As soon as hypertension was recognized as a

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1 Autonomic Nervous Dysfunction in Essential Hypertension Stevo Julius, MD, ScD Borderline hypertension, a condition in which the blood pressure oscillates between normal and high values, is a predictor of future more severe hypertension. Pathophysiologically, borderline hypertension is different from established hypertension. A large proportion of such patients have elevated cardiac output and a normal vascular resistance. In established hypertension, the output is normal and resistance is elevated. The elevation of cardiac output in borderline hypertension is neurogenic; it can be abolished by an autonomic blockade of the heart. In addition to an increased cardiac sympathetic drive, increased sympathetic tone to the kidney, arterioles, and veins has also been found. In parallel with the hypersympathetic state, patients with borderline hypertension also show decreased parasympathetic tone. The enhanced sympathetic tone leads to a decreased cardiac responsiveness, and eventually, the cardiac output returns to the normal range. High blood pressure causes vascular hypertrophy, and hypertrophic vessels are hyperresponsive to vasoconstriction. These secondary changes in the responsiveness of the heart and blood vessels are the basis of transition from a high cardiac output to high-resistance hypertension. These hemodynamic changes are associated with a downregulation of the sympathetic tone. A picture of an apparently nonneurogenic high-resistance hypertension emerges. Nevertheless, when assessed in regard to the enhanced pressor responsiveness, the sympathetic drive in such patients is still excessive. Despite the apparently normal tone, the sympathetic nervous system continues to play an important pathophysiological role in established hypertension. Borderline hypertension is From the Department of Internal Medicine, Division of Hypertension, University of Michigan, Ann Arbor, Michigan. Address correspondence and reprint requests to Stevo Julius, MD, ScD, University of Michigan Medical Center, Department of Internal Medicine, Division of Hypertension, 3918 Taubman Center, Ann Arbor, Ml associated with numerous metabolic abnormalities including obesity and insulin resistance. It is tempting to view all these abnormalities as a common expression of the increased sympathetic drive in hypertension. Explanation of the basis of the association of hypertension and metabolic abnormalities promises to bring new insights into the pathophysiology of two common diseases of civilization: hypertension and diabetes mellitus. Diabetes Care 14:249-59, 1991 As soon as hypertension was recognized as a clinical entity, physicians began speculating about the possible role of the autonomic nervous system in its pathophysiology. The thought was logical; acute emotional arousal is invariably accompanied by a brief increase in blood pressure. What else could hypertension be but a permanent state of emotional excitement? In 1905, Geisbock (1) was impressed by the life-style of his patients with polycythemic hypertension, finding among them many busy executives with very demanding jobs. Psychoanalytically oriented physicians focused on the personality, and Ayman (2) in 1933 described the passive-submissive nature of his patients with hypertension. From this auspicious start, the pendulum swung to the opposite pole, and research on the role of the nervous system in hypertension fell into the background. Probably most responsible for this turn of events was the development of various animal models of hypertension. Hypertension developing after renal arterial stenosis, deoxycorticosteroid acetate (DOCA), coarctation, perirenal wrapping, partial renal ablation, and other interventions became seductive paradigms to study the evolution of blood pressure elevation. Later, genetic DIABETES CARE, VOL. 14, NO. 3, MARCH

2 AUTONOMIC DYSFUNCTION IN HYPERTENSION prototypes of hypertension set the stage for pursuit of various model-driven hypotheses about causes of high blood pressure. As animal research continues to attract intense investigative attention, certain factors favor renewal of scientific curiosity about the role of the nervous system in hypertension. First, animal work has little to offer for understanding human essential hypertension. Which, if any, of the numerous genetically inbred strains resembles the patient's predicament and in which type of patients? Second, it is now clear that the nervous system plays an important role in the pathophysiology of diverse forms of experimental hypertension. Destruction of the AV3V region in the midbrain prevents development of renovascular, DOCA, and other forms of sodium-sensitive hypertension (3). The autonomic nervous system is now strongly implicated in the genesis of blood pressure elevation in the most pervasive model, the Kyoto SHR rat (4). The third reason for increased interest is the weight of new evidence about an autonomic abnormality in human essential hypertension. In this article, I review the growing clinical and epidemiological evidence about the role of the nervous system in human hypertension. It will be shown that 7) an autonomic nervous abnormality is easily demonstrated in young subjects with early phases of hypertension (borderline hypertension); 2) we understand in considerable detail the nature of this autonomic abnormality; 3) as hypertension advances, the role of the nervous system becomes less evident; 4) the mechanism for these changes of autonomic tone in the course of hypertension can be explained; 5) the autonomic abnormality in hypertension is part of a complex syndrome that also includes abnormalities in insulin, glucose, and lipid status. NEUROGENIC BORDERLINE HYPERTENSION IN YOUNG SUBJECTS The basic hemodynamic fault in established essential hypertension is elevated vascular resistance. Consequently, the initial report from Czechoslovakia by Widimsky et al. (5), followed by similar findings in the United States (6,7) that, in young borderline hypertensive subjects, the resistance tends to be normal but cardiac output is increased, created considerable interest. Confirmation came from all over the world (8-12), and this hemodynamic peculiarity soon generated its own set of questions. Will these individuals later develop classic established hypertension? What is the mechanism of the cardiac output elevation? If there is a transition from this state of high cardiac output in borderline hypertension to a later state of high vascular resistance in established hypertension, what mechanism could underlie such a transition? Some of these questions are still in the forefront, but many have been answered. It is now clear that the elevated cardiac output in borderline hypertension is entirely neurogenic. Autonomic blockade of the heart with intravenous propranolol and atropine abolishes the difference in cardiac output between patients and control subjects (13; Fig. 1). Note that (3-adrenergic blockade by itself was not sufficient; the cardiac output of the two groups became similar only after the additional injection of atropine, suggesting that both sympathetic and parasympathetic systems partake in the elevation of cardiac output in borderline hypertension. The decreased cardiac output after propranolol in patients with borderline hypertension was larger, indicating that they had a greater sympathetic cardiac drive. Conversely, after atropine, the cardiac output in borderline hypertensive subjects in- X UJ o z O 30 cr u 2 5 REST PROPRANOLOL ATROPINE FIG. 1. Cardiac index in 16 young male patients with hyperkinetic borderline hypertension (A) and 18 control subjects ( ) before and after stepwise autonomic blockade with propranolol (0.2 mg/kg i.v.) and atropine (0.04 mg/kg i.v.). Note that cardiac output remained elevated after propranolol but became normal after atropine. ***P < Bars, SE. From Julius and Esler (13). by American Journal of Cardiology. 250 DIABETES CARE, VOL. 14, NO. i, MARCH 1991

3 S. JULIUS creased less than in normotensive subjects, suggesting that their hearts were under less-than-normal parasympathetic restraint. Such a reciprocal change in the tone of the two branches of the autonomic nervous system is characteristic for the functional organization of the cardiovascular centers in the medulla oblongata. A central command to increase the sympathetic tone is coupled with a simultaneous decrease of the parasympathetic activity and vice versa. This finding is useful to define the abnormality in borderline hypertension as being not secondary to receptor hypersensitivity. A hyperdynamic p-adrenergic state secondary to receptor supersensitivity has been described, and some of these individuals also have borderline hypertension (14). However, in classic patients with borderline hypertension, p-adrenergic sensitivity is actually decreased (15). The fact that autonomic abnormality in borderline hypertension emanates from the CNS has important research implications. If central, the abnormality is likely to be widespread throughout the body; if the abnormality originates in the brain, we may test specific hypotheses regarding the mechanism of this central abnormality. EVIDENCE FOR WIDESPREAD AUTONOMIC DYSREGULATION IN BORDERLINE HYPERTENSION In addition to abnormal autonomic control of the heart as described above, we also tested the autonomic function in other segments of the circulation in borderline hypertension. Of particular interest was the autonomic tone to arterioles. Although the vascular resistance in high-cardiac-output (hyperkinetic) borderline hypertension was not significantly higher than in the control group, conceptually, these values should not be viewed as normal. Usually increased cardiac output is associated with low vascular resistance, and blood pressure remains normal. Hyperkinetic borderline hypertensive subjects, however, do not accommodate the high cardiac output by appropriate vasodilation, and their blood pressure is elevated. If this relative vasoconstriction in borderline hypertension is neurogenic, a-adrenergic blockade should remove the excess vascular resistance and normalize blood pressure. This hypothesis was tested, and -30% of subjects with mild hypertension became normotensive after additional blockade with phentolamine (16). Such patients with neurogenic hypertension also had high plasma renin and norepinephrine values. We speculated that high plasma renin could be explained by an increased sympathetic tone to the (3-adrenergic cells in the kidneys. Esler et al. (17) directly tested renal sympathetic tone in hypertension and proved that this speculation was justified. Renal catecholamine spillover is elevated in hypertension, and this is particularly characteristic of young patients with hypertension (17). Increased sympathetic outflow in human hypertension also reaches platelets in the blood. Kjeldsen et al. (18) found elevated 3-thromboglobulin and plasma epinephrine levels in hypertension, which correlated with each other. Higher thromboglobulin levels reflect increased overall platelet turnover, and the correlation to epinephrine provides a link between platelet and sympathetic overactivities in hypertension. Direct recording of the sympathetic nerve traffic in the peroneal nerve also shows how widespread the autonomic abnormality is in borderline hypertension. Anderson et al. (19) documented increased sympathetic traffic to muscles to the lower leg in borderline hypertension. The most fascinating documentation of widespread autonomic abnormality in borderline hypertension comes from Rahn et al.'s (20) work on salivary flow. As mentioned earlier, cardiac parasympathetic tone is decreased in borderline hypertension (13). The production of saliva is under parasympathetic control. Rahn et al. and later Bohm et al. (21) placed cotton-wool cylinders in the mouths of patients and control subjects, the weight of wet cylinders being a measure of saliva production. Saliva production in patients with borderline hypertension was decreased. Finding a decreased parasympathetic tone to a noncirculatory exocrine organ suggests that the dysfunction of the autonomic control in borderline hypertension may also involve many other organ systems. Particularly interesting is the possible connection between the hypersympathetic state, insulin secretion, insulin resistance, and metabolic factors, a connection explored in some depth in other articles in this issue. MECHANISM OF AUTONOMIC ABNORMALITY IN BORDERLINE HYPERTENSION The widespread autonomic abnormality and the reciprocal relationship between low-parasympathetic and high-sympathetic tone suggests that the abnormality emanates from higher cardiovascular centers in the midbrain. A few modifying inputs converge on the cardiovascular centers in the medulla oblongata, and some of them can be examined in humans. Baroreceptors. The function of arterial baroreceptors in borderline hypertension has been well investigated. If baroreceptors do not properly regulate the blood pressure in borderline hypertension, the blood pressure variability should be increased. However, spontaneous blood pressure variability in borderline hypertension is not excessive (22). Furthermore, the blood pressure response to isometric exercise (23), dynamic exercise (12), blood-volume expansion (24), and cold pressor test (25) is normal in borderline hypertension. In borderline hypertensive patients, blood pressure is set at a higher point, but around that point, blood pressure regulation is normal. The only exception to this rule of a normal blood pressure response to physical stressors is the adjustment to upright posture. Whereas the response to passive tilting is normal (26), a few articles report an exaggerated blood pressure response to standing in borderline hypertension (27,28). The baroreceptor function can also be directly tested DIABETES CARE, VOL. 14, NO. 3, MARCH

4 AUTONOMIC DYSFUNCTION IN HYPERTENSION in humans by observing the heart-rate response to acute changes of blood pressure. The slope of the heart rateblood pressure curve roughly describes the sensitivity of the baroreceptor. Positive reports notwithstanding (29), we (30) and others (31) failed to find a primary abnormality of arterial baroreceptor function in borderline hypertension. Furthermore, animal experiments suggest that even total removal of baroreceptors does not lead to sustained borderline hypertension (32). Chemoreceptors have also been investigated, and one report from the Iowa group finds them to be hypersensitive in patients with borderline hypertension (33). Psychosomatic influences descending from the cortex and paleocortex can also profoundly affect the function of cardiovascular regulatory centers. Research into these psychoemotional factors in borderline hypertension took two major directions: investigations of personality and studies of reactivity. Reactivity. The reactivity hypothesis holds that patients with borderline hypertension are overly responsive to stress. Eventually, these repeated temporary stress-induced blood pressure elevations lead to permanent hypertension. The major elements of this hypothesis are: /) Various laboratory tasks are representative of the response pattern; e.g., if a subject is hyperresponsive to the test of mental arithmetic, he or she will also be overresponsive to other stresses in life. Consequently, the response in the laboratory should predict the overall blood pressure variability in real life. 2) Repeated pressor episodes eventually lead to sustained hypertension. 3) Patients with borderline hypertension are characteristically hyperresponsive to mental stresses. We have serious reservations about the veracity of the first two assumptions. These objections have been stated in an editorial, and a detailed discussion would exceed the scope of this article (34). However the third topic, whether patients with borderline hypertension and prehypertension are hyperresponsive to mental stresses, deserves comment. Since the pioneering report by Brod et al. (35), hyperresponsiveness to mental stress has been described in borderline hypertension (25,36,37) and in young individuals with genetic predisposition for hypertension (38,39). A different hemodynamic pattern in response to stress has been found in prehypertensive individuals (37,40). It is impossible to disregard this evidence. Obviously, subjects with borderline hypertension and children of hypertensive parents tend to be hyperresponsive to mental stress when studied in specialized laboratories. However, the specificity (for hypertension) of the hyperreactivity to mental stress has not been investigated. Subjects selected for hospital studies are psychologically different than the general population. Jem (41) found that borderline hypertensive subjects studied in the hospital differ from borderline hypertensive subjects discovered during routine Swedish army physicals. This may be an important distinction. Rostrup et al. (42) measured the blood pressure of recruits to the Norwegian army. The results of the exam were not immediately communicated, but a follow-up letter was sent a few weeks later inviting those with borderline hypertension to partake in further tests. Two different letters were randomly mailed, either a letter advising the subject that he has a blood pressure problem or another neutral letter suggesting that further tests are required as a matter of course. The initial blood pressure of the two groups were similar, but during the subsequent hospital testing, the blood pressure-informed group had higher blood pressure readings and higher pressure reactivity than the group that received the neutral letter. Recent work also suggests that knowledge of the diagnosis of hypertension and the laboratory environment may be conducive to increased reactivity to mental stress in borderline hypertension (43). We studied many subjects living in Tecumseh, Michigan. Generally, these subjects were unaware of any blood pressure problems, and mental stress testing was performed on the premises situated in Tecumseh. Special attention was paid to avoid frustration during the test of mental arithmetic. Subjects with borderline hypertension in Tecumseh were not hyperresponsive to mental stress, and subjects who were hyperresponsive to mental stress (defined as the upper 20% of the distribution of responses) did not have elevated blood pressure. Personality. In studies of personality, the individual is not exposed to an actual behavioral provocation. Rather, the subject is asked to describe his habitual interaction with the environment and how he handles emotions. If a characteristic personality trait is present in patients, we speculate whether such a personality may be conflict-prone and thereby predisposed to frequent emotional blood pressure elevation. Two dimensions of personality appear to be affected in borderline hypertension. One is related to the experience and expression of anger and the other to the degree of dominance versus submissiveness. Harburg et al. (44) studied the relationship between blood pressure level and personality in a representative sample of the population in Detroit, Michigan. Anger held in (e.g., a tendency not to show anger in interaction with others) was strongly correlated with blood pressure levels both in black and white subjects. Esler et al. (16) used the Harburg questionnaire in subjects with mild hypertension. Those with a neurogenic high-renin hypertension had lesser scores on anger expression. The issue was revisited in a study of University of Michigan students by Schneider et al. (45). Subjects with borderline hypertension whose blood pressure was elevated both in the clinic and at home were compared with those whose blood pressure was elevated only in the clinic. The sustained borderline hypertensive subjects reported greater intensity of anger and generally suppressed expression of anger. Inasmuch as the expression of anger was related to consistently elevated blood pressure in the physician's office and at home, we speculated that personality structure in these subjects may be conducive to sustained autonomic arousal and through that mechanism may contribute to the later development of established hypertension. 252 DIABETES CARE, VOL. 14, NO. 3, MARCH 1991

5 S. JULIUS Patients with borderline hypertension also describe themselves as submissive to other people's opinion. This characteristic was confirmed in separate studies with the same personality inventory (Cattell's 16 factors). Borderline hypertensive students in Ann Arbor, Michigan (46), Yugoslavia (47), and patients culled from the hypertension clinic in Ann Arbor (16) always scored less on the dominance scale. Interestingly, this particular personality pattern is present in patients with neurogenic high renin hypertension (16) compared with normalrenin subjects whose hypertension is not neurogenic. Holding in anger and being submissive to others are not conducive to inner peace. Such individuals may harbor unexpressed feelings and "boil inside." They also constantly assess how they are perceived by others. This lack of inner peace and increased vigilance to adjust and respond in an ostensibly calm way may lead to a sustained higher level of sympathetic activity. Studies of personality are on somewhat firmer grounds than those of reactivity. At least one of them was done in an epidemiological setting on the general population of a large metropolitan area (44). It remains to be seen whether neurogenic hypertension and a connection between it and a typical personality can be found in less stressful environments. TRANSITION FROM BORDERLINE TO ESTABLISHED HYPERTENSION Is there transition from borderline to essential hypertension? As indicated above, almost all of the work on the connection between neurogenic factors and blood pressure elevation has been performed on young subjects with borderline hypertension. If a patient with borderline hypertension, that is blood pressure oscillating above and below 140 and/or 90 mmhg, were not to progress to later established treatment-requiring hypertension, hemodynamic and autonomic nervous abnormalities in borderline hypertension would be of little interest. It is generally accepted that only long-standing hypertension causes organ damage, and labile blood pressure elevation is considered of little clinical relevance. Furthermore, essential hypertension is a progressive disease, and if subjects with borderline hypertension remained forever in the marginal zone between normotension and hypertension, they would have to be considered as having a separate condition whose natural history differs from the clinical course of essential hypertension. Conversely, whether borderline hypertension predicts for future more severe established hypertension than its peculiar pathophysiology (e.g., it is associated with a high cardiac output) presents an exciting research question. Does the pathophysiology of hypertension change from a high cardiac output state to a state of high vascular resistance? High blood pressure begets future hypertension. Almost two decades ago, we reviewed the existing literature and firmly concluded that borderline hypertension is a precursor of future hypertension (48). There are no new data to change these conclusions. Compared with normotensive subjects, borderline hypertensive subjects have a fourfold chance of developing established hypertension. However, the absolute incidence of hypertension is low, and within 10 yr, only 20% of borderline hypertensive subjects will develop hypertension. To which subset do the subjects with hyperkinetic-neurogenic borderline hypertension belong: the minority that will proceed to develop the disease or the majority that remain in the borderline or normotensive range? Already in 1966, Eichetal. (49) reported that subjects with high cardiac output after a few years maintained borderline blood pressure elevation but tended to show a higher vascular resistance. It took two decades of painstaking work by Lund-Johansen and Omvik (50) to show the actual hemodynamic progression from high cardiac output borderline hypertension via high-resistance borderline hypertension to a later high-resistance treatmentrequiring established hypertension. However, this important demonstration did not answer all the questions. Are the normotensive volunteers excessively calm? Are the concerned subjects with borderline hypertension seen in hospitals typical of most borderline hypertensive patients? Does hyperkinetic borderline hypertension exist also outside of the invasive laboratories, or does that particular circulatory pattern represent only an emotional response to the circumstances of the measurement? High cardiac output in invasive studies of borderline hypertension is associated with faster heart rates. An association of rapid heart rate and higher blood pressure levels is also seen in populations at large hospitals (51). Thirty-seven percent of all subjects with borderline hypertension investigated in Tecumseh, Michigan, have high cardiac output and elevated plasma norepinephrine levels (52). A few epidemiological studies found that tachycardia at youth is a predictor of future hypertension (53-55). These findings indirectly indicate that the autonomic nervous abnormality is a significant factor for the development of hypertension in many patients. Mechanism of hemodynamic transition from highoutput to high-resistance state. If a large proportion of hypertensive patients start with a high cardiac output and later evolve into a high-resistance state, it is important to explicate the mechanism underlying such a hemodynamic transition. Borst and Borst-de Gues (56) first proposed and Guyton and Coleman (57) later described in detail the autoregulatory sequence that occurs in volume-expanded states. When intravascular volume is expanded, cardiac output increases, which triggers an autoregulatory response of the vasculature. If the flow increases above or falls below the metabolic needs of the tissue, the vasculature will respond and bring the flow into the desired optimal range. In the case of overperfusion, vascular resistance increases and the flow decreases, whereas during underperfusion, the response is vasodilation and increased flow. Guyton and Cole- DIABETES CARE, VOL. 14, NO. 3, MARCH

6 AUTONOMIC DYSFUNCTION IN HYPERTENSION man proved that the whole body has the capacity to autoregulate under conditions of volume expansion. First cardiac output increases, which triggers an autoregulatory increase of vascular resistance and blood pressure. The increased pressure causes diuresis, and a new equilibrium of normal cardiac output but high blood pressure is established. This sequence is well documented in volume-expanded models, but it cannot explain the sequence observed in hyperkinetic borderline hypertension. First, there is no evidence for volume expansion in borderline hypertension; plasma volume in these patients is decreased (58). Second, the basic prerequisite for an autoregulatory increase of vascular resistance is an excessive perfusion; e.g., cardiac output should exceed the metabolic needs of the body. Hyperkinetic borderline hypertension is associated with increased oxygen consumption, suggesting that the increase of cardiac output is appropriate for the increased metabolic needs of the body (9,10,12). Because there is no evidence for overperfusion of the whole body, the stimulus for an autoregulatory increase of vascular resistance is not present in borderline hypertension. Parenthetically, the increased oxygen consumption and decreased plasma volume can also be viewed as additional signs of increased sympathetic tone in borderline hypertension. Enhanced sympathetic drive to metabolic receptors might cause an increased basic metabolic rate (59), and sympathetically mediated postcapillary vasoconstriction can decrease the plasma volume (60). We have proposed another mechanism for the transition of high cardiac output to high vascular resistance. Longstanding sympathetic stimulation and prolonged blood pressure elevation can change the responsiveness of various cardiovascular organs. Chronotropic responsiveness to (3-adrenergic stimulation of the heart is decreased in borderline hypertensive subjects whose cardiac output is in the normal range (61). Presumably, these individuals at one stage had increased cardiac output, and the decreased adrenergic responsiveness may have played a role in the return of the cardiac output into the normal range. Such functional downregulation after prolonged sympathetic stimulation is a frequently observed physiological phenomenon. Decreased cardiac compliance to venous filling may be another independent factor that contributes to the gradual decrease of cardiac output in borderline hypertension. Lund-Johansen (10) noted that patients with borderline hypertension do not increase the stroke volume during exercise to the same degree as normotensive control subjects. He hypothesized that the decreased stroke volume is due to decreased cardiac compliance in borderline hypertension. Our studies strongly support this notion (61). A substantial decrease of stroke volume is observed in patients with borderline hypertension after autonomic blockade first with propranolol and then with atropine. At similar levels of cardiac filling (approximated by measurements of the cardiopulmonary blood volume), patients with borderline hypertension had substantially lower stroke volumes, suggesting that their cardiac compliance may be decreased. The decreased stroke volume combined with a decreased sympathetic chronotropic responsiveness may explain the decreased cardiac output in the course of borderline hypertension. However, the other half of the observed changes in hemodynamics, the increase of the vascular resistance in borderline hypertension, must also be explained. Cardiac restructuring in response to the increased load results in increased cardiac stiffness, which negatively affects the ejection fraction. When arterioles undergo a similar pressure-induced restructuring, the functional consequence is potentiation of vasoconstriction. This structural reinforcement of vasoconstriction has been described in great detail by Folkow (62). With vascular hypertrophy the vessel wall becomes thicker and encroaches on the lumen. When such a hypertrophic vessel constricts, the wall encroaches even more on the lumen, and the net result is a steeper increase of resistance. The hypertrophy-related vascular hyperresponsiveness in hypertension has been well documented and is the most likely cause of the shift from a high cardiac output to a high-resistance hemodynamic pattern (63). Change of sympathetic tone in course of hypertension. One of the major arguments against an important role of the sympathetic nervous system in hypertension rests on the apparent normal sympathetic tone in patients with a more advanced established hypertension. In a thorough review, Goldstein (64) analyzed available data on catecholamine levels in hypertension and concluded that plasma norepinephrine is elevated only in younger patients with the mildest forms of hypertension. Esler et al. (65), with a sophisticated technique to assess the sympathetic tone in humans, found the norepinephrine spillover rates to be increased only in young hypertensive subjects (65). In normotensive subjects, norepinephrine was higher in old subjects, whereas in hypertensive subjects, the trend was reversed: older hypertensive subjects had lower norepinephrine values. Korner et al. (66) used autonomic blockade to analyze the adrenergic and parasympathetic tone in established hypertension and found a decreased parasympathetic inhibition of the heart but no evidence for enhanced sympathetic tone. Compared to our results in borderline hypertension, this points to interesting similarities and dissimilarities (13). If indeed there is a transition from borderline to established hypertension, why would parasympathetic tone remain similarly diminished in established as in borderline hypertension but the sympathetic tone change from high in borderline hypertension to apparently normal in established hypertension? We addressed this question within the context of a conceptual analysis for CNS regulation of the circulation (67). Focal to the concept is the blood pressure-seeking property of the CNS. Within the framework of that concept, the observed decrease of sympathetic tone in hypertension is a fully expected outcome of interaction between the CNS and the altered peripheral responsive- 254 DIABETES CARE, VOL. 14, NO. 3, MARCH 1991

7 S. JULIUS ness in the course of hypertension. The following is a short outline of the hypothesis about the blood pressure-seeking property of the CNS. Figure 2 presents the basic hemodynamic relationship between flow, pressure, and resistance. The degree to which flow increases in response to increased pressure depends on resistance to the flow. Resistance to the flow in turn is largely dependent on the cross-sectional area of the vascular lumen. When blood vessels are wide open (Fig. 2, lowest isoresistance line), the resistance is low, and a small increase of pressure elicits a large increase of flow. By contrast, when resistance is high, a large increase of pressure results in a small increase of flow (Fig. 2, highest isoresistance line). This diagram permits simultaneous assessment of the relationship between the three principal components of circulation: flow, pressure, and resistance. Pressure and flow can be read from the corresponding axis, whereas the direction of the arrow in relationship to the isoresistance line denotes the changes in resistance. A scheme of CNS regulation of the circulation is given in Fig. 3. The CNS is organized as a negative-feedback loop. Whenever there is a perturbance of the circula- Pressure - Flow x Resistance FIG. 3. General schema of negative feedback from circulation to central nervous system (CNS). From Julius (67). by Current Science. ID CO co LU FLOW FIG. 2. Pressure-flow resistance relationship (resistance = pressure/flow). Diagonal lines, lines of isoresistance; lowest diagonal line, low resistance; highest diagonal line, high resistance. Note that vascular caliber at low resistance is larger and that small increases of pressure cause large increases of flow. At high-resistance line, vascular caliber is narrow and large increase of pressure causes only small increases in flow. Horizontal vector (fop dashed line) shows decrease in flow associated with increase in resistance and no pressure change. Diagonal (bottom dashed line) shows decrease in flow with unchanged resistance and fall in blood pressure. From Julius (67). by Current Science. tion, the feedback tends to limit the magnitude of the response in order to arrive at a new equilibrium. In terms of the feedback analysis, the variable that is most tightly controlled is the regulated variable. The CNS invariably chooses to regulate the blood pressure while allowing a wide swing of the other two components of the circulation (cardiac output and vascular resistance). We call this phenomenon the "blood pressure-seeking property of the central nervous system." Figure 4 shows one of many specific circumstances that illustrate how the CNS seeks to preserve a pressure response regardless of the state of vascular resistance or cardiac output (67). When hindquarters of dogs are compressed by a special pressure suit, it elicits a long-lasting neurogenic increase of the dog's blood pressure (68,69). The usual hemodynamics is increased vascular resistance (Fig. 4, dashed arrow). When the increase in vascular resistance is prevented by a-adrenergic blockade with dibenzyline, the blood pressure response remained essentially the same, but the pressure increase was due to increased cardiac output (Fig. 4, solid arrow). This hemodynamic plasticity, in which the CNS achieves the same blood pressure response regardless of the underlying hemodynamics, has been observed under a number of circumstances. Normally, mental stress and isometric exercise cause an increase of blood pressure, mediated by an elevation of the cardiac output. (3-Adrenergic blockade does not alter the magnitude of the blood pressure response to these maneuvers, but the hemodynamic pattern changes from high cardiac output to elevated vascular resistance (67). Conversely, in patients treated with calcium antagonists, the blood pres- DIABETES CARE, VOL. 14, NO. 3, MARCH

8 AUTONOMIC DYSFUNCTION IN HYPERTENSION advanced hypertension is fully anticipated. In advanced hypertension, the CNS is still the prime mover and the proximate cause of blood pressure elevation, but due to changed peripheral responsiveness, the sympathetic tone need not be excessive. MBP I[mm Hg) Cardiac Index (ml/kg) FIG. 4. Response to 60 min of hindquarter compression in 8 chloralose-anesthetized dogs. Dashed arrow, response before phenoxybenzamine; solid arrow, response to 60 min of compression after 1 mg/kg i.v. phenoxybenzamine. MBP, mean blood pressure. From Julius (67). by Current Science. sure response is preserved but mediated by an excessive increase of the cardiac output (68). From this and other examples, we can conclude that, for the CNS, the blood pressure is the regulated variable. To regulate blood pressure, the brain also must be capable of sensing the achieved blood pressure. The CNS will switch from one organ to the other until the desired pressure has been achieved. If we accept that, in subserving the circulation, the CNS primarily regulates the blood pressure and is capable of sensing the achieved pressure, it is easy to conceptualize what would happen in the course of hypertension. If for some reason the centers in the brain were reset to function at a higher blood pressure set point in the early phase, this would be associated with a generalized increase of the sympathetic tone apportioned equally to the heart and the blood vessels. As the cardiac responsiveness decreased and through vascular hypertrophy the arterioles became overresponsive, the vascular resistance would increase. As the vascular hypertrophy continued to increase, the blood vessels would eventually become so hyperresponsive that less sympathetic drive is needed to achieve the same blood pressure level. If the CNS senses that the desired pressure has been achieved with less sympathetic discharge, the previously elevated sympathetic discharge may be substantially diminished. Within this context, the observed decrease of sympathetic tone in INTERRELATIONSHIP BETWEEN AUTONOMIC DYSFUNCTION AND OTHER ABNORMALITIES IN BORDERLINE HYPERTENSION The etiology of the autonomic abnormality in borderline hypertension remains unresolved. As indicated earlier, behavioral factors may play a role, but the evidence is not strong. Efforts to explicate the etiology may have failed because of the complex interrelationship between neurogenic and other pathophysiological factors in borderline hypertension. First, borderline hypertension is invariably associated with increased weight. In some of our earlier studies, subjects with borderline hypertension were on average 12 kg heavier than the control subjects (12,58). Whereas we tended to correct for this difference by indexing the hemodynamic variables to body weight or surface (58,61), we failed to consider that being overweight may be etiologically important for the evolution of the blood pressure. Landsberg (59) proposed a theory, which is discussed in detail in this issue, that views eating behavior as possibly a central component of a complex relationship between insulin, insulin resistance, and CNS activation of sympathetic nerves. Insulin resistance is closely associated with hypertension (70). Whether high insulin levels or insulin resistance is the mechanism whereby blood pressure increases in hypertension is not resolved. It has been described that, although resistant to insulin-mediated glucose utilization, overweight subjects are not resistant to the sodium-retaining properties of insulin (71). This raises the possibility that hyperinsulinemia in overweight non-insulin-dependent diabetes mellitus and frequently hypertensive subjects may lead to excessive sodium retention and through that mechanism favor the development of a volume-dependent form of human hypertension. An illustration of the interrelationship of pathophysiological factors in blood pressure regulation comes from our studies in Tecumseh, Michigan, a rural community located 35 miles from Ann Arbor. Figure 5 illustrates the intercorrelation between various risk factors, insulin, plasma norepinephrine, heart rate, and blood pressure in a sample of the general population in Tecumseh. None of the subjects were receiving treatment for hypertension, and for the overall population, the blood pressure values were normal. This apparent linear relationship between blood pressure and numerous other abnormalities is also seen when subjects in Tecumseh are classified as borderline hypertensive and normotensive. There were 801 normotensive and 123 borderline hypertensive subjects in Tecumseh (average age 32 yr). The following are variables of interest adjusted for sex differences: weight (normal vs. borderline 256 DIABETES CARE, VOL. 14, NO. 3, MARCH 1991

9 S. JULIUS important new insights into the pathophysiology of both conditions. ACKNOWLEDGMENTS This work was supported by a grant from the National Institutes of Health, National Heart, Lung and Blood Institute Grant HL-37464, and by Michigan Diabetes Training and Research Center Grant P560-DK REFERENCES FIG. 5. Sex-adjusted correlates of diastolic blood pressure (DBP) in subjects from general population in Tecumseh, Michigan (n = 436). Subjects' average age was 32 yr. Blood pressure was measured by physician in field clinic after subjects were in sitting position for 5 min. Two consecutive readings were averaged. Heart rate (HR) was taken just before blood pressure reading. NE, norepinephrine. *P < 0.05, **P < 0.01, ****P < hypertensive) 74.3 vs kg (P < by analysis of covariance); percentage overweight, 13.6 vs. 30.1% (P < ); triglycerides, 94.6 vs mg/dl (P < ); fasting insulin, 12.2 vs nu/ml (P < ); heart rate, 68.7 vs beats/min (P < ). Clearly, in the unselected general population in Tecumseh, there is a substantial interrelationship between hyperkinetic circulation, being overweight, and elevated plasma insulin levels. This fascinating complexity sets the agenda for future research. Why are these conditions interrelated? Does this constellation bespeak one common etiological factor? Does the congruence of these factors speak for some evolutionary selection, and do unrelated variables eventually converge on a group of subjects? What is genetic and what is environmental? Would prevention of becoming overweight and insulin resistance prevent hypertension? The fields of hypertension and diabetology are growing closer, and as the result of this trend, we can expect 1. Geisbock W: Die bedeutung der blutdruckmessung fur die praxis. Dtsh Archiv Klin Med 83:363-74, Ayman D: Personality type of patients with arteriolar essential hypertension. Am j Med Sci 186:213-23, Brody MJ, Johnson AK: Role of the anteroventral third ventricle region in fluid and electrolyte balance, arterial pressure regulation, and hypertension. In Frontiers in Neuroendocrinology. Vol. 6. Martini L, Ganong WF, Eds. New York, Raven, 1980, p Lundin S, Nordlander M: Hemodynamics in the spontaneously hypertensive rat. In Handbook of Hypertension. Pathophysiology of Hypertension Cardiovascular Aspects. Vol. 7. Zanchetti A, Tarazi RC, Eds. Amsterdam, Elsevier, 1986, p Widimsky J, Fejfarova MH, Fejfar Z: Changes of cardiac output in hypertensive disease. Cardiologia 31:381-89, Eich RH, Peters RJ, Cuddy RP, Smulyan H, Lyons RH: The hemodynamics in labile hypertension. Am Heart j 63: , Bello CT, Sevy RW, Harakal C: Varying hemodynamic patterns in essential hypertension. Am } Med Sci 250:24-35, Finkielman S, Worcel M, Agrest A: Hemodynamic patterns in essential hypertension. Circulation 31:356-68, Sannerstedt R: Hemodynamic response to exercise in patients with arterial hypertension. Ada Med Scand Suppl 458:1-83, Lund-Johansen P: Hemodynamics in early essential hypertension. Acta Med Scand Suppl 482:1-105, Safar ME, Weiss YA, Levenson JA, London GM, Milliez PL: Hemodynamic study of 85 patients with borderline hypertension. Am J Cardiol 31:315-19, Julius S, Conway J: Hemodynamic studies in patients with borderline blood pressure elevation. Circulation 38:282-88, Julius S, Esler M: Autonomic nervous cardiovascular regulation in borderline hypertension. Am) Cardiol 36:685-96, Frohlich ED, Tarazi RC, Dustan HP: Hyperdynamic betaadrenergic circulatory state: increased beta-receptor responsiveness. Arch Intern Med 123:1-7, Julius S: Neurogenic component in borderline hypertension. In The Nervous System in Arterial Hypertension. Julius S, Esler M, Eds. Springfield, IL, Thomas, 1976, p Esler M, Julius S, Zweifler A, Randall O, Harburg E, Gardiner H, DeQuattro V: Mild high-renin essential hyper- DIABETES CARE, VOL. 14, NO. 3, MARCH

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