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.