Autonomic Cardiovascular Responses in Acclimatized Lowlanders on Prolonged Stay at High Altitude: A Longitudinal Follow Up Study

Acute exposure to hypobaric hypoxia at high altitude is reported to cause sympathetic dominance that may contribute to the pathophysiology of high altitude illnesses. The effect of prolonged stay at high altitude on autonomic functions, however, remains to be explored. Thus, the present study aimed at investigating the effect of high altitude on autonomic neural control of cardiovascular responses by monitoring heart rate variability (HRV) during chronic hypobaric hypoxia. Baseline electrocardiography (ECG) data was acquired from the volunteers at mean sea level (MSL) (<250 m) in Rajasthan. Following induction of the study population to high altitude (4500–4800 m) in Ladakh region, ECG data was acquired from the volunteers after 6 months (ALL 6) and 18 months of induction (ALL 18). Out of 159 volunteers who underwent complete investigation during acquisition of baseline data, we have only included the data of 104 volunteers who constantly stayed at high altitude for 18 months to complete the final follow up after 18 months. HRV parameters, physiological indices and biochemical changes in serum were investigated. Our results show sympathetic hyperactivation along with compromise in parasympathetic activity in ALL 6 and ALL 18 when compared to baseline data. Reduction of sympathetic activity and increased parasympathetic response was however observed in ALL 18 when compared to ALL 6. Our findings suggest that autonomic response is regulated by two distinct mechanisms in the ALL 6 and ALL 18. While the autonomic alterations in the ALL 6 group could be attributed to increased sympathetic activity resulting from increased plasma catecholamine concentration, the sympathetic activity in ALL 18 group is associated with increased concentration of serum coronary risk factors and elevated homocysteine. These findings have important clinical implications in assessment of susceptibility to cardio-vascular risks in acclimatized lowlanders staying for prolonged duration at high altitude.     

Cardiac MIBG imaging at the edge of clinical application in heart failure

Neuronal innervation plays a crucial role in cardiac function. The heart is richly innervated with sympathetic and parasympathetic fibers that work in conjunction with circulating catecholamine mediators, such as norepinephrine (NE), to tightly regulate cardiac output at rest and during periods of increased cardiac demand. An impairment of cardiac autonomic function, most often the result of cardiac disease (ischemic or nonischemic cardiomyopathy), can reflect the severity of the condition, and in many cases is associated with and likely contributing to worsening of the clinical condition, increasing the potential for life-threatening cardiac arrhythmias and death. Because cardiac autonomic function involves numerous molecular processes, use of radiotracers for imaging is an ideal method of assessment.     

Proinsulin C-peptide activates vagus efferent output in rats

The aim of this study was to examine the effect of proinsulin C-peptide on the autonomic nervous systems in rats. Intravenous administration of C-peptide gradually increased electrophysiological activity of the vagus nerves into the stomach and pancreas for at least 90 min. It also slightly increased gastric acid secretion that was suppressed by the treatment with atropine. Intraperitoneal injection of C-peptide did not affect the basal and stress-induced norepinephrine (NE) turnover rate, a biochemical index of sympathetic nerve activity. These results indicate that C-peptide increases parasympathetic nerve activity without affecting sympathetic nerve activity. This could explain, at least in part, the ameliorating effects of C-peptide on impaired cardiac autonomic nerve functions in patients with type 1 diabetes.     

Vascular control of the pig nasal mucosa: distribution and effect of somatostatin in relation to noradrenaline and neuropeptide Y

By means of immunohistochemistry and radioimmunoassay (RIA), we have investigated the possible occurrence of somatostatin (SOM)-like immunoreactivity (-LI) in the autonomic innervation of the pig nasal mucosa. SOM-immunoreactive (-IR) fibres were present around nasal arteries, arterioles and venous sinusoids. Double-labelling experiments revealed that SOM-LI was co-localized with the noradrenaline (NA) markers tyrosine hydroxylase and dopamine-β-hydroxylase as well as with neuropeptide Y (NPY) in a subpopulation of neurons in the superior cervical sympathetic ganglion and in perivascular nerve terminals. Furthermore, SOM-LI was also present in perivascular fibres containing vasoactive intestinal polypeptide (VIP) and NPY of presumably parasympathetic origin. The parasympathetic fibres that were associated with glands contained peptide histidine isoleucine (PHI), VIP and NPY but not SOM, suggesting that in the nasal mucosa SOM-IR is restricted to perivascular nerves. As revealed by RIA, the content of SOM-LI in biopsies of both nasal mucosa and superior cervical sympathetic ganglion was about 12 pmol/g and the reverse phase HPLC characterisation of SOM-LI shown two separate peaks for SOM-28 and SOM-14.     

Autonomic control of heart rate differs with electrocortical activity and chronic hypoxaemia in fetal lambs

We aimed to determine the effects of the electrocortical (ECoG) cycle on fetal heart rate and its autonomic control under normoxaemic and hypoxaemic conditions. Heart rate was measured and selective pharmacological blockade was used to quantify sympathetic and parasympathetic tone in low voltage (LV) and high voltage (HV) ECoG. We studied 3 groups of fetal lambs: 6 normal-sized, normoxaemic fetuses (control); 5 growth-retarded, normoxaemic carunclectomy fetuses (carunclectomy-normoxaemic); and 5 growth-retarded, hypoxaemic carunclectomy fetuses (carunclectomy-hypoxaemic). We found slower heart rate in LV compared to HV ECoG in all groups. This was explained by greater parasympathetic tone in LV in all groups, and by a complementary change of sympathetic tone in control fetuses. Hypoxaemic fetuses had slower heart rate than normoxaemic fetuses in both ECoG states. This was due to augmented parasympathetic tone (in LV ECoG) and reduced sympathetic tone (in LV and HV ECoG). We conclude that complementary changes of autonomic tone underly the normal variation of fetal heart rate with the ECoG cycle, with the parasympathetic arm dominant in LV and the sympathetic arm dominant in HV ECoG. In chronic hypoxaemia, complementary changes of autonomic tone contribute to slowing of fetal heart rate. Increased parasympathetic tone and decreased sympathetic tone may enhance cardiac efficiency when the oxygen supply is chronically reduced.     

Effects of sleep pressure on endogenous cardiac autonomic activity and body temperature.

This study investigated the effects of variations in sleep pressure on cardiac autonomic activity and body temperature. In a counterbalanced design, 12 healthy, young subjects (6 men and 6 women) remained recumbent during 30 h of wakefulness (high sleep pressure) and 6 h of wakefulness (low sleep pressure). Both periods of wakefulness were immediately followed by a sleep opportunity, and the first 2 h of sleep were analyzed. During extended hours of wakefulness, a reduction in heart rate was mediated by a decline in cardiac sympathetic activity (measured via preejection period) and the maintenance of cardiac parasympathetic activity (measured via respiratory sinus arrhythmia). In subsequent high-pressure sleep, parasympathetic activity was amplified and sympathetic activity was negatively associated with electroencephalographic slow-wave activity. Sleep deprivation had no impact on foot temperature, but it did alter the pattern of change in core body temperature. A downregulation of cardiac autonomic activity during both extended hours of wakefulness and subsequent sleep may respectively provide "protection" and "recovery" from the temporal extension of cardiac demand.     

Meal-induced insulin secretion in dogs is mediated by both branches of the autonomic nervous system

We investigated the relationship between autonomic activity to the pancreas and insulin secretion in chronically catheterized dogs when food was shown, during eating, and during the early absorptive period. Pancreatic polypeptide (PP) output, pancreatic norepinephrine spillover (PNESO), and arterial epinephrine (Epi) were measured as indexes for parasympathetic and sympathetic nervous activity to the pancreas and for adrenal medullary activity, respectively. The relation between autonomic activity and insulin secretion was confirmed by autonomic blockade. Showing food to dogs initiated a transient increase in insulin secretion without changing PP output or PNESO. Epi did increase, suggesting beta(2)-adrenergic mediation, which was confirmed by beta-adrenoceptor blockade. Eating initiated a second transient insulin response, which was only totally abolished by combined muscarinic and beta-adrenoceptor blockade. During absorption, insulin increased to a plateau. PP output showed the same pattern, suggesting parasympathetic mediation. PNESO decreased by 50%, suggesting withdrawal of inhibitory sympathetic neural tone. We conclude that 1) the insulin response to showing food is mediated by the beta(2)-adrenergic effect of Epi, 2) the insulin response to eating is mediated both by parasympathetic muscarinic stimulation and by the beta(2)-adrenergic effect of Epi, and 3) the insulin response during early absorption is mediated by parasympathetic activation, with possible contribution of withdrawal of sympathetic neural tone.     

Functional state of the cardiovascular system in 13-year-old adolescents with different types of autonomic nervous regulation

The features of the functional state of cardiovascular system in 13-year-old children with different types of autonomic nervous regulation were studied. Children with normotonic and parasympathetic types of autonomic regulation were found to have the highest adaptation capacities. The autonomic nervous system influences the bioelectrical processes in myocardium, the duration of cardiac cycle phases, and cerebral blood flow. Schoolchildren aged 13 years with higher sympathetic activity have shorter duration of the cardiac cycle, the phase of isometric contraction, and diastole. They have a lower pulse blood flow rate and a higher tone of large and medium cerebral vessels. No relationship was revealed between the initial autonomic nervous regulation of heart rate and the type of adaptation of myocardium to physical dynamic loads, as well as the type of adaptation of cerebral circulation to mental stress.     

Functional organization of autonomic neural pathways

There is now abundant functional and anatomical evidence that autonomic motor pathways represent a highly organized output of the central nervous system. Simplistic notions of antagonistic all-or-none activation of sympathetic or parasympathetic pathways are clearly wrong. Sympathetic or parasympathetic pathways to specific target tissues generally can be activated tonically or phasically, depending on current physiological requirements. For example, at rest, many sympathetic pathways are tonically active, such as those limiting blood flow to the skin, inhibiting gastrointestinal tract motility and secretion, or allowing continence in the urinary bladder. Phasic parasympathetic activity can be seen in lacrimation, salivation or urination. Activity in autonomic motor pathways can be modulated by diverse sensory inputs, including the visual, auditory and vestibular systems, in addition to various functional populations of visceral afferents. Identifying the central pathways responsible for coordinated autonomic activity has made considerable progress, but much more needs to be done.     

Sympathetic activation increases basilar arterial blood flow in normotensive but not hypertensive rats

The close apposition between sympathetic and parasympathetic nerve terminals in the adventitia of cerebral arteries provides morphological evidence that sympathetic nerve activation causes parasympathetic nitrergic vasodilation via a sympathetic-parasympathetic interaction mechanism. The decreased parasympathetic nerve terminals in basilar arteries (BA) of spontaneously hypertensive rat (SHR) and renovascular hypertensive rats (RHR) compared with Wistar-Kyoto rats (WKY), therefore, would diminish this axo-axonal interaction-mediated neurogenic vasodilation in hypertension. Increased basilar arterial blood flow (BABF) via axo-axonal interaction during sympathetic activation was, therefore, examined in anesthetized rats by laser-Doppler flowmetry. Electrical stimulation (ES) of sympathetic nerves originating in superior cervical ganglion (SCG) and topical nicotine (10-30 μM) onto BA of WKY significantly increased BABF. Both increases were inhibited by tetrodotoxin, 7-nitroindazole (neuronal nitric oxide synthase inhibitor), and ICI-118,551 (β(2)-adrenoceptor antagonist), but not by atenolol (β(1)-adrenoceptor antagonist). Topical norepinephrine onto BA also increased BABF, which was abolished by atenolol combined with 7-nitroindazole or ICI-118,551. Similar results were found in prehypertensive SHR. However, in adult SHR and RHR, ES of sympathetic nerves or topical nicotine caused minimum or no increase of BABF. It is concluded that excitation of sympathetic nerves to BA in WKY causes parasympathetic nitrergic vasodilation with increased BABF. This finding indicates an endowed functional neurogenic mechanism for increasing the BABF or brain stem blood flow in coping with increased local sympathetic activities in acutely stressful situations such as the "fight-or-flight response." This increased blood flow in defensive mechanism diminishes in genetic and nongenetic hypertensive rats due most likely to decreased parasympathetic nitrergic nerve terminals.     

Sympathetic overactivity in active ulcerative colitis: effects of clonidine

Previous reports suggest that inflammatory bowel diseases may be accompanied by abnormalities in the neural autonomic profile. We tested the hypotheses that 1) an exaggerated sympathetic activity characterizes active ulcerative colitis (UC) and 2) a reduction of sympathetic activity by clonidine would be associated with clinical changes of UC. In 23 patients with UC and 20 controls, muscle sympathetic nerve activity (MSNA), ECG, blood pressure, and respiration were continuously recorded, and plasma catecholamine was evaluated both at rest and during a 75 degrees head-up tilt. Autonomic profile was assessed by MSNA, norepinephrine, epinephrine, spectral markers of low-frequency (LF) cardiac sympathetic (LF(RR); normalized units) and high-frequency (HF) parasympathetic (HF(RR); normalized units) modulation and sympathetic vasomotor control (LF systolic arterial pressure; LF(SAP)), obtained by spectrum analysis of the R-R interval and systolic pressure variability. Among UC patients, 16 agreed to be randomly assigned to 8-wk transdermal clonidine (15 mg/wk, 9 subjects), or placebo (7 patients). An autonomic profile, Disease Activity Index (DAI), and endoscopic pattern were compared before and after clonidine/placebo. At rest, MSNA, heart rate (HR), LF(RR), LF/HF, and LF(SAP) were higher and HF(RR) was lower in patients than in controls. Tilt decreased HF(RR) and increased MSNA and LF(RR) less in patients than in controls. Clonidine decreased HR, MSNA, epinephrine, LF(RR), and increased HF(RR), whereas placebo had no effects. Changes of the autonomic profile after clonidine were associated with reduction of DAI score. An overall increase of sympathetic activity characterized active UC. Normalization of the autonomic profile by clonidine was accompanied by an improvement of the disease.     

Mechanisms of the inhibitory effect of the stellate ganglion on cardiac activity

The mechanisms of cardiac activity inhibition caused by stimulation of the stellate ganglion were studied in acute experiments on 28 dogs and 37 cats and chronic experiments on 12 cats. It was shown that inhibition of cardiac activity is caused by stimulation of the parasympathetic fibers of the vagus, anastomozing with stellate ganglion branches and ingoing as part of these fibers to the heart. The hypothesis of change over of the sympathetic nerve fibers to the intracardial cholinergic neurons and the hypothesis of the cholinergic component in the mechanism of catecholamine release by the sympathetic nerve terminals was not confirmed. Therefore, the known Dale's principle as to that one neuron exerts its efferent effect with the aid of one transmitter is quite just. alpha-Adrenoreceptors does not produce any noticeable effect on cardiac activity.     

Autonomic activation links CNS oxygen toxicity to acute cardiogenic pulmonary injury

Breathing hyperbaric oxygen (HBO?), particularly at pressures above 3 atmospheres absolute, can cause acute pulmonary injury that is more severe if signs of central nervous system toxicity occur. This is consistent with the activation of an autonomic link between the brain and the lung, leading to acute pulmonary oxygen toxicity. This pulmonary damage is characterized by leakage of fluid, protein, and red blood cells into the alveoli, compatible with hydrostatic injury due to pulmonary hypertension, left atrial hypertension, or both. Until now, however, central hemodynamic parameters and autonomic activity have not been studied concurrently in HBO?, so any hypothetical connections between the two have remained untested. Therefore, we performed experiments using rats in which cerebral blood flow, electroencephalographic activity, cardiopulmonary hemodynamics, and autonomic traffic were measured in HBO? at 5 and 6 atmospheres absolute. In some animals, autonomic pathways were disrupted pharmacologically or surgically. Our findings indicate that pulmonary damage in HBO? is caused by an abrupt and significant increase in pulmonary vascular pressure, sufficient to produce barotrauma in capillaries. Specifically, extreme HBO? exposures produce massive sympathetic outflow from the central nervous system that depresses left ventricular function, resulting in acute left atrial and pulmonary hypertension. We attribute these effects on the heart and on the pulmonary vasculature to HBO?-mediated central sympathetic excitation and catecholamine release that disturbs the normal equilibrium between excitatory and inhibitory activity in the autonomic nervous system.     

Effects of glucagon-like peptide-1, yohimbine, and nitrergic modulation on sympathetic and parasympathetic activity in humans

Glucagon-like peptide-1 (GLP-1), an incretin, which is used to treat diabetes mellitus in humans, inhibited vagal activity and activated nitrergic pathways. In rats, GLP-1 also increased sympathetic activity, heart rate, and blood pressure (BP). However, the effects of GLP-1 on sympathetic activity in humans are unknown. Our aims were to assess the effects of a GLP-1 agonist with or without alpha(2)-adrenergic or -nitrergic blockade on autonomic nervous functions in humans. In this double-blind study, 48 healthy volunteers were randomized to GLP-1-(7-36) amide, the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl-l-arginine acetate (l-NMMA), the alpha(2)-adrenergic antagonist yohimbine, or placebo (i.e., saline), alone or in combination. Hemodynamic parameters, plasma catecholamines, and cardiac sympathetic and parasympathetic modulation were measured by spectral analysis of heart rate. Thereafter, the effects of GLP-1-(7-36) amide on muscle sympathetic nerve activity (MSNA) were assessed by microneurography in seven subjects. GLP-1 increased (P = 0.02) MSNA but did not affect cardiac sympathetic or parasympathetic indices, as assessed by spectral analysis. Yohimbine increased plasma catecholamines and the low-frequency (LF) component of heart rate power spectrum, suggesting increased cardiac sympathetic activity. l-NMMA increased the BP and reduced the heart rate but did not affect the balance between sympathetic and parasympathetic activity. GLP-1 increases skeletal muscle sympathetic nerve activity but does not appear to affect cardiac sympathetic or parasympathetic activity in humans.     

Cardiac Autonomic Activity During Human Sleep: Analysis of Sleep Stages and Sleep Cycles

In this study characteristics of cardiac functioning were investigated in nine subjects during their nocturnal sleep. The pre-ejection period and the high frequency component of heart rate variability were used as indices of cardiac sympathetic and parasympathetic activity of the autonomic nervous system respectively. Heart rate and the autonomic indices were assessed across physiological determined sleep stages and consecutive temporal sleep cycles. Repeated measures ANOVA analyses indicated a significant pattern of heart rate as a function of sleep stages, which was mirrored by parasympathetic activity. Further, a significant decrease of heart rate as a function of sleep cycles was mirrored by an increase of sympathetic activity. Moreover, non-REM/REM differences revealed a dominant role of parasympathetic activity during sleep stages as well as sleep cycles. These findings demonstrate that sympathetic activity is influenced by time asleep, whereas parasympathetic activity is influenced by the depth of sleep.     

The effects of bright light and nighttime melatonin administration on cardiac activity

Although melatonin has an important physiological role in the facilitation of sleep, its precise mechanism of action is not clear. To investigate the potential contribution of melatonin to influence cardiac autonomic activity in the evening, 16 young healthy subjects participated in a repeated measures design where cardiac autonomic activity, heart rate and blood pressure were examined during three experimental conditions. An initial baseline condition involved dim light exposure (< 10 lux), permitting the normal nocturnal rise in endogenous melatonin. In other sessions, subjects were exposed to bright light (> 3000 lux) to suppress melatonin secretion and administered a placebo or melatonin (5 mg) capsule at the estimated time of increase in endogenous melatonin (wake time + 14 hours). Heart rate, pre-ejection period (a measure of cardiac sympathetic activity) and respiratory sinus arrhythmia (a measure of parasympathetic activity) were not significantly altered in response to the three melatonin levels. While melatonin had no effect on diastolic blood pressure, systolic blood pressure was maximally decreased by 6 +/- 1.93 mmHg (mean +/- SEM, p < 0.005) 150 minutes after exogenous melatonin. The results indicate that melatonin does not directly modulate cardiac autonomic activity, but may rather act directly on the cardiovascular system.     

Cardiac Autonomic Activity During Human Sleep: Analysis of Sleep Stages and Sleep Cycles

In this study characteristics of cardiac functioning were investigated in nine subjects during their nocturnal sleep. The pre-ejection period and the high frequency component of heart rate variability were used as indices of cardiac sympathetic and parasympathetic activity of the autonomic nervous system respectively. Heart rate and the autonomic indices were assessed across physiological determined sleep stages and consecutive temporal sleep cycles. Repeated measures ANOVA analyses indicated a significant pattern of heart rate as a function of sleep stages, which was mirrored by parasympathetic activity. Further, a significant decrease of heart rate as a function of sleep cycles was mirrored by an increase of sympathetic activity. Moreover, non-REM/REM differences revealed a dominant role of parasympathetic activity during sleep stages as well as sleep cycles. These findings demonstrate that sympathetic activity is influenced by time asleep, whereas parasympathetic activity is influenced by the depth of sleep.     

Influence of alcohol on peripheral neurotransmitter function

Presently available evidence for the action of ethanol on the peripheral noradrenergic system is reviewed. Acute ethanol treatment produces an initial elevation in catecholamine levels in blood, and in the excretion of catecholamines, which may be followed by a decrease in catecholamine release. Correspondingly, a hyposensitivity of peripheral beta receptors has been noted. Other tissues such as vascular smooth muscles show a biphasic response to ethanol: a hypersensitivity to norepinephrine at low concentrations of ethanol, and hyposensitivity to norepinephrine at high ethanol concentrations. In the adrenal medulla the activity of various enzymes involved in catecholamine synthesis is increased by ethanol treatment. Chronic treatment with ethanol does not alter endogenous norepinephrine levels in heart, but does increase its turnover. Chronic treatment also lowers the number of beta-adrenergic receptors in the heart, and decreases the response to peripherally administered isoproterenol, which suggests a hyposensitivity of peripheral beta receptors. Tolerance may develop to the chronic effects of ethanol in the heart and the vas deferens, but in the adrenals the activity of enzymes for catecholamine synthesis remains elevated with chronic treatment. During withdrawal, there is generalized hyperexcitability of the sympathetic nervous system. Norepinephrine and amine turnover in the heart is increased, as is the activity of adrenal medullary enzymes involved in catecholamine synthesis.     

Cardiovascular Vagosympathetic Activity in Rats with Ventromedial Hypothalamic Obesity

Objective: Rats with ventromedial hypothalamic lesion (VMH) are massively obese with endogenous hyperinsulinemia, insulin resistance, low sympathetic activity, and high parasympathetic activity, which are likely to induce hypertension. The goal was to follow in this model the long‐term hemodynamic changes and to investigate the role of autonomic nervous system and insulin resistance in these changes. Research Metho ds and Procedures: Heart rate and blood pressure were monitored for 12 weeks after operation using a telemetric system in VMH and sham rats. Plasma catecholamines and heart β‐adrenoceptors were measured. Glucose tolerance was studied after an intravenous glucose injection and insulin sensitivity during a euglycemic hyperinsulinemic clamp test. Results: A marked bradycardia and only a mild increase in blood pressure occurred in VMH rats compared with sham animals. Response to autonomic‐acting drugs showed an increase in heart vagal tone and responsiveness to a β‐agonist drug. Plasma catecholamine levels were markedly increased, and the density and affinity of heart β‐adrenoceptors were similar in VMH, sham, and control rats. Muscle glucose use was reduced by 1 week after operation in VMH animals. Discussion: These results show the following in this model of massively obese rats with sympathetic impairment: 1) adrenal medulla secretion is increased, probably as a result of hyperinsulinemia and increased vagal activity; 2) cardiac responsiveness to β‐agonist stimulation is increased; and 3) despite these changes and suspected resistance to the vasodilative effect of insulin, blood pressure does not increase. We conclude that high vagal activity may be protective against hypertension associated with obesity.     

Decreased response of epinephrine and norepinephrine to insulin-induced hypoglycemia in diabetic autonomic neuropathy

The responses of epinephrine, norepinephrine and other counter-regulatory hormones to insulin-induced hypoglycemia were investigated in 5 diabetics who showed signs of autonomic neuropathy, in 7 age-matched diabetics without autonomic neuropathy and in 7 healthy subjects. The presence of autonomic neuropathy was evaluated by decreased beat-to-beat variation in heat rates during hyperventilation or orthostatic hypotension. Catecholamines were determined by a totally automated plasma catecholamine analyzing system using a two-column system of high performance liquid chromatography. Plasma epinephrine and norepinephrine responses to hypoglycemia in diabetics with autonomic neuropathy were significantly lower than those in diabetics without autonomic neuropathy. Plasma glucagon response in diabetics was apparently attenuated compared to normal controls and there was no significant difference in glucagon response between the two patient groups. Other counter-regulatory hormone responses did not differ among the three groups. The data demonstrate that the responses of plasma epinephrine and norepinephrine to insulin-induced hypoglycemia are impaired in diabetics with autonomic neuropathy.