Hypertension Journal

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Sympathetic Nervous System and Hypertension
  JOHTN
BLOOD PRESSURE MECHANISM
Sympathetic Nervous System and Hypertension
Narsingh Verma
Professor
Department of Physiology, King George's Medical UniversityLucknow, Uttar Pradesh, India
Correspondence Author: Narsingh Verma, ProfessorDepartment of Physiology, King George's Medical UniversityLucknow, Uttar Pradesh, India
Phone: +919839064560
e-mail: narsinghverma@gmail.com
 
ABSTRACT
Aim: The review emphasizes on the sympathetic and parasympatheticabnormalities in essential hypertension, the possiblemechanisms underlying these abnormalities, and their importancein the development and progression of the structuraland functional cardiovascular (CV) damage that characterizeshypertension.
Background: Apart from being a hemodynamic phenomenon,primary hypertension is a vicious syndrome involving abnormaladiposity, overactivation of the adrenergic system, metabolicabnormalities, and activation of the immune system. Physiologicalstudies have established the key role played by theautonomic nervous system in modulating CV functions and incontrolling arterial pressure values. Many factors contribute toincreased sympathetic nerve activity in metabolic abnormalitiesincluding obesity, impaired baroreflex sensitivity, hyperinsulinemia,and elevated adipokine levels.
Review results: Experimental and clinical investigations clearlyindicate that the origin, progression, and outcome of hypertensionare related to dysfunction of the autonomic CV system,especially to abnormal activation of the adrenergic division.The activation of the sympathetic nervous system is essentialin energy homeostasis and can exert intense metaboliceffects. Accumulating data from a number of studies suggestthat central sympathetic overactivity plays a crucial role inthe causative factors and complications of several metabolicconditions that can cluster to form the metabolic syndrome.
Conclusion: This review provides an evidence of attenuationof autonomic CV control in essential hypertension and thatsympathetic overdrive is a major component of this autonomicdysregulation. Arterial pressure control requires complex integrationof regulatory mechanisms across multiple physiologicalsystems. A continuous increase in blood pressure therefore,reflects a failure of one or more of these controls.
Clinical significance: The findings discussed herein providea rationale for pursuing sympathetic deactivation by nonpharmacologicalas well as pharmacological interventions aimed atlowering elevated blood pressure values and protecting patientsfrom hypertension-related complications.
Keywords: Hypertension, Neural regulation, Sympatheticnervous system.
How to cite this article: Verma N. Sympathetic NervousSystem and Hypertension. Hypertens J 2017;3(1):27-36.
Source of support: Nil
Conflict of interest: None
 
 

BACKGROUND

Arterial hypertension has been recognized as a majorkiller and cause of the global cardiovascular (CV) morbidity.Despite clinical and research advances in hypertensionprevention and management,1 hypertension ispresent in one-third adults, with a growing incidenceand prevalence worldwide.2 Despite the increase inhypertension awareness and the use of blood pressure(BP)-lowering drugs, patients with a higher CV risk haveless controlled pressure in comparison to average riskpatients.3

In this review, our focus is limited to the relation ofautonomic nervous system (ANS) to essential or primaryhypertension, with no obvious reference to the secondaryhypertension because its prevalence is less,4 andits causes do not include alterations of central or reflexautonomic drive.



 
The sympathetic nervous system (SNS) is part of theANS which is important for the regulatory mechanismsof blood pressure, electrolyte balance, and maintenanceof homeostatic state. The SNS is instrumental in theregulation of daily energy expenditure through thecontrol of resting metabolic rate and thermogenesis inresponse to various physiological stimuli, changing statesof energy, intake of food, consumption of carbohydrate,and hyperinsulinemia. Furthermore, the activation ofsympathetic nerves in various target organs includingpancreas, liver, skeletal muscle, and adipose tissue canelicit acute catabolic responses like glycogenolysis andlipolysis. Overactivation of SNS is strongly associatedwith at least two components of the metabolic syndrome,i.e., hypertension and obesity.

In the last 40 years, the relationship of SNS todevelopment, progression, and complications of hypertensionhas been investigated extensively. Enhancedsympathetic activation is the key mechanism involvedin human hypertension, and its deleterious CV consequencesare well recognized.5-8 Increased sympatheticnerve activity of muscle4 and augmented cardiac andrenal noradrenaline release from the sympatheticnerves5,9,10 feature in essential hypertension. Sympatheticoveractivity starts early in course of time andhas been reported even in very low-risk subjects withhigh-normal BP.7 The magnitude of this sympatheticoverdrive has been closely related to hypertensionrelatedend-organ damage.8,11,12

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Narsingh Verma

RESULTS

Sympathetic activation in hypertension arises fromeither compromised peripheral regulatory mechanismsor a primary increase in sympathetic outflow withinthe central nervous system.13 Peripheral regulators ofsympathetic activation and CV function include cardiopulmonarymechanoreceptors, arterial baroreceptors,and chemoreceptors.

Baroreceptor dysfunction has been found in patientswith hypertension as well as in subjects with a positivefamily history of hypertension with normal BP levels.14Likewise, gain of the cardiopulmonary baroreflex regulationof sympathetic activity is higher in hypertensivepatients in comparison to their normal counterparts andthe augmentation is not related with attenuation of thearterial baroreflex.15

Another causal mechanism leading to higher sympatheticactivation is potentiated sensitivity of vascularchemoreceptors. The impairment of arterial chemoreceptorscontributes to the pathogenesis of human hypertension.16 Microneurography-based studies have confirmedan exaggerated hypoxic sympathetic drive in hypertension;17 the deactivation of peripheral chemoreceptorsresulted in BP and muscular sympathetic nerve activity(MSNA) reduction in essential hypertension.16,18 Persistentgeneralized sympathetic activation evident in arterialhypertension is critical in progression of disease leadingto increased CV morbidity and mortality.

Hypertension is the chronic derangement of autonomicCV regulation. These sympathetic and parasympatheticCV influences play a vital primary role inhomeostatic control of the CV system. In animal models ofhypertension, not only increased sympathetic nerve activitybut also decreased parasympathetic tone is associatedwith and responsible for the causation and maintenanceof high BP, and even hypertension-related sequelae.19-21Abnormal increase in circulating plasma levels of thesympathetic neurotransmitters has been demonstratedrepeatedly in normotensive persons with a family historyof hypertension. Moreover, these abnormalities are traceablewhen measured during various maneuvers thatactivate sympathetic CV control.22-26 Pressor responses toa variety of laboratory stressors have also predicted forthe subsequent development of hypertension.27,28

Further, to strengthen the concept, a more refinedexperimental approach (measurement of the clearanceof neurotransmitter norepinephrine after the infusionof small amounts of its radiolabeled form) demonstratedthat the rise in norepinephrine is not due to itsreduced tissue disposal but rather due to an increasedspillover rate from neuroeffective junctions and thusto enhance norepinephrine secretion from sympathetic nerve terminals.29 In the microneurographic studieswhich were originally aimed to find out postganglionicsympathetic nerve traffic to the circulation of skeletalmuscle, including controls with normal blood pressure,both the quantity and amplitude of sympatheticbursts were higher in individuals with family history ofhypertension30 as well as in those with white-coat andmasked hypertension,31-33 i.e., subjects with greater riskof progressing to true hypertension.34 Thus, it suggeststhat a central sympathetic oversecretion is present inindividuals predisposed to developing high BP, whichcan be because of either a genetic background or a specificBP phenotype.
 
Interestingly, this sympathetic hyperactivity is likelyto be accompanied by an impaired (decreased) vagalinfluence on the heart. Evidence for this has arrived fromstudies of the normotensive offspring of hypertensiveparents. In this study, spectral analysis of the R-R intervalshowed a reduction of low-frequency fluctuations in heartrate;35,36 these are known to be a component of heart ratevariability (HRV) act by vagal modulation of the sinusnode.37 Thus, both sympathetic and parasympatheticdivisions may be altered in greater risk individuals, evenwhen an overt BP abnormality is not yet visible. Thisexplains the important role of the SNS in the developmentof hypertension.

Further support for a causative role of sympatheticdysfunction in high BP comes from the multiple lines ofevidence showing the association of increased sympathetictone along with decreased cardiac vagal drive toyoung hypertensive individuals even in the early stagesof hypertension. Seminal studies revealed that in youngpatients with hyperkinetic syndrome (increase in systolicBP, increase in cardiac output, and a resting tachycardia),38 the elevations in heart rate depended on a reducedvagal inhibitory influence on the sinus node because theIV administration of atropine (which selectively blocksthe effect of the vagal neurotransmitter acetylcholine onmuscarinic receptors) restored both heart rate and BPto the normal values of the control group.39 A smallerreduction in glandular secretions under parasympatheticcontrol, such as salivary flow,40 in borderline hypertensiveindividuals suggest that in early hypertension, parasympatheticimpairment is not confined to the heart or tothe CV system; rather, it is generalized to all functionsinvolving parasympathetic division of ANS.

A reduction in sympathetic nerve activity and anenhancement in cardiac vagal drive have also beenattributed as an explanation for the lifestyle interventionsused in clinical practice to lower an elevated BP,such as physical exercise and loss of body weight.41,42 Thedecrease in pressure is accompanied in either case by areduction of muscle sympathetic nerve traffic and the increased plasticity of baroreceptor activity to regulatethe sympathetic drive.
 
28

Sympathetic Nervous System and Hypertension

In hypertensive individuals with their normal saltintake (9-18 gm/day), the concentrations of plasmasodium and cerebrospinal fluid (CSF) sodium are slightlyraised as compared with values observed in the sameindividual on a low-salt (3-4 gm/day) intake. Studiesperformed by using the animal models hypothesizedthat these increased plasma sodium and/or CSF sodiumconcentrations activate brain's sodium/osmoreceptors,which are located mainly at the hypothalamus, to triggersympathoexcitation.43,44 These osmoreceptors do nothave ability to reset significantly with prolonged changein osmolality and thus can provide a continued signalto chronically increase sympathetic tone.44 Similarly,dehydration-induced increase in osmolality also acts inthe hypothalamus to promote sympathoexcitation andsupport BP.45,46

In established cases of hypertension, dietary sodiumrestriction seems to further alter autonomic balance, i.e.,to impair reflex sympathetic control, and to side by sidefurther enhance the number of sympathetic bursts tothe skeletal muscle circulation. The effect is more whenthe sodium restraint is marked but present even withmoderately low-sodium intake (80 mmol NaCl/day), suggestingthat a low-sodium diet, as usually implemented indaily life, enhances the hypertension-related alterationsof autonomic CV control.

The adrenergic hyperactivity accompanying earlyhypertension has both a central and a peripheral componentthat can further amplify the CV effects of adrenergicstimuli. This may change in the subsequent phase of thedisease, however, because a permanent increase of sympatheticdrive generates a downregulation of adrenergicreceptors47 that may partly offset the consequences ofsympathetic hyperactivation. The downregulation ofperipheral ß-adrenergic receptors has been observed instage 1 hypertension, thus generating the hypothesis thatits occurrence leads to an alteration of energy balance thatfavors weight gain.48

The adrenergic overdrive that characterizes hypertensionis not stable but instead follows the blood pressureincrease and the progression from uncomplicated tocomplicated stages that may occur in the course of thedisease.49,50 A number of studies revealed that sympatheticactivation is normally more pronounced in complicatedthan in noncomplicated stages of hypertension.As compared with the respective controls, sympatheticactivations has been shown to be more pronounced inhypertensive patients with (1) left ventricular hypertrophy,51-53 (2) impaired left ventricular diastolic function,54(3) systolic heart failure,55 and (4) advanced ventricular arrhythmias. There are consistent data to suggest thatactivation of the adrenergic nervous system evolves fromless to more severe hypertensive states, i.e., it increaseswith the increase in blood pressure values, the developmentof organ damage, and the appearance of clinicallyapparent renal or cardiac disease or of treatment ineffectiveness.

 
The sympathetic overactivity associated with theestablished hypertensive phase is not uniformly distributedthroughout the body; rather, regional differences aresuch that it is marked in some districts and modest oreven absent in others. For example, radiolabeling studieshave shown that in established hypertension, there isincreased norepinephrine spillover into the cerebral,coronary, and renal circulation but not at the level of thesplanchnic and pulmonary vascular districts.56,57

Most importantly, sympathetic nerve activity may be,either directly or indirectly, a predictor of CV morbidityand mortality. First, sympathetic activity is associatedwith and is probably a determinant of blood pressurevariability,58,59 which itself is a CV risk factor independentof average blood pressure values.60 Second, sympathetichyperactivity, as measured by plasma norepinephrine,systemic norepinephrine spillover, or microneurography,is known to be an independent prognostic factor forCV-related morbid or fatal events in patients with heartfailure, end-stage renal failure, major cardiac arrhythmias,obstructive pulmonary disease, or after an acutestroke.61-67

Several mechanisms have been proposed to explainthe sympathetic overdrive seen in individuals withessential hypertension. An attractive hypothesis is thatoverdrive depends on an excessive adrenergic response toenvironmental stimuli, leading initially to greater bloodpressure variability and later to a sustained hypertensivestate.68 It has also been proposed that sympathetic overdriveoriginates from a reduced inhibitory influence ofthe arterial baroreceptors because cellular impairment ora stiffening of the arterial wall where these baroreceptorsare located attenuates their responsiveness to bloodpressure changes. Furthermore, in hypertensive humans,the arterial baroreflex loses much of its ability to controlthe heart rate, but it continues to effectively modulateblood pressure and sympathetic activity.50 As the bloodpressure increases, so does the range of blood pressureand sympathetic modulation exerted by the baroreflex;this resetting phenomenon helps to stabilize both bloodpressure and sympathetic activity at the higher values.41Secondly, an increased sympathetic drive may be favoredby the reduced inhibitory influence of cardiac stretchreceptors, which occurs when hypertension-relateddiastolic dysfunction and left ventricular hypertrophy reduce the stimuli (changes in cardiac volume and myocardialcontractility) to which these receptors respond.69
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Narsingh Verma

Other possible mechanisms are chemoreceptor stimulationby hypoxemia, hypercapnia, acidosis, reduction ofarterial blood flow, temperature change, and low levelsof glucose.58,70-72 Reflex cardiorespiratory responses arecharacterized by hyperventilation and increased sympatheticdischarge to the vascular beds and the heart. Tachycardiaassociated with hyperventilation in turn augmentscardiac output, acutely raising arterial blood pressure. Thecarotid body (CB) chemoreceptor (glomus or type I) cellsare considered the sensors of the natural stimuli.58,70-72Its potential role as a sympathostimulating factor hasbeen strengthened by the observation that hypoxia isimportant for the increased sympathetic activity seen inindividuals with sleep apnea,73 a condition frequentlyassociated with obesity and, as such, highly prevalentin hypertension as well.74 Further studies revealed thatinsulin and leptin increase postganglionic sympatheticdrive75 and that central and peripheral sympathostimulatingeffects are also exerted by angiotensin II.76,77 Inthese instances, the stimulation is reciprocated by theSNS in a kind of positive feedback relationship.78 Thus,several mechanisms are potentially capable of activatingsympathetic nervous influences in essential hypertension,but the relative importance of each one in the differentstages or types of hypertension remains to be clarified.

Autonomic dysfunction, characterized by sympathetichyperactivity, vagal impairment, and impaired baroreflexsensitivity (BRS), is characteristic of the metabolicsyndrome and of disease conditions where the CB maybe implicated, such as hypertension.79-82 In addition,patients with metabolic disorders also have increasedlevels of leptin, reactive oxygen species (ROS), and proinflammatorycytokines. It is conceivable that CB chemosensoryfunction may be compromised in the metabolicsyndrome. In fact, it is known that obesity increasesadipokine levels [i.e., leptin, resistin, tumor necrosis factor(TNF)-α, and interleukin (IL)-6], which through cascadeof reactions contributes to the endothelial dysfunction.83Endothelial dysfunction is characterized by an imbalancein the release of vasoconstrictors and the endotheliumdependentrelaxants. Hence, increases in endotheliumderivedconstriction factors (EDCFs) are common inpathophysiological conditions like hypertension.

The specific causes of the increased sympathetic activityin essential hypertension include genetic influences(family history), behavioral (salty food preference), psychosocial(mental stress), and lifestyle (physical inactivity).84,85 Of prime importance is obesity. The prevalenceof hypertension in middle-age obese subjects is 40 to50%. Obesity increases the sympathetic (including therenal sympathetic) nervous system activity through the high sodium intake-related mechanisms and throughother mechanisms, such as hyperleptinemia.86,87 On thecontrary, clinical and epidemiological studies indicate theimportance of chronic mental stress in the pathogenesisof essential hypertension.88,89 Hypertensive subjectsmay decrease their blood pressure with a meditationprogram.90,91
 
Psychosocial stress can increase the activity of theSNS by potentiating the neural mechanisms activatedby a high-salt intake.92 Race and ethnicity may alsoinfluence the predisposition to the sensitivity of bloodpressure to salt. Black Africans have a higher prevalenceof hypertension and more frequent severe hypertension;they also have a greater blood pressure sensitivity to saltintake than do people of other ethnic origins.88,93 Physicalinactivity also appears to be important.84 Aerobic fitnessand physical activity are each inversely related to thedevelopment of hypertension.94 Aerobic exercise trainingin sedentary normotensive and hypertensive peoplereduces blood pressure and renal and muscle sympatheticnerve activity.95,96

Activation of the renal sympathetic nerves causes achange in functionality in terms of renal hemodynamic,excretory and secretory functions. At very low rates ofactivity, there is a prompt increase in renin secretion, abeta-adrenoceptor-mediated effect. At slightly higherlevels, there is a concomitant increase in fluid reabsorption,and it is only at the highest level of sympathoexcitationthat there is a reduction in renal hemodynamics.Normally, in response to everyday activities (e.g., takingin a meal containing a high content of sodium chloride),sympathetic control is exerted on renin release and fluidreabsorption to ensure that there is a smooth excretion ofan appropriate proportion of the sodium load. It is onlywhen there are acute threatening "fight and flight" situationsrequiring redistribution of blood that sympatheticactivity increases to a level at which renal blood flowand glomerular filtration rate are reduced, but these areshort-term responses that have little long-term impacton fluid balance.

The long-term increase in arterial BP often affectsheart and kidneys. The higher the blood pressure, thegreater is the resistance needed by heart to function. Ahigher blood pressure could lead to an increase in the frequencyand contractile force. In the long term, this changein blood pressure could compromise cardiac function.

Increase in sympathetic activity enhances systemicand regional norepinephrine spillover and elevate restingheart rate. This condition has been linked to hypertension,obesity, and insulin resistance. Furthermore, it hasbeen shown that high levels of fasting insulin, an indexof insulin resistance, were positively associated with thelow-to-high frequency (LF/HF) ratio of the heart rate variability - an index of the sympathovagal balance atthe heart level.
 
30

Sympathetic Nervous System and Hypertension

In view of the strong relationship among obesity, metabolicsyndrome, and the development of CV risk factors,it is important to elucidate autonomic disturbances thatoccur in obese individuals. Though the autonomic disordersare not homogeneous in obesity, some studies havedemonstrated that most individuals exhibit sympathetichyperactivity. Both BRS and HRV are impaired in obesewomen. Esler et al97 demonstrated that the sympathetictone in obese individuals is increased in some targetorgans like kidney, skeletal muscle, and vessels.

Sympathetic hyperactivity in obesity indicates thatobesity impairs renal-pressure natriuresis, increasesrenal tubular sodium reabsorption, and causes hypertension.Various studies have demonstrated increasedblood pressure and serum catecholamine levels in obeseindividuals. The loss of weight is associated with thedecrease in plasma concentration norepinephrine. Obesehypertensive children show increase in sympatheticnerve activity. However, in these patients, a low-salt diet(or hyposodic diet) is capable of promoting a decreasein arterial pressure. These studies point out the fact thatsympathetic hyperactivity is related to sodium retentionand increase of arterial blood pressure in obese children.Furthermore, MSNA is increased in obese (normotensiveand hypertensive) as compared with nonobese normotensiveindividuals.

Moreover, it has been shown that the MSNA andthe plasmatic norepinephrine are reduced and the BRSis increased after weight loss in normotensive obeseindividuals. The heart rate variations are a visible effectof the autonomic influences on the heart in cases ofemotional stress. An inability to sustain varying heartrate is an important risk factor to the development of cardiovasculardisease (CVD). The study of Brunner et al98demonstrated a relative sympathetic dominance and alower vagal tone to the heart in MS cases, thereby indicatingsympathovagal imbalance in those individuals.

Jamerson et al99 demonstrated an inverse relationshipbetween sympathetic vascular tone and insulin-mediatedcellular consumption of glucose. Thus, the increased SNAas observed in obese individuals increases the vascularconstriction and impairs the glucose transportation intothe cells. Previous studies with obese models have implicatedvascular constriction in insulin resistance. Specificalfa-adrenergic vasoconstriction seems to be more maleficon glucose consumption than the angiotensin-inducedvasoconstriction. This suggests the sympathetic influenceon glucose metabolism.

In patients with type II diabetes mellitus (T2DM), metabolicsyndrome has approximately 70% of prevalencerate. The basic mechanism involved in the pathogenesis of T2DM is the insulin resistance. The insulin resistance,in turn, is strongly associated with sympathovagal imbalance.Furthermore, many data suggest the involvementof increased SNS activity in insulin resistance. Epidemiologicalstudies have found a correlation between insulinresistance and hypertension. In patients with type Idiabetes mellitus, the hypertension is usually developedafter the onset of nephropathy and it is associated withrenin-angiotensin-induced SNS activation. On the contrary,the prevalence of hypertension in patients withT2DM is extremely common. Thus, it can be assumed thatinsulin resistance and hypertension as observed in theMS are closely linked with sympathetic overactivation.

 
Sympathetic overload is implicated in the pathogenesisand/or deterioration of essential hypertension throughthe modification of heart rate, cardiac output, peripheralvascular resistance, and renal sodium retention. Somestudies with essential hypertensive patients have plasmaticoverflow of norepinephrine. This overflow indicatesan increase in the activation of sympathetic outflow tothe heart, kidneys, and cerebrovascular circulation ofthese individuals. These observations are evidences thatsome target organs are negatively affected by increasedblood pressure.

DISCUSSION

The sympathetic hyperactivity with early hypertensionhas both central and peripheral component that furtheramplifies the CV effects of adrenergic stimuli. This canchange the progression of the disease because a permanentincreased sympathetic drive creates a downregulationof adrenergic receptors47 that may partly offset theconsequences of sympathetic overdrive. The downregulationof peripheral beta-adrenergic receptors as observedin stage 1 hypertension generates the hypothesis that itsoccurrence leads to an alteration of energy balance thatfavors increase in weight.48

The adrenergic overdrive, which is one of the causeof hypertension and characterizes it, follows the bloodpressure increase and the progression from uncomplicatedto complicated stages of hypertension that mayoccur in the course of the disease.49,50 A number ofstudies revealed that sympathetic activation is normallymore pronounced in complicated than in uncomplicatedstages of hypertension. As compared with the respectivecontrols, sympathetic activation is more pronounced inhypertensive patients with (1) left ventricular hypertrophy,51-53 (2) impaired left ventricular diastolic function,54(3) systolic heart failure,55 and (4) advanced ventriculararrhythmias. There are sufficient data to suggest thatactivation of the SNS evolves from less to more severehypertensive states, i.e., it increases with the increase inblood pressure values, the development of organ damage and the appearance of clinically apparent renal or cardiacdisease or even with treatment failure.
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Narsingh Verma

The sympathetic overactivity associated with theestablished hypertensive phase is not in uniform distributionthroughout the body; rather, regional differencesare such that it is marked in some districts and modest oreven absent in others. For example, radiolabeling studiesrevealed that in established hypertension, the increasednorepinephrine spillover is restricted to the cerebral,coronary, and renal circulation but not at the level of thesplanchnic and pulmonary vascular districts.56,57

Most importantly, sympathetic nerve activity may bea predictor of CV morbidity and mortality. First, sympatheticactivity has an association with and is probably adeterminant of blood pressure variability,58,59 which itselfis a CV risk factor independent of average blood pressurevalues.60 Secondly, sympathetic hyperactivity is knownto be an independent prognostic factor for CV-relatedmorbid or fatal events in patients with heart failure, endstagerenal failure, major cardiac arrhythmias, obstructivepulmonary disease, or after an acute stroke.61-67

Several mechanisms have been proposed to explainthe adrenergic overdrive seen in subjects with essentialhypertension. This overdrive depends on an excessiveadrenergic response to environmental stimuli, leadinginitially to greater blood pressure variability and laterto a sustained hypertensive state.68

Furthermore, in hypertensive humans, the arterialbaroreflex loses much of its ability to control the heartrate, but continues to effectively modulate blood pressureand adrenergic activity.50 The increased blood pressureincreases the range of blood pressure and sympatheticmodulation exerted by the baroreflex; this resettingphenomenon helps to stabilize both arterial pressureand adrenergic activity at the higher values.41 Secondly,an enhanced sympathetic drive may be favored by thereduced inhibitory influence of cardiac stretch receptors,which occurs when hypertension-related diastolicdysfunction and left ventricular hypertrophy reducethe stimuli (changes in cardiac volume and myocardialcontractility) to which these receptors respond.69

Other possible mechanisms are chemoreceptor stimulationby hypoxemia, hypercapnia, acidosis, reduction ofarterial blood flow, temperature change, and low levelsof glucose.58,70-72 Reflex cardiorespiratory responses arecharacterized by hyperventilation and increased sympatheticdischarge to the vascular beds and the heart. Tachycardiaassociated with hyperventilation in turn increasescardiac output, acutely raising arterial blood pressure.The CB chemoreceptor (glomus or type I) cells have beenconsidered as the sensors of the natural stimuli.58,70-72 Itspotential role as a sympathostimulating factor has beenproven by the observation that hypoxia is important for the increased sympathetic activity seen in individualswith sleep apnea,73 a condition frequently associated withobesity and hypertension.74 Further studies revealed thatinsulin and leptin increase postganglionic sympatheticdrive75 and in addition, central and peripheral sympathostimulatingeffects are also exerted by angiotensin II.76,77In these instances, the stimulation is reciprocated by theSNS in a kind of positive feedback relationship.75 Thus,several mechanisms are potentially capable of activatingsympathetic nervous influences in essential hypertension,but the relative importance of each one in the differentstages or types of hypertension remains to be clarified.
 
Autonomic dysfunction, characterized by adrenergichyperactivity, vagal impairment, and impaired BRS,is a feature of the metabolic syndrome and of diseaseconditions where the CB may be implicated, such ashypertension.79-82 In addition, patients with metabolicdisorders also have increased levels of leptin, ROS, andproinflammatory cytokines. It is agreeable that CB chemosensoryfunction may be compromised in the metabolicsyndrome. In fact, obesity increases adipokine levels(i.e., leptin, resistin, TNF-α, and IL-6), which throughcascade of reactions contributes to the endothelial dysfunction.83 Endothelial dysfunction is characterized byan imbalance in the release of vasoconstrictors and theendothelium-dependent relaxants. Hence, increases inEDCFs are commonly associated with pathophysiologicalconditions like hypertension.

The relevant causes of the increased sympatheticactivity in essential hypertension include geneticinfluences (family history), behavioral (salty foodpreference), psychosocial (mental stress), and lifestyle(physical inactivity).84,85 Of prime importance is obesity.The prevalence of hypertension in obese subjects ofmiddle-age group is 40 to 50%. Obesity increases theSNS activity through the high-sodium intake-relatedmechanisms and through other mechanisms, such ashyperleptinemia.86,87 On the contrary, clinical studiesindicate the importance of chronic mental stress in thepathogenesis of essential hypertension.88,89 Hypertensivesubjects may decrease their blood pressure with ameditation program.90,91

Psychosocial stress increases the activity of the SNSby potentiating the neural mechanisms activated by ahigh-salt intake.92 Race and ethnicity also influence thepredisposition to the sensitivity of arterial pressure to salt.Black Africans have a higher prevalence of hypertension,more frequent severe hypertension, and greater bloodpressure sensitivity to salt intake in comparison withpeople of other ethnic origins.88,93 Physical inactivity alsoappears to be important.84 Aerobic fitness and physicalactivity have an inverse relationship to the developmentof hypertension.94 Fitness training in sedentary normoten sive and hypertensive individuals reduces blood pressureand renal and muscle sympathetic nerve activity.95,96
 
32

Sympathetic Nervous System and Hypertension

Activated renal sympathetic nerves cause a change infunctionality in terms of renal hemodynamic, excretory,and secretory functions. The low rates of activity resultin prompt increase in renin secretion, a beta-adrenoceptor-mediated effect. At slightly higher levels, there is aconcomitant increase in fluid reabsorption, and it is onlyat the highest level of sympathoexcitation that there is areduction in renal hemodynamics. Normally, in responseto everyday activities (e.g., taking in a meal containing ahigh content of sodium chloride), sympathetic control isexerted on renin release and fluid reabsorption to ensuresmooth excretion of an appropriate proportion of thesodium load. It is only when there are acute threatening"fight and flight" situations requiring redistribution ofblood that sympathetic activity increases to a level atwhich renal blood flow and glomerular filtration rate arereduced, but these are short-term responses that havelittle long-term impact on fluid balance.

The long-term increase in arterial blood pressure oftenaffects heart and kidneys. The higher the blood pressure,the greater is the resistance needed by the heart to function.A higher blood pressure could lead to an increase in the frequencyand contractile force. In the long term, these bloodpressure changes could compromise cardiac function.

Increase in sympathetic activity enhances systemicand regional norepinephrine spillover and elevate restingheart rate. This condition has been linked to hypertension,obesity, and insulin resistance. Furthermore, highlevels of fasting insulin are positively associated with theLF/HF ratio of the HRV - an index of the sympathovagalbalance at the heart level.

In view of the strong relationship among obesity, metabolicsyndrome, and the development of CV risk factors,it is important to elucidate autonomic disturbances thatoccur in obese individuals. Though the autonomic disordersare not homogeneous in obesity, some studies havedocumented that most individuals exhibit sympathetichyperactivity. Both BRS and HRV are impaired in obesewomen. Esler et al demonstrated that the sympathetictone in obese subjects is increased in some target organslike kidney, skeletal muscle, and vessels.

Sympathetic hyperactivity in obesity indicates thatobesity impairs renal-pressure natriuresis, enhancesrenal tubular sodium reabsorption, and causes hypertension.Various studies have demonstrated increasedarterial pressure and serum catecholamine levels inobese individuals. The weight loss is associated with thedecreased plasma concentration norepinephrine. Obesehypertensive children show increase in sympatheticnerve activity. However, in these patients, a low-salt dietis capable of promoting a decrease in arterial pressure.
 
These studies emphasize that sympathetic hyperactivityis related to sodium retention and increased arterialblood pressure in obese children. Furthermore, MSNAis increased in obese as compared with nonobese normotensiveindividuals.

In addition, the MSNA and the plasmatic norepinephrineare reduced and the BRS is increased after weightloss in normotensive obese subjects. The heart rate variationsare a visible effect of the autonomic influences onthe heart in cases of emotional stress. An inability tosustain varying heart rate is an important risk factor ofdevelopment of CVD. Brunner et al demonstrated a relativesympathetic dominance and a lower vagal tone to theheart in cases of metabolic syndrome, thereby indicatingsympathovagal imbalance in those individuals.

Jamerson et al documented an inverse relationshipbetween sympathetic vascular tone and the insulinmediatedcellular glucose consumption. Therefore, theincreased adrenergic activity as observed in obese individualsincreases the vascular constriction and impairsglucose transportation into the cells. Further studieson obesity have implicated vascular constriction ininsulin- resistance. Specific alfa-adrenergic vasoconstrictionis more malefic on glucose consumption than theangiotensin-induced vasoconstriction, thus suggestingthe sympathetic influence on glucose metabolism.

In type II diabetic patients, metabolic syndrome hasapproximately 70% of prevalence rate. The basic mechanisminvolved in the pathogenesis of T2DM is insulinresistance. In turn, the insulin resistance is strongly associatedwith sympathovagal imbalance. Further, numerousdata suggest the involvement of increased SNS activity ininsulin resistance. Epidemiological studies have found acorrelation between insulin resistance and hypertension.In type I diabetic patients, the hypertension is usuallydeveloped after the onset of nephropathy and has anassociation with renin-angiotensin-induced SNS activation.On the contrary, the prevalence of hypertension intype II diabetic patients is extremely common. Thus, itcan be hypothesized that insulin resistance and hypertensionin the metabolic syndrome are closely linked withsympathetic overactivation.

Sympathetic overload is implicated in the pathogenesisas well as in the deterioration of essential hypertensionthrough the modification of heart rate, cardiac output,peripheral vascular resistance, and renal sodium retention.Some studies documented a plasmatic overflow ofnorepinephrine in essential hypertensive patients, thusindicating an increase in the activation of sympatheticoutflow to the heart, kidneys, and cerebrovascular circulationof these subjects. These observations conclude thatsome target organs are negatively affected by increasedarterial pressure.

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Narsingh Verma

CONCLUSION

This review supports the attenuation of autonomicCV control in essential hypertension, thus concludingthat adrenergic overdrive is a major component of thisautonomic dysregulation. It also shows that adrenergicactivation appears early in the course of the disease andbecomes more prominent with the increasing severityof the hypertensive state. The adrenergic mechanismsalso participate in the development of target-organdamage, which is frequently detectable in hypertensivepatients.

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