephrine, and norepinephrine were determined. The reactivity of the sympathoadrenal system and of BP depended on the social position achieved. In subordinates, urinary norepinephrine excretion was constantly elevated while epinephrine excretion was elevated only transiently. Adrenal norepinephrine, epinephrine, and TH were increased whereas PNMT remained unaffected. Despite the sympathoadrenal arousal, the increase in BP was only temporary. In dominant animals, PSC had no effects on BP, adrenal parameters or urinary norepinephrine. These results reinforce the concept of distinctive neuroendocrine and hemodynamic response patterns to psychosocial stimuli depending on the type and degree of control which an individual can exert over the challenge.     

Effects of centrally administered angiotensin on sympathetic nerve activity and blood flow to the kidney in conscious rats

The effects of intracerebroventricular (i.c.v.) administration of different doses (10 pg-100 ng) of angiotensin II (AII) on renal sympathetic nerve activity (RSNA), mean arterial blood pressure (MAP), heart rate (HR), renal blood flow and femoral blood flow have been examined in conscious rats. Administration of AII (10 ng) through a chronically implanted cannula induced an increase in MAP (20-22 mmHg), a decrease in HR (24 bpm), a decrease in RSNA by 57%, a decrease of femoral blood flow by 21% but no change in renal blood flow. The effects on MAP, HR and RSNA are greatly attenuated by the prior i.c.v. injection of an AII-antagonist saralasin. In anesthetized rats, renal denervation significantly attenuated an increase in urinary sodium excretion induced by i.c.v. injection of AII. Since activation of the renal nerve is known to induce sodium reabsorption from the renal tubule and renin release, the relevance of the present finding is discussed in relation to the effect of AII on sodium excretion.     

Superoxide anions modulate the effects of alarin in the paraventricular nucleus on sympathetic activity and blood pressure in spontaneously hypertensive rats

Neuropeptides are involved in the regulation of the sympathetic activity and blood pressure in the paraventricular nucleus of the hypothalamus (PVN). The present study was designed to determine how alarin modulates the renal sympathetic nerve activity (RSNA), arterial blood pressure and mean arterial pressure (MAP) in the PVN, and whether superoxide anions regulate the effects of alarin in the PVN of spontaneously hypertensive rats (SHRs). Acute experiment was carried out with male Wistar-Kyoto rats (WKY) and SHRs under anesthesia. RSNA, systolic blood pressure (SBP), diastolic blood pressure (DBP), and MAP were measured. Alarin microinjection into the PVN increased RSNA (7.8 ± 1.8 vs. 14.8 ± 2.3%), SBP (5.9 ± 1.4 vs. 12.1 ± 1.6 mmHg), DBP (5.1 ± 0.8 vs. 10.0 ± 1.1 mmHg), and MAP (5.4 ± 1.2 vs. 10.7 ± 1.3 mmHg) in WKY rats and SHRs,. Alarin antagonist ala6–25 Cys decreased RSNA, SBP, DBP, and MAP in SHRs, and inhibited the effects of alarin. The alarin level was increased in the PVN of SHR compared to WKY rats. (29.7 ± 4.9 vs. 14.6 ± 2.4 pg/mg protein). PVN microinjection of superoxide anion scavengers tempol and tiron, or NAD(P)H oxidase inhibitor apocynin, decreased RSNA, SBP, DBP, and MAP in SHRs, and inhibited the effects of alarin, but the superoxide dismutase inhibitor diethyldithiocarbamic acid potentiated the effects of alarin. Superoxide anions and NAD(P)H oxidase activity levels in the PVN were increased by alarin, but decreased by alarin antagonist ala6–25 Cys. The alarin-induced increases in superoxide anions and NAD(P)H oxidase activity levels were abolished by pre-treatment with ala6–25 Cys. The results suggest that alarin in the PVN increases sympathetic outflow and blood pressure. The enhanced activity of endogenous alarin in the PVN contributes to sympathetic activation in hypertension, and the superoxide anion is involved in these alarin–mediated processes in the PVN.     

Resetting of the sympathetic baroreflex is associated with the onset of hypertension during chronic intermittent hypoxia

Chronic intermittent hypoxia (CIH) is a model of arterial hypoxemia that accompanies sleep apnea and increases resting arterial pressure (AP). We examined the effects of 7 days of exposure to CIH on arterial baroreflex control of renal sympathetic nerve activity (RSNA) and heart rate (HR) in rats. Sprague–Dawley rats (15 plus/minus 2 weeks old) were exposed to CIH (9% oxygen for 3 min every 10 min, 8 h per day) for 7 days (n = 16) while control rats (n = 18) were maintained in normoxia. Baroreflex regulation of RSNA and HR were estimated in Inactin anesthetized and artificially ventilated rats during infusions of phenylephrine and nitroprusside to manipulate AP. After exposure to CIH, resting mean AP was higher in CIH than that in control group (115 ± 7 vs. 105 ± 7, P < 0.001). Resting HR did not differ between the two groups. Exposure to CIH shifted the AP–RSNA relationship rightward (approximately 10 mm Hg, P < 0.01). CIH did not alter maximum gain of the baroreflex control of RSNA (? 2.6 ± 0.6 vs. ? 2.5 ± 0.6 arbitrary units (a.u.)/mm Hg) and HR (? 1.8 ± 0.6 vs. ? 1.8 ± 0.7 bpm/mm Hg, CIH vs. control). In addition, cardiac spontaneous baroreflex sensitivity in conscious rats (n = 8) also did not change during exposure to CIH. These results indicate that resetting of the sympathetic baroreflex control, rather than an impairment of its sensitivity, is associated with an onset of hypertension induced by CIH.     

Effect of nimodipine on blood pressure in acute ischemic stroke in humans

Nimodipine is currently under investigation for the treatment of acute stroke. Although relatively specific for the cerebrovasculature, acute reductions in blood pressure after a dose may adversely affect neurologic outcome. We studied 29 consecutive acute ischemic stroke patients treated with placebo (n = 9) or either 120 (n = 10) or 240 (n = 10) mg/day of nimodipine. Blood pressure was recorded before and 30 and 60 minutes after a dose for the first 8 days. Ten neurologic physicians were asked to predict the treatment group (placebo or drug) of randomly selected patients based on blood pressure results. Only those patients on 240 mg/day of nimodipine had significant decreases in blood pressure after a dose (p less than 0.001); however, these were minimal (average 10 mm Hg systolic). Only 26 of 48 treatment predictions (54%) were correct. At the studied doses, nimodipine has a minimal effect on blood pressure in the acute stroke period.     

Parallel changes in resting muscle sympathetic nerve activity and blood pressure in a hypertensive OSAS patient demonstrate treatment efficacy

Studies comparing the efficacy of continuous positive airway pressure (CPAP) versus surgery in correcting cardiovascular abnormalities in OSAS are lacking. We describe an OSAS patient with hypertension who responded favorably to CPAP treatment, whereas subsequent uvulopalatopharyngoplasty (UPPP) was less successful. While CPAP markedly lowered daytime muscle sympathetic nerve activity (MSNA) and blood pressure (BP), findings after UPPP were comparable to pre-treatment baseline. Thus, parallel changes in MSNA and BP demonstrated treatment efficacy.     

Effects of activation and blockade of P2x receptors in the ventrolateral medulla on arterial pressure and sympathetic activity.

Sympathoexcitatory and sympathoinhibitory neurons in the rostral and caudal ventrolateral medulla (VLM) play a crucial role in the tonic and reflex control of sympathetic vasomotor activity. Recent evidence also indicates that the VLM contains a high density of P2x purinoceptors. In this study, we investigated the cardiovascular effects of selective activation of P2x purinoceptors in the rostral and caudal VLM, and the effects of blockade of P2x purinoceptors in the rostral VLM on the tonic and reflex control of sympathetic vasomotor activity. In anesthetized barodenervated rabbits, microinjection into the rostral and caudal VLM of the P2x purinoceptor agonist, alpha,beta-methylene adenosine triphosphate (alpha,beta-meATP) (4-400 pmol) elicited dose-dependent increases and decreases, respectively, in arterial pressure (AP), heart rate (HR) and renal sympathetic nerve activity (RSNA). The response evoked by alpha,beta-meATP in the rostral VLM was blocked by prior injection into the same site of the P2 purinoceptor antagonist suramin but not by the ionotropic glutamate receptor antagonist kynurenic acid. Bilateral injections of suramin into the rostral VLM sympathoexcitatory region had no significant effect on resting cardiovascular variables, nor on the reflex increase in RSNA evoked by sciatic nerve stimulation (which is known to be mediated by the rostral VLM sympathoexcitatory neurons). The results demonstrate that: (1) activation of P2x purinoceptors in the VLM are capable of producing marked excitation of both sympathoexcitatory and sympathoinhibitory neurons; (2) these effects are not due to modulation of glutamatergic inputs to these neurons; and (3) P2x purinoceptors do not play a significant role in maintaining the tonic activity of rostral VLM sympathoexcitatory neurons or in modulating their responses to excitatory synaptic inputs evoked by stimulation of sciatic nerve afferents.     

Orthostatic challenge does not alter skin sympathetic nerve activity in heat-stressed humans

Perturbations that load or unload baroreceptors do not alter skin sympathetic nerve activity (SSNA) in normothermic individuals. However, in pronounced heat-stressed individuals, when a significant component of the SSNA signal is sudomotor and possibly vasodilator in origin, the effects of baroreceptor unloading via an orthostatic stress on SSNA remain unclear. The purpose of the present study was to test the hypothesis that low and moderate levels of orthostatic stress via lower body negative pressure (LBNP) alter SSNA in pronounced heat-stressed individuals. In both normothermic and heat-stressed conditions, progressive LBNP at -3, -6, -9, -12, -15, -18, -21 and -40 mm Hg were applied to 11 subjects for 2 min per stage. Whole-body heating increased sublingual temperature by 0.7+/-0.1 degrees C, heart rate by 28+/-2.1 bpm, SSNA by 259+/-76 %, forearm skin blood flow by 631+/-142% and forearm sweat rate to 0.68+/-0.14 mg/cm(2)/min (all p<0.005), but did not change mean arterial blood pressure (MAP) (p>0.05). LBNP did not change total SSNA in normothermic or heat-stressed conditions (both p>0.05), although skin blood flow and sweat rate decreased during moderate levels of LBNP while heat stressed. These data suggest that in pronounced heat-stressed individuals, when a significant component of the SSNA signal contains sudomotor and possibly cutaneous active vasodilator activities, low and moderate levels of baroreceptor unloading via LBNP do not alter total SSNA. This observation, coupled with reductions in skin blood flow and sweating during moderate levels of LBNP, suggests that integrated SSNA should not be used as an indicator of baroreflex modulation of the cutaneous vasculature or sweat rate in heat-stressed subjects.