Journal of Human Hypertension (2002) 16 (Suppl 1), S64–S69  2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh The sympathetic nervous system: the muse of primary hypertension

V DeQuattro1 and M Feng1,2 Keck School of Medicine, University of Southern California, Los Angeles, California, USA

Von Euler characterised the sympathetic neuro- anger ambience and blood pressure of PH with raised transmitter noradrenaline (NA) and postulated that plasma NA vs those with normal NA levels. Campese excessive neural tone was a cause of primary hyperten- found a hypothalamic source of raised blood pressure sion (PH). Thirty years ago, we found raised NA levels in two rat models – microphenol treated and ischaemic in 30–40% of young patients with PH. Laragh found kidney. The resulting hypertension was associated with plasma renin activity (PRA) a risk marker for coronary raised NA turnover of their hypothalamic centres. artery disease. With Esler, Miura, and Campese, a close Finally, with Hsueh and Hodis, we found raised plasma association was found of plasma NA with PRA. We NA in association with insulin resistance increased left found raised tyrosine hydroxylase activity (AC) in the ventricular mass and intimal medial hypertrophy in Mex- hearts of a rabbit model of sinoaortic denervated hyper- ican-American diabetics and their yet unaffected off- tension and in PH with raised plasma NA. Esler utilised spring. Reliable estimates of human sympathetic AC, titrated NA infusion and described increased spillover including levels of plasma NA in the effluent of selected of NA from heart, kidney and subcortical areas of brain organs and peripheral venous and arterial sites, may of patients with PH. With Eide we found raised cerebro- eventually be displaced by techniques using genetic spinal fluid (CSF) NA in PH (not secondary analysis and molecular biology. Never the less, the sym- hypertension) and with Kolloch and Miura, we found pathetic nervous system appears to play an important raised plasma/CSF NA in conjunction with reduced role in the pathogenesis, sequelae and therapy of PH. dopaminergic tone. With Shkvatsabaya, Yurenev and Journal of Human Hypertension (2002) 16 (Suppl 1), S64– Davison, we found that relaxation therapy improved the S69. DOI: 10.1038/sj/jhh/1001346

Keywords: sympathetic nervous system; primary hypertension

Introduction (CHF), atherosclerotic cardiovascular disease, and renal dysfunction. Muse, one of the nine daughters of the Greek Gods of mythology – Mnemosynl and Zeus, is a guiding spirit or influence over one of the Arts and Sciences. SNS activity in the clinical setting In our view, the sympathetic nervous system (SNS) There are several ways to assess SNS function in the is the Muse over the circulatory system, and thus a patient with hypertension or with other types of major influence or cause of primary hypertension. adrenergic dysfunction. Spectroanalysis can be used The evidence seems to indicate that the control of for heart rate and RR variability, baroceptors testing, raised blood pressure begins in the brain, probably valsalva manoeuver, depressor responses to sym- 1 in the hypothalamus. Recent work by Campese et al pathoplegic agents, heart rate response to posture – indicates that a drop of phenol on the kidney can that is often a bedside indicator of the SNS activity, elicit a central noradrenergic pressor response. So whether it is paramount, present, or absent in that a central outflow of increased SNS activity may patients with postural hypotension. Cardiac cat- not be the initiating factor in blood pressure elev- echolamine (CA) turnover has been measured by ation, but that it may reside in a peripheral organ or Goldstein et al2 and other workers using fluro- vessel. So we will leave open where it actually dopamine uptake and turnover or flurodesoxyglu- starts, though we believe that the SNS plays an cose. These techniques appear to offer a quantitative important role as a causative factor in primary assay of cardiac noradrenaline (NA) content and hypertension, and is also a major factor in the gen- turnover in autonomic disorders before and after the esis of the complications of hypertension, including effects of various drugs. Systolic time intervals have ischaemic heart disease, congestive heart failure also been used to characterise the disordered SNS function. For years blood CA, generally measured in an antecubital vein, reflects CA produced by the Correspondence: V DeQuattro, MD, Keck School of Medicine, nerve ending and via the synapse entering the University of Southern California, Los Angeles, CA, USA venous circulation. This is an averaging of nor- 2M Feng, MD, Visiting Scholar, People’s Republic of China adrenergic activity to that limb. Relative contributors The sympathetic nervous system V DeQuattro and M Feng S65 of the limb or an organ to the circulation may be Arbor and now at the Baker Institute in Australia, obtained from both arterial and venous sampling. Dr Eide in Oslo Norway, Dr Kobayashi in Sendai, Murray Esler,3 went further in these assessments by and Dr Kolloch in Bonn. All of these people reported measuring NA spillover rates using both the results similar to our findings of 30 years ago. In endogenous level of CA and the level of radiolabel summary, the theory was: somewhere in the central after graded infusion. nervous system, probably central command in the bedroom of the brain – the hypothalamus, was sti- Dopa, dopamine and the metabolites mulating peripheral nerves and raising NA levels. We believed that the increased SNS tone caused the What is the role of dopamine (DA)? Is it a precursor blood pressure elevation in some patients with to NA or does it represent some other activities of hypertension. the central or peripheral SNS. And also the CA metabolites – which serves best to assess SNS func- Myths, muses and neurogenic factors tion? The primary metabolite used to detect or rule out pheochromocytoma are the plasma levels of the One of the earliest meta-analyses in cardiovascular metanephrines. Plasma levels of metanephrines medicine was that done by David Goldstein at NIH. have replaced the urinary levels as the more sensi- He evaluated 32 published studies and found that tive test. In fact, other precursors and metabolites, plasma NA or CA levels were elevated in 80% of dihydroxyphenylalanine, dihydroxyphenylglycol, them, and in 40% there was a significant rise in dihydroxyphenylacetic acid, and dihydroxymand- plasma NA or CA in patients with primary hyperten- elic acid, can give an indication of SNS activity.4 sion.7 Thus, younger hypertensive patients have But, it is important to keep in mind that the neuro- raised NA levels. Is that just anxiety? That led my transmitter, NA, is present in the nerve ending of colleague, Yukio Miura, one of a long line of the SNS, and along with adrenaline (A) in the coworkers from Sendal and myself in our paper in adrenal gland, the latter in a ratio of A:NA of about 1973 to address the question ‘Neurogenic factors in 3 or 4 to 1. This ratio is helpful in localising pheoch- primary hypertension: mechanism or myth’.8 romocytomas using venous sampling. The major Amaterasu Ohmikami – mythology, and later its metabolite of the CA is vanilmandelic acid (VMA). adoption into the Shinto religion holds that the birth However, VMA excretion is often normal in patients of the Japanese nation and the divine linking of the with pheochromocytoma, and usually the CA and emperors to the Sun Goddess, Amaterasu, started normetanephrines are the best reliable assay. Often, when her grandson became the father of the first the only metabolite that is elevated in pheochromo- emperor. Thus, a mysterious but powerful woman cytoma are the metanephrines, especially in patients was believed to be the Muse of the nation of Japan. with malignancy. This myth/belief was removed officially by the Allied command in 1945, but it flourishes in some Raised plasma catecholamines (CA) circles. One of the first papers on plasma CA in primary Noradrenaline, renin and cardiac output hypertension was from LAC+USC Medical Center. It was almost 30 years ago on the Surgical Wards at Is the SNS a more powerful Muse than renin? In LA County where we studied patients with primary 1970, John Laragh, after measuring plasma renin in hypertension and age-matched normal volunteers. patients with hypertension, found that some We found increased CA levels – about 30% higher patients with high renin had a greater morbidity in the hypertensive patients than in controls – after from heart attack than those with low renin. Sub- the patients were supine for an hour while resting sequently, Laragh et al followed patients for 10 years comfortably and with an indwelling line. This was and examined their heart attack rate along with the second report of a raised level of CA in primary blood glucose and renin profiling.9 The interaction hypertension.5 The first paper preceded ours by 2 of renin and cholesterol revealed that in patients in years using the double isotope assay of Engleman whom both values were high, event rates were high- and Lovenberg.6 We studied 27 patients and seven est; conversely, they were low in patients with the (27%) had raised CA. At that time therefore, we pos- opposite profile. That renin is predictive of morbid tulated that there are some patients with primary events has been validated with the advent of the car- hypertension whose SNS is over active and contrib- dioprotective angiotensin-converting enzyme utes to blood pressure elevation. inhibitory. These were generally younger people and the Murray Esler (who was working in Julius’ lab in studies therefore were extended by ourselves and Ann Arbor where raised cardiac output was found others over the next 10 years. Various contributors in young patients with primary hypertension) and found very similar results when they measured I measured both renin and catecholamines, cardiac plasma CA in patients with primary hypertension. output, peripheral resistance and behavioural fac- Many of these scientists had worked with us – Dr tors in young patients with hypertension. We found Miura in Sendai, Dr Esler who was then at Ann that the patient with the higher plasma renin

Journal of Human Hypertension The sympathetic nervous system V DeQuattro and M Feng S66 activity (PRA) had higher cardiac output, heart rate, Human vas deferens peripheral vascular resistance and ‘anger in’.10 Further, the CA levels were raised in these patients Similar biochemical attributes of SNS function were compared with the normal subjects and the normal found in human vas deferens of patients with pri- renin patients.10 In addition, Miura et al11 studied mary hypertension whose tissues were being patients at both the Los Angeles County and the removed for elective sterilization. With Bob Men- 13 White Memorial Medical Center. We again found dez we found that plasma CA and tissue levels of that plasma NA levels of high renin patients NA were both raised and CA biosynthesis activity exceeded those of the other patients. Systolic time was increased. The rate limiting step, tyrosine intervals, cardiac index, and heart rate were also hydroxylase activity, was also increased. increased. Julius and Esler, examining depressor responses to sequential autonomic blockade via CSF NA and signals from the brain renin status (atropine then propranolol then the alpha blocker phentolamine), found that patients We found CSF NA levels were higher than the with high renin had greater reductions in mean respective levels in the plasma of patients with pri- 14 blood pressure with total autonomic blockade, sug- mary hypertension. On the other hand, in patients gesting an adrenergic role for blood pressure elev- with phenochromocytoma the levels of CA were ation.10 High heart rate, perhaps reflecting high SNS much lower in the spinal fluid than they were in the tone is predictive of increased coronary risk. There plasma. Thus there appeared to be no penetration of were strident non-believers in plasma CA as a SNS the blood brain barrier by the CA in the blood of the marker. In fact, Folkow had said ‘not so seldom it is patients with pheochromocytoma. Our findings with about as difficult to judge a differentiated sympath- metanephrines in CSF and plasma were similar: etic activity from plasma noradrenaline levels as it they were elevated in patients with primary hyper- 15 is to judge from a beach the size, speed and direction tension. Plasma and CSF DA were lower in pri- of a ship passing beyond the horizon by means of mary hypertensives compared with normoten- 16 the swells that it delivers at the beach line’. This sives. Young hypertensives with raised NA had was his way of saying I do not believe it. greater blood pressure and plasma NA reductions to the dopamine agonists bromocriptine, suggesting that these patients had impaired dopaminergic con- Animal models, human tissue, and CSF trol and secondarily heightened SNS function; anal- ogous perhaps to Parkinson’s disease wherein poor studies dopaminergic control within the basal ganglia of In the 1960s with Alexander and Nagatsu here at patients leads to tremor and motor dysfunction. Per- USC, we studied our first hypertensive animal haps in the hypothalamus impaired dopaminergic stimulation leads to enhanced NA in patients with model, the sino aortic denervated rabbit. Later we 17 studied the rat Goldblatt and Okamoto SHR models, primary hypertension. These findings and the and human hypertensives vas deferens. We also many other contributions of our colleagues from studied central SNS function via the cerebrospinal Japan, Sato, Nagatsu, Miura, Kobayashi, and fluid (CSF) in human hypertensive patients; with Kimura, suggest to me that perhaps the SNS Muse either primary hypertension, pheochromocytoma, or and Amaterasu are one and the same. renovascular disease. We looked for a neurogenic Esler initiated studies of NA spillover to measure general SNS activity, as well as that of specific role in primary hypertension by measurements of 10 spinal fluid CA and metabolites and other neurologi- organs. He assessed central SNS function in cal functions. We assessed plasma prolactin and human hypertension by measures of catecholamine dopamine centrally (CSF) and peripherally (blood). spillover in both jugular veins. He found that the We used the dopamine agonist bromocriptine to major jugular vein drained the superior saggital stimulate the dopaminergic system. sinus, and the right jugular vein drained the basal ganglia mid brain and hypothalamus.18 He found elevated NA spillover coming from the hypothala- SAD model mus areas. He found similar results in patients with CHF, suggesting that in the patient with CHF the It was found that cardiac NA and protein synthesis well spring of the sympathetic activity is in the increased within 2 days in rabbits who had their hypothalamus, probably in response to their low left buffer nerves severed12 and also that within 2 days ventricular filling pressures and the high pulmonary left ventricular mass along with protein synthesis artery pressures. increased consonant with a prompt rise in sympath- etic activity in this model, akin to human labile Noradrenergic behaviour and relaxation hypertension. The lability of the hypertension therapy depended in part on the ambient environment of the animal. This was the initial finding of raised NA We studied the source of the sympathetic storm synthesis in an animal model of hypertension, early on with Kiley and his colleagues in the psy-

Journal of Human Hypertension The sympathetic nervous system V DeQuattro and M Feng S67 chiatry department at LA County/USC. We exam- example is a lady that was ‘rule out pheochromo- ined flight and fight responses in patients with cytoma’.Ifirst saw her when I came into the examin- hypertension, looking at their responses to noxious ing room and she had already disrobed because ‘I tasks and their behavioural ambience of anxiety, am burning up’. Her face was red and hot, both her anger, and depression. We found that primary blood pressure and heart rate were elevated. Many hypertensives had more anxiety, depression, and similar patients are referred to us to ‘rule out’ anger than normotensives. Patients with secondary pheochromocytoma – they are sweating, flushing hypertension had the same psychological features as and have other autonomic features. The work-up normal volunteers. Thus, there seems to be a differ- does not reveal a pheochromocytoma. This clinical ent psychological ambience in patients with primary presentation demands a differential diagnosis to hypertension. We characterised which of our exclude thyroid and serotonin disorders, but some patients were type ‘A’ personality, the joyless, striv- probably do have ‘hyperadrenergic’ spells. Irvine ing categorisation of Ray Rosenmen, and then we Page described patients with these features over 60 attempted to lower their blood pressure with relax- years ago as ‘diencephalic epilepsy’ simulating a ation therapy. We espoused an adrenergic hypoth- tumor in the diencephalon. Many of his patients esis for some of these patients as well. We looked at were women with paroxysmal hypertension and the influence of behaviour on patients with hyper- profound autonomic features. Thus, in some tension. patients, the adrenergic spells may represent norad- In 1982, with Shkhvatsabaya, Yurenev, and renergic fits that arise in the hypothalamus. Salenko in the Myasnikov Institute of Cardiology in Approximately 10% of our referred patients had Moscow, we assessed the influence of a relaxation very low levels of VMA despite high levels of met- therapy technique of SNS tone, blood pressure and anephrines in the urine. The dominant ratio of left ventricular mass.19 Using relaxation therapy, we amines to acid metabolites suggested that these were controlled blood pressure and reversed left ventricu- taking a monoamine oxidase inhibitor.22 As in lar mass in some patients with hypertension. We Page’s syndrome, these patients are predominantly brought their technique to USC, and with the assist- women with prominent flushing, tachycardia, labile ance and modifications by Davison in the psy- hypertension and raised plasma NA. The biochemi- chology department at USC, we found that patients cal and clinical features may be linked to oes- with raised levels of NA had greater anger and hos- trogen dysregulation. tility.20 Relaxation training methods to these patients resulted in greater reductions of blood Noradrenergic genesis of ischaemic pressure, heart rate, and anger thoughts.21 Thus, it appeared amazing that a simple technique like heart disease and CHF learning how to relax can really reduce both abnor- We wished to examine the role of the SNS in mal behaviour and blood pressure. ischaemic heart disease. Earlier, Horwitz and The diary of a type A patient; see the boss early, Sjoerdsma23 described patients who developed ST sales meeting confirmed, get out the order no matter segment depression first on exercise and then a rise what, hurry up; this is a real diary of a patient who in the blood pressure. This suggested that some died at 8.00 that evening probably at the PTA meet- patients with ischaemic heart disease have hyper- ing. We divided our patients into type A and B tension secondary to coronary ischaemia.23 James according to his structured interview and we did described an area of the heart in the septum called find that the type A patients had a greater left ven- ‘the body of James’. Hypoxia leads to platelet release tricular mass than the type B patient and raised NA of serotonin, stimulation of these cardiac chemo- levels. There have been other studies in animals receptors and activation of afferents to the brain relating NA to hypertrophy of the heart. The which raises central SNS activity, blood pressure researchers at Harbor UCLA had an animal model and heart rate. Generally, a patient who is hyperten- of left ventricular hypertrophy involving only septal sive, because of increased blood pressure and heart hypertrophy. This was obtained by using NA rate product, encounters ischaemia when coronary infusions at low levels so that the dogs did not perfusion is limited. However, there are some develop hypertension, but did develop hypertrophy patients who have ischaemia, and subsequently the of their septum and left ventricle. We believe that SNS seems to be activated. Thus, there are several type A subjects have behaviour patterns of striving possible roles for SNS in patients with stable angina. which leads to increased sympathetic tone, and We measured ambulatory blood pressure, real time therefore organ changes of left ventricular hyper- ischaemia, and using an automated device which trophy independent of the blood pressure. draws blood when the patients is having an ischaemic episode, we found that CA levels were Spells, autonomic features, impaired raised in the silent ischaemic attack. We prevented the angina in these patients with beta-blocker ther- oxidative deamination apy.24 Oral immediate release nifedipine therapy Some patients with raised adrenergic features serve was not very effective.25 Thus, in most of our as caricatures – mimicking pheochromocytoma. One patients with stable angina, SNS stimulation pre-

Journal of Human Hypertension The sympathetic nervous system V DeQuattro and M Feng S68 ceded the rise in blood pressure, heart rate and ST In studies with Hsueh and Hodis, we related car- segment depression, and it could be modulated with diovascular sequelae to SNS tone and to insulin metoprolol therapy. resistance.30 We studied Mexican American families We worked with Elkayam in Los Angeles and Losa with diabetes, the offspring were not involved, 25 in Argentina. Patients with Chagas induced CHF were hypertensive. Diastolic blood pressures were had lower plasma CA levels related to Chagasic related to noradrenaline levels. Patients with higher denervation.26 plasma NA had greater left ventricular mass index The higher the level of CA in CHF, the higher the and intimal medial thickness. Patients with insulin SNS influence and the poorer the prognosis. Drugs resistance also had a greater left ventricular mass such as carvedilol and metoprolol can block and index. Thus, in these families insulin resistance and shield the way of sympathetic influence and allow SNS tone appeared related to cardiovascular damage the myocyte to come back more to its adult function. as well as salt sensitivity. There may be a link to an Plasma CA levels are related to muscle sympathetic abnormal beta-3 adrenergic receptor and work is in nerve activity, and predict an earlier demise in progress in that area. patients with CHF. Cardiac muscle release of CA can be assessed in the coronary sinus: coronary sinus CA are increased more in hypertensive patients and are Summary greater in hypertensives with left ventricular Our task for the past 35 years has been to assess SNS hypertrophy and highest in those with hypertrophic function in the clinical setting often utilising plasma cardiomyopathy. Thus, there appears to be a role for NA as a sensitive, reproducible, readily available SNS dysfunction in the hypertrophy process. and inexpensive invaluable marker. Generally, NA spillover measurements are superior in aspects of Conclusion specificity and regionality, but the technical avail- ability is constrained by the inherent nature of the John Laragh made the astute observation that hyper- methodology. Perhaps genetic analysis and the mol- tensive patients had different biochemical and ecular biology of the new millennium will replace haemodynamic qualities, and those with high renin these older methods. Current evidence supports were at great risk. More recent demographic studies neurogenic factors as causative in the genesis and by Julius demonstrate that patients with high renin sequelae of some patients with primary hyperten- tend also to have a higher cholesterol, NA and sys- sion. Despite its limitations, plasma NA may con- tolic blood pressure.27 Approximately 20% of their tinue to provide a marker for SNS tone, and further patients had high plasma renin. We described a 27– it may just be possible from the ripples on the beach 30% incidence of raised catecholamine in patients to tell the speed, direction and size of a passing ship with primary hypertension. NA and cholesterol unseen beyond the waves.31 The SNS muse has a levels both increase in response to postural chal- powerful influence on the cardiovascular system. lenge. Thus, SNS activity can adversely influence cholesterol levels and metabolism, and therefore the SNS can crucially activate coronary risk. John Lar- References agh and his colleagues have provided solid evidence 1 Campese V. Personal communication. Manuscript in that plasma renin activity is a marker for cardio- preparation. vascular risk. Studies of ischaemic heart disease 2 Goldstein D et al. Cardiac sympathetic denervation in morbidity with ACE inhibitors or beta-blockers Parkinson disease. Ann Int Med 2000; 133: 338–347. show important cardioprotection. Thus, it is still 3 Esler M et al. Am J Cardiol 1997; 80: 76. plausible and possible that the SNS is the dog wag- 4 Robertson D. Dissociation between neural and vascular ging the tail of the renin angiotensin system. Julius responses to sympathetic stimulation. Hypertension has described the relationship of the SNS to left ven- 2000; 35:76–81. 5 DeQuattro V, Chan S. Raised plasma catecholamines tricular hypertrophy, independent of blood press- in some patients with primary hypertension. Lancet ure, leading to arrhythmia, sudden death, a 1972; 1: 806–809. reduction of plasma volume (as in patients with 6 Engelman K, Portnoy B, Sjoerdsma A. Catecholamine- pheochromocytoma), increased vascular hypertro- cylic-AMP-angiotensin receptors. Plasma catechol- phy and changes in haematocrit and blood platelets amine concern in patients with hypertension. Circ Res contributing to thrombosis, coronary spasms, insu- (Suppl 1): 141–146. lin resistance, dyslipidaemia, and thus coronary 7 Goldstein D. Plasma norepinephrine in essential heart disease.28 Thus the SNS is a major player in hypertension: a study of the studies. Hypertension coronary risk. Heart rate, a risk marker of adrenergic 1981; 3: 48. tone is related to insulin resistance. Additional stud- 8 DeQuattro V, Miura Y. Neurogenic factors in hyperten- sion: mechanism or myth? Am J Med 1973; 55: 362– ies found increased alpha-1 adrenergic tone in 378. patients with syndrome X. We assessed the morning 9 Alderman MH et al. N Engl J Med 1991; 324: 1098. pressure surge in patients with hypertension and 10 Esler M et al. Mild high-renin essential hypertension: demonstrated that it could be blunted with an alpha a neurogenic human hypertension? N Engl J Med 1977; and beta-blocker, labetalol.29 296: 405–511.

Journal of Human Hypertension The sympathetic nervous system V DeQuattro and M Feng S69 11 DeQuattro V, Campese V, Miura Y, Meijer D. Increased 20 Lee DP et al. Neurohumoral mechanisms and left ven- plasma catecholamines in high renin hypertension. tricular hypertrophy in primary hypertension. Effects Am J Cardiol 1976; 38: 801–804. of hygienic therapy. J Hum Hypertens 1987; 1: 147– 12 DeQuattro V, Nagatsu T, Maronde R, Alexander N. Cat- 151. echolamine synthesis in rabbits with neurogenic 21 Hagaa D et al. Mode-specific impact of relaxation train- hypertension. Circ Res 1969; 24: 545–555. ing for hypertensive men with type A behavior pat- 13 DeQuattro V et al. Increased plasma catechlamines tern. Behav Ther 1994; 25: 209–223. and vas deferans norepinephrine biosynthesis in men 22 Atakhanov C, Kim D, DeQuattro V. Noradrenergic with elevated blood pressure. Circ Res 1975; 36: excess in primary hypertensives with reduced oxidat- 118–126. ive deamination: a syndrome mimicking pheochromo- 14 Eide I et al. Raised cerebrospinal fluid noradrenaline cytoma. Am J Hypertens 1995; 8: 125A. in some patients with primary hypertension. Hyper- 23 Horwitz D, Sjoerdsma A. Hypertension 1964; 8:39–48. tension 1979; 1: 255–260. 24 Lee DP, Kimura S, DeQuattro V. Noradrenergic activity 15 DeQuattro V et al. Central and regional normet- and silent ischaemia in hypertensives with stable anephrine in evaluation of neurogenic aspects of angina: effect of metoprolol. Lancet 1989; 1: 403–406. hypertension: aid to diagnosis of pheochromocytoma. 25 Lee DP, Rigonan K, DeQuattro V. Increased blood Clin Sci 1980; 59: 275S–277S. pressure and neural tone in the silent ischemia of 16 DeQuattro V et al. Central and peripheral norad- hypertension: disparate effects of of immediate release renergic mechanisms in primary hypertension. Fed nifedipine. JACC 1993; 22: 1438–1445. Proceed 1984; 43:47–51. 26 Iosa D et al. Plasma norepinephrine in Chagas’ car- 17 Kolloch R, Kobayashi K, DeQuattro V. Dopaminergic dioneuropathy: a marker of progressive dysautonomia. control of sympathetic tone and blood pressure: evi- Am Heart J 1989; 117: 882–886. dence in primary hypertension. Hypertension 1980; 2: 27 Julius Tecumeseh. Am J Hypertens 1993; 6: 891. 390–394. 28 Julius S. Clin Exp Hypertens 1996; 18: 305–321. 18 Ferrier C et al. J Hypertens 1993; 11: 1217. 29 DeQuattro V et al. Labetalol blunts morning pressor 19 DeQuattro V et al. Left ventricular hypertrophy and neu- surge in systolilc hypertension. Hypertension 1988; 11 ral tone in hypertension: divergent effects of diuretic and (Suppl 1): I-198–I-201. relaxation therapy. Hypertension: neural tone and the 30 Li DP et al. Neurogenic factors and insulin resistance heart. In: Hegyeli R (ed). Proceedings of the Fourth Joint participate in the genesis and sequelae of the hyper- US-USSR Symposium on Arterial Hypertension,NHLBI, tension in Mexican Americans. J Hypertens 1998; 16 1985. US Department of Health & Human Service, NIH (Suppl 2): S176. Pub. #86–2704, January 1986. 31 Folkow B. Acta Physiol Scand 1984; (Suppl S27): 9.

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