The sympathetic nervous system through the ages: from Thomas Willis to resistant hypertension

The 17th century London neuroanatomical school headed by Thomas Willis provided us with the first identifiable images of the sympathetic nervous system. Nineteenth century giants of European physiology (Bernard, Waller and Brown-Sequard) identified these as the 'pressor nerves'. Von Euler's demonstration that the sympathetic transmitter was noradrenaline brought the field into the modern era. The development of ganglion-blocking drugs by Paton, whose name this review commemorates, allowed comprehensive pharmacological antagonism of this system in patients. With the development of contemporary techniques for recording from human sympathetic nerves and quantifying rates of noradrenaline release, the sympathetic nervous system became accessible to clinical scientists investigating possible contributions to cardiovascular and other diseases. Sympathetic nervous system responses typically are regionally differentiated, with activation in one outflow sometimes accompanying no change or sympathetic inhibition in another. Regional sympathetic activity is best studied in humans by recording from postganglionic sympathetic efferents (multi-unit or single-fibre recording) and by isotope dilution-derived measurement of organ-specific noradrenaline release to plasma from sympathetic nerves (regional 'noradrenaline spillover'). With the application of these techniques, evidence has been assembled in the past three decades which indicates that sympathetic nervous system activation is crucial in the development of cardiovascular disorders, most notably heart failure and essential hypertension. An important goal for clinical scientists is translation of knowledge of pathophysiology, such as this, into better treatment for patients. The achievement of this 'mechanisms to management' transition is mature in cardiac failure, with knowledge of cardiac neural pathophysiology having led to introduction of β-adrenergic blockers, an effective therapy. Perhaps we are now on the cusp of effective translation in patients with essential hypertension, with recent successful testing of selective catheter-based renal sympathetic nerve ablation in patients with resistant hypertension, an intervention firmly based on prior demonstration in them of activation of the renal sympathetic outflow.     

Motor innervation of the coronary arteries of the cat

1. The effect on coronary vascular resistance of selective stimulation of the Adelta, B and sC fibre groups of the post-ganglionic cardiac sympathetic nerves was studied. The main left coronary artery was perfused at constant flow. The oxygen saturation of coronary sinus blood was measured continuously.2. Stimulation of the peripheral ends of the cut Adelta afferent fibres, normally excited by myocardial ischaemia, had no effect on coronary vascular resistance; these fibres do not evoke an axon reflex in the heart.3. Stimulation of the preganglionic B fibres that run without synapse through the stellate ganglion also had no measurable effect on coronary resistance.4. Stimulation of the post-ganglionic sC fibres of the cardiac sympathetic nerves caused coronary vasodilatation which occurred earlier than, and was initially independent of the decrease in coronary sinus oxygen saturation.5. The injection of noradrenaline into the perfusion system had the same effect as stimulation of the sC fibres. In the K(+)-arrested heart, both noradrenaline and stimulation of the post-ganglionic nerves elicited coronary vasodilatation without changing the oxygen saturation of coronary sinus blood.6. The intracoronary injection of acetylcholine caused coronary vasodilatation followed by an increase of coronary sinus oxygen saturation.7. Vagal stimulation caused brady cardia and a fall in coronary resistance.8. Propranolol blocked coronary vasodilatation elicited by sympathetic stimulation or noradrenaline without affecting the vasodilatation due to myocardial ischaemia or acetylcholine. Atropine blocked coronary vasodilatation evoked by acetylcholine without affecting that due to ischaemia or noradrenaline. Therefore smooth muscle of the coronary arteries has at least three different receptor sites from which vasodilatation can be elicited.9. Hypertensin caused coronary vasoconstriction.10. The presence of sympathetic cholinergic vasodilator fibres innervating the coronary arteries could not be demonstrated.     

The neurobiology of human obesity

Earlier ideas that sympathetic nervous system activity is low in human obesity, contributing to weight gain through absence of sympathetically mediated thermogenesis, can now be discounted. The application of sympathetic nerve recording techniques and isotope dilution methodology quantifying neurotransmitter release from sympathetic nerves has established that the sympathetic outflows to the kidneys and skeletal muscle vasculature are activated in obese humans. The cause remains unclear. The adipocyte hormone, leptin, stimulates the sympathetic nervous system in rodents, but whether this applies in humans is uncertain. Cross-sectional studies suggest a quantitative link exists between regional sympathetic nervous tone (most notably in the kidneys) and rates of leptin release, but definitive studies documenting that leptin administration activates the human sympathetic nervous system have not been done. What might be the clinical implications of these new findings? The demonstration that the suppressed sympathetic tone characterizing many experimental models of obesity does not exist in human obesity weakens the case for the use of beta3-adrenergic agonists as thermogenic agents to facilitate weight loss. Although the neurogenic character of obesity-related hypertension is now established, whether antiadrenergic antihypertensive drugs are the preferred agents for blood pressure reduction has not been adequately tested. Multiple site central venous sampling, disclosing release of leptin into the internal jugular veins, led to the demonstration that the leptin gene is also expressed in the brain, in addition to adipocytes. Brain resistance to leptin has been inferred in human obesity, given that overweight is accompanied by high plasma leptin levels. The fact that the genes for leptin and its receptors are normally expressed in the brain in human obesity, and that release of leptin from the brain is actually increased, argues against this. Brain leptin release has the potential to override the peripheral, adipocyte leptin system.     

Bursting into space: alterations of sympathetic control by space travel

AIM: Astronauts return to Earth with reduced red cell masses and hypovolaemia. Not surprisingly, when they stand, their heart rates may speed inordinately, their blood pressures may fall, and some may experience frank syncope. We studied autonomic function in six male astronauts (average +/- SEM age: 40 +/- 2 years) before, during, and after the 16-day Neurolab space shuttle mission. METHOD: We recorded electrocardiograms, finger photoplethysmographic arterial pressures, respiration, peroneal nerve muscle sympathetic activity, plasma noradrenaline and noradrenaline kinetics, and cardiac output, and we calculated stroke volume and total peripheral resistance. We perturbed autonomic function before and during spaceflight with graded Valsalva manoeuvres and lower body suction, and before and after the mission with passive upright tilt. RESULTS: In-flight baseline sympathetic nerve activity was increased above pre-flight levels (by 10-33%) in three subjects, in whom noradrenaline spillover and clearance also were increased. Valsalva straining provoked greater reductions of arterial pressure, and proportionally greater sympathetic responses in space than on Earth. Lower body suction elicited greater increases of sympathetic nerve activity, plasma noradrenaline, and noradrenaline spillover in space than on Earth. After the Neurolab mission, left ventricular stroke volume was lower and heart rate was higher during tilt, than before spaceflight. No astronaut experienced orthostatic hypotension or pre-syncope during 10 min of post-flight tilting. CONCLUSION: We conclude that baseline sympathetic outflow, however measured, is higher in space than on earth, and that augmented sympathetic nerve responses to Valsalva straining, lower body suction, and post-flight upright tilt represent normal adjustments to greater haemodynamic stresses associated with hypovolaemia.     

Postnatal development of inotropic responses to nerve stimulation and tyramine in rat atria

Summary Inotropic responses were measured in isolated rat left atria using an isometric force transducer. In atria from adult rats tyramine administration or field stimulation of intramural cardiac nerves (in the presence of atropine) caused a positive inotropic response which was as great as that obtainable with exogenous noradrenaline. In contrast, atria from newborn animals showed very poor inotropic responses to nerve stimulation or tyramine although they already responded well to noradrenaline. The responses developed progressively with age, reaching adult levels at 3 to 4 weeks of age. It is concluded that the postnatal development of myocardial sympathetic nerves is correlated with a development of the positive inotropic response to sympathetic nerve stimulation or to tyramine.     

Catecholaminergic neurotransmission: flagship of all neurobiology

The paper describes, with focus on the first half of the century, the roles played by study of the sympathoadrenal system for developing modern neurobiology. Adrenaline isolated from extracts of adrenal medulla was the first intercellular messenger to be chemically identified and synthesized. Similarities between effects of adrenaline and sympathetic nerve stimulation led to the first concrete proposal of chemical neurotransmission. That effluent from a sympathetically or parasympathetically stimulated frog heart induced acceleration or slowing of an unstimulated recipient heart was the first conclusive proof of chemical neurotransmission. Acetylcholine (in parasympathetic or somatomotor) and noradrenaline (in sympathetic nerves) are the first identified mammalian neurotransmitters. The existence of a'receptive substance for adrenaline' represents the first proposal that target cells recognize and react to the released transmitter. Deviations for the '-ergic concept, in which sympathetic and parasympathetic nerves are termed 'adrenergic' and 'cholinergic', led to discovery of 'non-adrenergic, non-cholinergic' nerves and a range of other transmitters. That some effects of e.g. sympathetic nerve stimulation are not blocked by any noradrenaline antagonist led to the recognition that some nerves utilize more than one transmitter. Noradrenaline in sympathetic nerves was the first neurotransmitter to be visualized in the light microscope. catecholamines in adrenal medulla and sympathetic nerves were the first messengers to be shown to be stored in vesicles.     

Presynaptic inhibition of cardiac vagal postganglionic nerves by neuropeptide Y

Stimulation of cardiac sympathetic nerves evokes prolonged non-adrenergic, non-cholinergic attenuation of the action of the vagus nerve on heart rate-an effect mimicked by, and proposed to be due to neuropeptide Y (NPY), a peptide released from sympathetic nerve terminals. In anaesthetised dogs, the effects on heart rate of the cholinomimetic bethanechol were unaltered by sympathetic stimulation or administration of NPY sufficient to cause prolonged inhibition of cardiac vagal action. In isolated guinea pig atria, during effective ganglion blockade, the effects on heart rate of the cholinomimetic methacholine were unaltered by exogenous NPY which inhibited cardiac slowing induced by stimulation of vagal nerve terminals. It is suggested that NPY released from sympathetic nerves inhibits cardiac vagal effectiveness by an action on postganglionic nerve terminals.     

Sympathetic activation in human heart failure: diverse mechanisms,therapeutic opportunities

Plasma noradrenaline (NA) concentrations relate both to the severity of heart failure, and to its impact on survival, but have shortcomings that limit their usefulness as measures of sympathetic discharge. Neural recordings and the isotopic dilution method for determining organ‐specific rates of NA spillover into plasma have enhanced our understanding of mechanisms responsible for sympathetic activation. Because the arterial baroreceptor reflex control of heart rate is impaired in heart failure, a parallel reduction in the reflex inhibition of sympathetic outflow has been assumed. However, human heart failure is characterized by rapidly responsive arterial baroreflex regulation of muscle sympathetic nerve activity (MSNA), attenuated cardiopulmonary reflex modulation of MSNA, and activation of a cardiac‐specific sympatho‐excitatory reflex related to increased cardiopulmonary filling pressures. Together, these baroreceptor mediated mechanisms account only, in part, for the time course and magnitude of adrenergic activation in heart failure. Non‐baroreflex sympatho‐excitatory mechanisms include: a metaboreflex arising from exercising skeletal muscle, mediated, in part, by adenosine, co‐existing sleep apnoea, and pre‐junctional facilitation of NA release. Thus, sympathetic activation in the setting of impaired systolic function reflects the net balance and interaction between augmented excitatory and diminished inhibitory influences. Variation, between patients, in the dynamics, magnitude and progression of sympathetic activation mandates an individualized approach to investigation and therapy. Excessive sympathetic outflow to the heart and periphery can be addressed by several complimentary strategies: attenuating these sympatho‐excitatory stimuli, modulating the neural regulation of NA release, and blocking the actions of catecholamines at post‐junctional receptors.     

Involvement of thermosensitive TRP channels in energy metabolism

To date, 11 thermosensitive transient receptor potential (thermo-TRP) channels have been identified. Recent studies have characterized the mechanism of thermosensing by thermo-TRPs and the physiological role of thermo-TRPs in energy metabolism. In this review, we highlight the role of various thermo-TRPs in energy metabolism and hormone secretion. In the pancreas, TRPM2 and other TRPs regulate insulin secretion. TRPV2 expressed in brown adipocytes contributes to differentiation and/or thermogenesis. Sensory nerves that express TRPV1 promote increased energy expenditure by activating sympathetic nerves and adrenaline secretion. Here, we first show that capsaicin-induced adrenaline secretion is completely impaired in TRPV1 knockout mice. The thermogenic effects of TRPV1 agonists are attributable to brown adipose tissue (BAT) activation in mice and humans. Moreover, TRPA1- and TRPM8-expressing sensory nerves also contribute to potentiation of BAT thermogenesis and energy expenditure in mice. Together, thermo-TRPs are promising targets for combating obesity and metabolic disorders.     

Role of cardiac sympathetics in the tonic circulatory restraint by vagal afferents.

In anesthetized cats with aortic nerves sectioned and carotid arteries occluded, we determined the role of cardiac sympathetic nerves on the tonic inhibitory restraint by cardiac vagal afferents on the cardiovascular system. The effect of afferent vagal blockade on mean arterial pressure and cardiac contractility was determined when sympathetic tone to the heart was altered. Bilateral cardiac sympathectomy produced a significant decrease in left ventricular dP/dt and attenuated the arterial pressure response to afferent vagal cold block to less than 40% of the control. The increase in dP/dt normally observed with vagal blockade was also reduced significantly. Increasing dP/dt by efferent stimulation of cardiac sympathetic nerves restored the arterial pressure response to vagal blockade to near control levels. While the vagal inhibitory activity appeared to be dependent on the resting dP/dt, left ventricular peak pressure did not seem to be contributing to the reflex. Thus, the inhibitory effects of vagally mediated reflexes from the heart which contribute to arterial pressure regulation appear to be influenced by changes in cardiac contractility induced by cardiac sympathetic nerve stimulation.     

Degeneration release of noradrenaline in skin flaps in rats

To study if noradrenaline released from degenerating sympathetic nerves may contribute to metabolic stimulation and low blood flow in an experimental skin flap, we have determined noradrenaline levels in such skin flaps. Attempts to use radioenzymatic methodology for the determination of noradrenaline in rat skin extracts were unsuccessful due to interference with the assay. High performance liquid chromatography with electrochemical detection was, however, found to give accurate estimates of rat skin noradrenaline contents. Rat skin contained approximately 2.7 nmol (455 ng) noradrenaline per gram dry weight. Extensive depletion of skin flap noradrenaline, occurring mainly between 6 and 24 h postoperatively, was found. At 48 h nearly all sympathetic nerves in the skin flaps had degenerated as evidenced by noradrenaline levels of 0.13 nmol/g. The degeneration of sympathetic nerve endings appears to proceed from the sides towards the middle of the flap, indicating a segmental distribution of the nerves. Noradrenaline released from degenerating sympathetic nerves may adversely affect the survival of critical skin flaps by causing vasoconstriction and metabolic stimulation.     

Role of the sympathetic nervous system in cardiac performance during hyperkalaemia in the anaesthetized pig

Cardiovascular performance was studied in 18 α-chloralose anaesthetized pigs when arterial potassium ([K⁺]_a) was raised to levels observed in heavy exercise. The effects of hyperkalaemia were then studied during cardiac sympathetic nerve stimulation or during an infusion of noradrenaline. Elevation of [K⁺]_a up to ca. 10 mM caused a progressive decline in cardiovascular performance. However, right cardiac sympathetic nerve stimulation elevated all cardiovascular parameters in the presence of raised [K⁺]_a and offset the negative cardiac effects of hyperkalaemia. Electrical pacing of the right atrium to heart rates (HRs) equivalent to those observed during right cardiac sympathetic nerve stimulation did not offset the depressive effects of hyperkalaemia and, indeed, hastened the decline in cardiovascular performance. Infusion of noradrenaline (1 m?g kg min^-1 i. v.) during hyperkalaemia caused an increase in all cardiovascular parameters similar to that seen during sympathetic nerve stimulation. After propranolol (0.5 mg kg^-1 i. v.), sympathetic nerve stimulation slightly increased HR, systolic blood pressure (SBP) and dP/dt_max. Elevation of [K⁺]_a occurred more rapidly after propranolol, but the heart was still protected from hyperkalaemia during cardiac sympathetic stimulation. Infusion of noradrenaline elicited arrhythmias in six pigs. Infusion of KCI reduced the incidence of arrhythmias and in some cases abolished them. These findings may be related to how the heart is protected from exercise-induced changes in potassium and catecholamines.     

Prevention of exercise-induced cardiac hypertrophy in rats by chemical sympathectomy (guanethidine treatment)

The effect of 'chemical sympathectomy', produced by daily intraperitoneal injections of guanethidine sulphate for six weeks, was studied in sedentary rats and in rats chronically exercised by swimming. The guanethidine-treatment itself caused the following changes. There was a reduction in the rate of weight gain resulting in a 7% lower final body weight. Organ content of noradrenaline was decreased by 90% in spleen and submandibular glands and by 83% in the heart. Urinary excretion of noradrenaline was also decreased, but to a lesser degree, both during rest (45% lower) and after acute exercise (46% lower), while the urinary excretion of adrenaline was no different from that of controls. There was a compensatory adrenal hypertrophy in the guanethidine-treated rats, with a significant increase in adrenal catecholamine levels that was more pronounced for noradrenaline (+45%) than for adrenaline (+11%). Chronic physical exercise produced the expected degree of cardiac hypertrophy in untreated rats, but this adaptive cardiac hypertrophy was completely absent in the exercised guanethidine-treated rats. The results indicate, firstly that a good degree of chemical sympathectomy was obtained and that the persistence of a considerable urinary excretion of catecholamines in the guanethidine-treated rats was due to a compensatory increase in the secretory activity of the adrenal medulla. Secondly, it is suggested that the adaptive cardiac hypertrophy produced by chronic exercise is not caused by a direct effect of the increased work load on the cardiac muscle cell, but is instead mediated by release of a trophic factor from cardiac sympathetic nerves, probably noradrenaline itself but possibly a secretory protein.     

Neural mechanism of bradycardiac responses elicited by acupuncture-like stimulation to a hind limb in anesthetized rats

The effects of acupuncture-like stimulation of a hind limb on heart rate were examined in anesthetized rats. An acupuncture needle, having a diameter of either 160 or 340 microm, was inserted into the skin and underlying muscles at a depth of about 5 mm and twisted right and left twice every second for 1 min. Stimulation by a needle with a diameter of either 160 or 340 microm produced a decrease in heart rate. Severance of the femoral and sciatic nerves ipsilateral to the hind-limb stimulation completely abolished the bradycardiac response. Also, heart rate was significantly decreased by acupuncture-like stimulation of the hind-limb muscles alone, but was not significantly influenced by the stimulation of the hind-limb skin alone. The bradycardiac response induced by acupuncture-like stimulation was not influenced by bilateral severance of the vagal nerves at the cervical level, but was abolished by bilateral stellectomy. Acupuncture-like stimulation of the hind limb induced a decrease in the activity of the cardiac sympathetic efferent nerve as well as a decrease in heart rate. These results indicate that the decrease in heart rate induced by acupuncture-like stimulation of a hind limb is a reflex response. The afferent pathway is composed of hind-limb muscle afferents, and the efferent pathway is composed of cardiac sympathetic nerves.     

Sympathetic modulation of renal hemodynamics,renin release and sodium excretion

Summary In anesthetized animals it has been shown previously, that the influence of electrical stimulation of efferent renal nerves on renal function with increasing stimulation frequencies can be graded; renin release is affected at low, sodium excretion at intermediate and vascular resistance at high stimulation frequencies.Experiments in conscious dogs are reviewed, which present evidence for a similar functional dissociation under physiological conditions.Moderate activations of the renal sympathetic nerves, which do not change renal blood flow 1) decrease sodium excretion independent of changes in angiotensin II, 2) interact with the pressure-dependent mechanism of renin release by resetting its threshold pressure and 3) modulate autoregulation by increasing the lower limits of glomerular filtration rate and renal blood flow-autoregulation.These findings may contribute to our understanding of the role of the renal nerves in the pathophysiology of congestive heart failure and hypertension.     

Hypoxia and hypercapnia increase the sympathoadrenal medullary functions in anesthetized, artificially ventilated rats

Graded hypoxia (FETO2 14-6%) and hypercapnia (FETCO2 6-10%), which were applied for 45s and 2 min, respectively, to urethane anesthetized and artificially ventilated rats produced an increase in adrenal sympathetic efferent nerve activity in parallel with increases in adrenaline and noradrenaline secretion measured in the adrenal venous effluent. Percentage increases in adrenaline and noradrenaline were almost equal. In rats whose carotid sinus nerves (CSN) were bilaterally cut, hypoxia did not produce any effect on adrenal sympathetic nerve activity or catecholamine secretion. In contrast, excitatory adrenal nerve and catecholamine secretory responses to hypercapnia remained unchanged in CSN denervated rats. After severing a splanchnic nerve whose branches innervated the adrenal gland, while maintaining the resting level of catecholamine secretion by low-frequency stimulation of the peripheral end of the splanchnic nerve, hypoxia did not produce any increase in catecholamine secretion. Hypercapnia (FETCO2 8 and 10%), however, induced catecholamine secretion from denervated adrenal medulla, although the magnitude of the response was significantly lower than that in animals with adrenal nerve intact. It is concluded that hypoxia stimulates the adrenal medulla via the carotid chemoreceptor reflex whereas hypercapnia acts mainly via mechanisms besides carotid chemoreceptors such as central chemoreceptors with some direct stimulatory effect on the adrenal medulla. The functional significance of these dual mechanisms of sympathoadrenal excitation during hypoxia and hypercapnia is discussed.     

Spectral analysis of heart rate variability (HRV) may predict the future development of essential hypertension

Presently, essential hypertension (EH) is among the most common morbid disorders of mankind. The fundamental pathophysiology of EH is sympathetic overactivity. It has been observed that the people having common risk factors for hypertension such as obesity, insulin resistance and stress generally have increased sympathetic activity. Therefore, it is presumed that patients suffering from EH develop some degree of increased sympathetic activity much before they clinically develop hypertension. Spectral analysis of heart rate variability (HRV) has been demonstrated to accurately assess change in sympathovagal balance (autonomic activity) even when the alteration is in its minimal form. Therefore, in the present paper we hypothesize that spectral analysis of HRV could be utilized for early prediction of EH. We also suggest that the predictive knowledge of sympathovagal imbalance in the development of EH should be employed in elucidating the mechanisms for prevention of this dysfunction.     

The articulo-cardiac sympathetic reflex in spinalized, anesthetized rats

Somatic afferent regulation of heart rate by noxious knee joint stimulation has been proven in anesthetized cats to be a reflex response whose reflex center is in the brain and whose efferent arc is a cardiac sympathetic nerve. In the present study we examined whether articular stimulation could influence heart rate by this efferent sympathetic pathway in spinalized rats. In central nervous system (CNS)-intact rats, noxious articular movement of either the knee or elbow joint resulted in an increase in cardiac sympathetic nerve activity and heart rate. However, although in acutely spinalized rats a noxious movement of the elbow joint resulted in a significant increase in cardiac sympathetic nerve activity and heart rate, a noxious movement of the knee joint had no such effect and resulted in only a marginal increase in heart rate. Because this marginal increase was abolished by adrenalectomy suggests that it was due to the release of adrenal catecholamines. In conclusion, the spinal cord appears to be capable of mediating, by way of cardiac sympathetic nerves, the propriospinally induced reflex increase in heart rate that follows noxious stimulation of the elbow joint, but not the knee joint.     

Dopamine release from the porcine myocardium

Dopamine is a catecholamine with profound influence on cardiac function and known to be present in adrenergic nerve terminals as a precursor of noradrenaline. However, no previous study has examined whether dopamine is produced by myocardial tissue. During stable hemodynamic conditions in 13 young, thoracotomized pigs with the heart in situ, we found a net release of dopamine into the coronary sinus amounting to 1.39 ± 0.36 ng/min ± 100 g of left ventricular muscle mass (p<0.01). Dopamine was released from the myocardium whether the v-a difference for noradrenaline was positive or negative. This observation indicates a release of dopamine from the heart independent of sympathetic noradrenergic activity. Regulation of myocardial dopamine release remains unknown.