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Sympathetic neural mechanisms in the pathogenesis of human hypertension

Giuseppe Mancia 1-2-3 , Gino Seravalle 2-3, Guido Grassi 1-3

1.-Department of Internal Medicine. University of Milan. S. Gerardo dei Tintori Hospital. Monza
2.-Italian Auxologic Centre. IRCCS. S. Luca Hospital. Milan
3.-Department of Clinical Physiology and Hypertension. IRCCS. University of Milan.
Monza - Milan. Italy

Sympathetic activation in essential hypertension
Sympathetic activity in secondary hypertension
Mechanisms responsible for the sympathetic activation in essential hypertension
Sympathetic activity and structural cardiovascular alterations


Animal studies have conclusively documented that adrenergic mechanisms are involved in the development and maintenance of experimental hypertension (1). Although the difficulties posed by assessing sympathetic cardiovascular influences in man have made for a long time data collected on this issue in human hypertension questionable, the picture, however, has been substantially modified over the last decade, owing to the results of the studies in which adrenergic activity has been evaluated through more direct and sensitive approaches.

This paper will review three issues related to the role of the sympathetic nervous system in human hypertension, by discussing:

1) the evidences in favour of a state of sympathetic activation in the essential hypertensive forms,
2) the behaviour of central and peripheral adrenergic drive in secondary forms of hypertension and
3) the mechanisms and the consequences of the hyperadrenergic state characterizing essential hypertension.


Sympathetic activation in essential hypertension

The evidences that the sympathetic activity is increased in essential hypertension are multifold. One, years ago using pharmacological blockade of autonomic receptors Julius et al (2) showed that sympathetic drive to the heart and the peripheral circulation is increased in borderline hypertensives as compared to normotensive controls. Two, Goldstein reported that pooling together the results of all the studies performed in essential hypertensives by measuring circulating levels of the adrenergic neurotransmitters, plasma norepinephrine values are significantly increased in established essential hypertensives as compared to non-notensive individuals (3). Three, Esler and coworkers have more recently shown that the spillover rate of norepinephrine into plasma (a value derived by subtracting the norepinephrine clearance from plasma norepinephrine value) is increased in young hypertensives (4).

Similar findings have been obtained in three studies, which have directly measured sympathetic neural activity to the skeletal muscle district through microelectrodes inserted in the peroneal or brachial nerves. In one study, the number of sympathetic bursts per minute was found to be greater in borderline hypertensives than in normotensive individuals (5). This was the case also in the second study, which additionally showed a tendency of sympathetic bursts to be enhanced in normotensive subjects with a family history of essential hypertension as compared to the values displayed by individuals without this anamnestic feature (6). Finally in a third study the frequency of sympathetic bursts over time was found to be progressively enhanced going from the normotensive state to the mild and more severe essential hypertensive condition (Table 1) (7).

Table 1: Baseline hemodynamic data in normotensive subjets, patients with moderate EH,
patients with more severe EH and patients with SH

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Taken together these findings support the hypothesis of the existence of an increased sympathetic cardiovascular drive in essential hypertension. They also support the hypothesis that sympathetic activation is a finding not peculiar to the early hypertensive stages but common also to the stable hypertensive conditions.


Sympathetic activity in secondary hypertension

Whether secondary forms of hypertension are also characterized by an increased sympathetic cardiovascular drive is matter of debate. Years ago Japanese investigators, by using the microneurographic approach to assess adrenergic tone, have shown that in an hypertensive condition of secondary nature (renovascular hypertension) sympathetic nerve traffic to peripheral circulation was increased as compared to the normotensive state (8). However, in a study in which different groups of normotensive, essential and secondary hypertensive patients were carefully matched for age and baseline blood pressure values, sympathetic burst frequency has been found, in patients with an adrenal pheochromocytoma or a renal artery stenosis, to be less than that characterizing the other hypertensive groups and similar to that of normotensive individuals (Table 1) (7). In addition, because in patients with pheochromocytoma sympathetic nerve traffic increased after surgical removal of the tumor, the hypothesis can be advanced that some secondary forms of hypertension are characterized by a central sympathoinhibition rather than excitation. It thus appears that in pheochromocytoma while adrenergic activity at the peripheral nerve terminals is increased, central sympathetic outflow is reduced presumably because the high levels of circulating catecholamines exert, at the level of the central nervous system, marked sympathoinhibitory effects.

It should be emphasized in this contest that the influences of the sympathetic nervous system on its cardiac and vascular targets depend not only on the degree of neural activity but also on the secretion of norepinephrine from nerve terminals and on the responsiveness of peripheral adrenergic receptors to their physiological stimuli. Animal and human studies have shown both norepinephrine secretion and adrenoreceptor responsiveness to be enhanced by angiotensin 11, which thus may peripherally activate sympathetic drive (9-11). In different studies (10- 11) our group has shown that, in subjects with angiographically normal coronary arteries, an intra-coronary infusion of angiotensin 11, at doses that did not cause any change in coronary blood flow, markedly enhanced the coronary vasoconstriction induced by diving, i.e. a response whose "sympathetic" nature was demonstrated by its abolition following an infusion of phentolamine (Figure 1). Conversely, in patients with severe coronary lesions the diving-induced sympathetic constriction of coronary vessels was attenuated by reducing the production of angiotensin 11 through the administration of an ACE-inhibitor (Figure 1).

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Taken together these findings indicate that profound interactions between sympathetic neural factors and other systems involved in blood pressure and volume homeostatic control (such as the renin-angiotensin one) do exist and partecipate at the regulation of systemic as well as regional haemodynamics (12).


Mechanisms responsible for the sympathetic activation in essential hypertension

The causes of sympathetic activation in essential hypertension have not been conclusively determined. Normotensive offsprings of hypertensive parents, borderline hypertensive subjects, and more severe hypertensive patients have been found to be characterized by exaggerated cardiovascular responses to laboratory or enviromental stressors (13-15), which has led to the hypothesis of an initial temporary sympathetic activation (and blood pressure rise), eventually changing into a stable sympathetic overdrive and a blood pressure elevation. However, the approach based on the evaluation of the cardiovascular responses to stress to assess the role of the adrenergic factors in the pathogenesis of hypertension has important limitations (limited reproducibility, discrepant responses to different stressors, enviromental stressors and blood pressure variability, etc) (16-19), which drastically reduce the scientific value of the above mentioned findings. Alternative mechanisms, which have been suggested throughout the years to be involved in the pathogenesis of the adrenergic overactivity, are represented by alterations in cardiovascular reflex control of circulation and by abnormalities in the humoral homeostatic control of circulation.

There is for example evidence that in hypertension, the ability of arterial baroreceptor to modulate sympathetic and vagal cardiac drive is reduced (7, 20) and that this reduction is coupled with an impairment of the influences originating from volume sensitive receptors located in the cardiac chambers, i.e. the so called cardiopulmonary receptors (21). Years ago our group has shown that the ability of this reflexogenic area to modulate sympathetic vasoconstrictor tone in the forearm circulation as well as renin release from the kidney is blunted particularly in hypertensive patients with left ventricular hypertrophy (22). This is supported by the evidence that pharmacological regression of this cardiovascular structural damage allows to functionally restore this homeostatic reflex mechanism (Figure 2) (22).


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Sympathetic activity and structural cardiovascular alterations

Several lines of evidences indicate that sympathetic activity may accelerate the structural alterations of the cardiovascular system that accompany hypertension. It has been for example shown that the addition of adrenergic agonists to the perfusing medium stimulates the in vitro growth of myocites (23), b) and replication of vascular smooth muscle cells (24), both phenomena being blocked by adrenergic antagonists (25). In addition there is evidence in rats that regression of left ventricular hypertrophy is obtained when blood pressure is reduced by sympathoinhibitory drugs but not when vasodilators, which reduce blood pressure to an even greater extent but reflexly stimulate cardiac sympathetic drive, are employed (26). Some of these findings have been confirmed in man, in which it has been shown that cardiac organ damage is strictly associated with 24 hour systolic and dyastolic blood pressure variability, i.e. a parameter which is markedly influenced by sympathetic influences (19, 27).

A few other points deserve to be discussed. First in normotensive subjects with both parents hypertensive there is already evidence of an increased left ventricular mass and arteriolar wall thickness, which suggests that cardiovascular structural changes represent early phenomena in hypertension (28). Second, at least as far as cardiac organ is concerned, these changes have important clinical significance because echocardiographic left ventricular hypertrophy is associated with a threefold increase in the cardiovascular risk of the hypertensive patient (29).
Finally, sympathetic stimulation of vascular smooth muscle cell replication implies a facilitating impact of the sympathetic nervous system on atherogenesis, because this replication allows the young undifferentiated cells to migrate from the medial to the intimat layer where their transformation in macrophages occurs.

Sympathetic activation can also favour atherogenesis also through indirect means, i.e. by altering arterial mechanics. Our group has indeed shown in rats that carotid artery compliance is markedly increased after sympathectomy (30), possibly because contraction of vascular smooth muscle by sympathetic tone makes the arterial wall stiffer. We have confirmed this phoenomenon in man in whom radial artery compliance was 1) markedly increased by withdrawal of sympathetic tone through anesthesia of the brachial plexus (31) and 2) markedly reduced by infusion of norepinephrine into the brachial artery (31). Finally, we have seen that in both intact and sympathectomized rats a progressive increase in heart rate by pacing is accompanied by a progressive reduction in carotid artery compliance (32). This leaves no doubt that sympathetic activity leads to increased large artery stiffness, both because of smooth muscle contraction and because of time-dependent viscoelastic opposition to vessel distension. A stiffer artery may be more prone to atherosclerosis because of an increased traumatic effect of the intravascular pressure, as documented by the striking diffusion of atherosclerosis in segments of rabbit carotid arteries enclosed into rigid collars (33).



In conclusion, there is now evidence that the sympathetic nervous system is activated in essential hypertension. Evidence is also available demonstrating that the development of this activation is an early phoenomenon, which however is evident in stable hypertensive states and accelerates structural cardiovascular damage, including atherosclerosis. The causes of sympathetic activation in essential hypertension remain to be fully clarified, although an impaired reflex modulation of adrenergic cardiovascular tone remains a likely possibility.

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1. Folkow BUG, Hallback MIL. Physiopathology of spontaneous hypertension in rats. In Genest J, Koiw E, Kuchel 0 (eds). Hypertension: Physiopathology and treatment. McGraw-Hill: New York, 1978: pp 507-529
2. Julius S. The changing relationship between autonomic control and haemodynamics of hypertension. In: Swales JD (Ed) Textbook of Hypertension. Blackwell Sci Publ 1994: pp 77-84
3. Goldstein DS. Plasma catecholamines and essential hypertension: an analytical review. Hypertension 1983; 5: 86-99
4. Esler M, Lambert G, Jennings G. Regional norepinephrine turnover in human hypertension. Clin Exp Hypertens 1989; 1 1 (suppl 1): 75-89
5. Anderson EA, Sinkey CA, Lawton WJ, Mark AL. Elevated sympathetic nerve activity in borderline hypertensive humans: evidence from direct intraneural recordings. Hypertension 1988;14: 1277-1283
6. Yamada Y, Miyajima E, Tochikubo 0, Matsukawa T, Shionoiri H, Ishii M, et al. Impaired baroreflex changes in muscle sympathetic nerve activity in adolescents who have a family history of essential hypertension. J Hypertens 1988; 6 (suppl 4): S526-S528
7. Grassi G, Cattaneo BM, Seravalle G, Lanfranchi A, Mancia G. Baroreflex control of sympatehtic nerve activity in essential and secondary hypertension. Hypertension 1998; 31: 68-72
8. Miyajima E, Yamada Y, Yoshida Y, Matsukawa T, Shionoiri H, Tochikubo 0, et al. Muscle sympathetic nerve activity in renovascular hypertension and primary aldosteronism. Hypertension 1991; 17: 1057-1062
9. Webb DJ, Seidelin PH, Benjamin N, Collier JG, Strutheers AD. Sympathetically mediated vasoconstriction is augmented by angiotensin 11 in man. J Hypertens 1988; 6 (suppl 4): S542S543
10. Perondi R, Saino A, Tio AR, Pomidossi G, Gregorini L, Alessio P, et al. ACE inhibition attenuates sympathetic coronary vasoconstriction in patients with coronary disease. Circulation 1992; 85: 2004-2013
11. Saino A, Pomidossi G, Perondi R, Valentini R, Rimini A, DiFrancesco L, et al. Intracoronary angiotensin II potentiates coronary sympathetic vasoconstriction in man. Circulation 1997; 96: 148-153
12. Mancia G, Saino A, Grassi G. Interactions Between the sympathetic nervous system and renin angiotensin system. In: Laragh JH, Brenner BM (Editors). Hypertension: Pathophysiology, diagnosis, and management, second edition, Raven Press, New York 1995: pp 399-407.
13. Falkner B, Onesti G, Hamstra B. Stress response characteristics of adolescents with high genetic risk of essential hypertension: a five-year follow-up. Clin Exp Hypertens 1981; 3: 583-591
14. Timio M, Verdecchia P, Venanzi S, Gentili S, Ronconi M, Francucci B, et al. Age and blood pressure changes: a 20 year follow-up study of nuns in a secluded order. Hypertension 1988; 12: 457-461
15. Schnall PL, Pieper C, Schwartz JE, Karase RA, Schlussel Y, Devereux R, et al. The relationship between "job strain", work place, diastolic blood pressure and left ventricular mass index. JAMA 1990; 263: 1929-1935
16. Mancia G, Parati G. Reactivity to physical and behavorial stress and blood pressure variability in hypertension. In: Julius S, Basset DR, eds. Handbook of hypertension. hypertension. Vol 9. Behavioral factors in hypertension. Amsterdam: Elsevier Science, 1987: 104-122
17. Parati G, Pomidossi G, Ramirez A, Cesana B, Mancia G. Variability of the haemodynamic responses to laboratory tests employed in the assessment of neural cardiovascular regulation in man. Clin Sci 1985; 69: 533-540
18. Parati G, Pomidossi G, Casadei R, Ravogli A, Groppelli A, Cesana B, et al. Comparison of the cardiovascular effects of different laboratory stressors and their relationship with blood pressure variability. J Hypertens 1988; 6: 481-488
19. Mancia G. Bjorn Folkov Award Lecture.The sympathetic nervous system in hypertension. J Hypertens 1997;1 5:1553-1565.
20. Mancia G, Grassi G, Ferrari AU. Reflex control of the circulation in experimental and human hypertension. In: Zanchetti A, Mancia G, eds. Handbook of hypertension. Vol 17. Pathophysiology of hypertension. Amsterdam: Elsevier Science, 1997: 568-601
21. Mark AL, Mancia G. Cardiopulmonary reflexes in humans. In: Shepherd JT, Abboud FM (Editors). Handbook of Physiology, Section 2, The Cardiovascular System. Bethesda: American Physiological Society; 1983: pp 795-818.
22. Grassi G, Giannattasio C, Cleroux C, Cuspidi C, Sampieri L, Bolla GB, et al. Cardiopulmonary reflex before and after regression of left ventricular hypertrophy in essential hypertension. Hypertension 1988; 12: 227-237
23. Simpson P, McGrath A, Savion S. Myocyte hypertrophy in neonatal rat heart cultures and its regulation by serum and by catecholamines. Circ Res 1982; 51: 787-801
24. Blaes N, Boissel JP. Growth-stimulating effect of catecholamines on rat aortic smooth muscle cells in culture. J Cell Physiol 1983; 116: 167-172
25. Simpson P. Norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an alpha I adrenergic response. J Clin Invest 1983; 72: 732-738
26. Sen S, Tarazi RC, Kliairallah PA, Bumpus FM. Cardiac hypertrophy in spontaneously hypertensive rats. Circ Res 1974; 35: 775-781
27. Parati G. Pomidossi G, Albini F, Malaspina D, Mancia G. Relationship of 24 h blood pressure mean and variability to severity of target-organ damage in hypertension. J Hypertens 1987;5:93-98.
28. Giannattasio C, Cattaneo BM, Man-oni AA, Carugo S, Stella ML, Failla M, et al. Cardiac and vascular structural changes in normotensive subjects with parental hypertension. J Hypertens 1995; 13: 259-264
29. Koren NJ, Devereux RB, Casale PN, Savage DD, Laragh JH. Relation of left ventricular mass and geometry to morbidity and mortality in man and woman with essential hypertension. Ann Intern Med 1991; 114: 345-352
30. Ferrari AU, Mangoni AA, Mircoli L, Giannattasio C, Mancia G. Sympathetic activity tonically restrains large artery diameter and distensibility in anesthetized rats. Hypertension 1997; 28: 526 (abstract)
31. Grassi G, Giannattasio C, Failla M, Pesenti A, Peretti G, Marinoni E, et al. Sympathetic modulation of radial artery compliance in congestive heart failure. Hypertension 1995; 26:348354.
32. Mangoni AA, Mircoli L, Giannattasio C, Ferrari AU, Mancia G. Heart rate-dependance of arterial distensibility in vivo. J Hypertens 1996; 14: 897-901.
33. Booth RGF, Martin JF, Honey AC, Hassal DG, Beesley JE, Moncada S. Rapid development of atherosclerotic lesions in the rabbit carotid artery induced by perivascular manipulation. Atherosclerosis 1989; 76: 257-268.




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