Hypertension and the metabolic syndrome: closely related central origin?

In primary hypertension a mild hyperresponsiveness of hypothalamic, sympatho-hormonal centres to psychosocial stimuli forms a major pathogenetic element, although high salt intake in some subjects may contribute via volume expansion. Hypertension is often associated with another "civilisation" disorder, the metabolic syndrome, defined as abdominal obesity, insulin resistance and dyslipidaemia. According to recent research, the metabolic syndrome has in all likelihood a central neuroendocrine origin in the form of enhanced engagement of the hypothalamic-pituitary-adrenal (HPA) axis. Here the peripheral endocrine perturbations act as triggers for both central obesity and the metabolic abnormalities. The reaction pattern characterising early primary hypertension is identical with, or closely related to, the "defence reaction", while that leading to the metabolic syndrome is similar to that of the "defeat reaction". Both belong to the primitive survival reactions, common to all mammals, though man can control, or at least mask, his outward-behavioural part but not the neuro-hormonal expressions. Animal experiments show how frequent or chronic mental challenges are capable of engaging these limbic-hypothalamic centres, affecting blood pressure regulation as well as endocrine-metabolic regulation. Furthermore, these centres are tightly coupled functionally, and their signals to the periphery often combined. On a long-term basis their engagements appear to be decisive for the development of both primary hypertension and the metabolic syndrome, as suggested by intervention studies. In both these "disorders of civilisation", observations strongly indicate that psychosocial stress, socioeconomic handicaps, lack of exercise, abuse and also psychiatric traits are involved. Such factors, characteristic of current competitive society, probably cause mixed engagements of the two above-mentioned neuro-hormonal patterns, and thereby, with time, primary hypertension and the metabolic syndrome, with end-points such as coronary artery disease, diabetes mellitus type2 and stroke. Susceptibility to such developments is probably enhanced by genetic factors. This overview of recent developments therefore serves to emphasise how both primary hypertension and the metabolic syndrome seem to have a common central origin. Central regulatory factors are often overlooked, partly because it is not realised that limbic-hypothalamic centres are the major regulators of both circulatory and metabolic events, and partly because of the long period of time required before these disease end-points are reached.

Perspectives on the integrative functions of the 'sympatho-adrenomedullary system'.

An historic survey is given of the gradual change of views and concepts concerning how the sympatho-adrenomedullary system is organized and operates: While it for nearly a century was considered to merely exhibit more or less generalized activation-inhibition responses, experimental studies during the last 50 years have revealed how it instead constitutes a highly sophisticated instrument for control, engaged in a variety of differentiated response patterns by which the brain controls events in major organ systems, down to include their cellular-molecular levels of organisation.

Importance of the blood pressure-heart rate relationship.

In studies of the effects of salt intake on blood pressure (SBP, MBP, DBP), influences on heart rate (HR) are usually neglected even though the longterm load on both left ventricle (LV) and systemic arteries (SA) is better related to the product of HR x SBP (or MBP) than to pressure alone. After all, altered salt intakes often induce considerable volume-related changes in HR, and the heart operates more economically at low HR and high stroke volume (SV). Thus, about 3/4 of LV metabolism is used for the build-up of systolic tension, while the cost for SV expulsion, or for SV increases, is far lower. Moreover, low HR prolongs the diastolic period, so important for LV coronary supply. Against this background we have used results from studies in both rats and man, in which both BP and HR were followed during marked changes in salt intake, to explore how this affected the HR x SBP (or HR x MBP) product. Briefly, in ordinarily salt-resistant organisms, whether normo- or hypertensive, salt intake increases, which in man ranged from 10-20 to 250-300 mM (in rats over 100-fold), if anything reduced the computed longterm load (HR x SBP, or MBP) on LV and SA, as consequences of an efficient reflex volume control. By contrast, in salt-sensitive man, HR reflex reductions to increased salt intake were almost absent despite substantial SBP elevations, suggesting the influence of a CNS suppression of bulbar reflex centres combined with CNS neurohormonal interference with renal salt volume excretion, as in SHR.

Physiological aspects of the "defence" and "defeat" reactions.

By means of tele-receptor signals (vision, hearing, olfaction) the mammalian brain is almost continuously informed about environmental events, and whenever these are interpreted as positive or negative challenges the cerebral "super-controller" can, for coping with the anticipated situation, select the most appropriate among a number of pre-formed hypothalamic reaction patterns. These are organized as combined engagements of the somatomotor, visceromotor and hormonal efferent links, whereby a variety of behavioural responses can be elicited, where each is accompanied by appropriate adjustments of inner organ systems, metabolism, etc., to achieve optimal performance. For eons of time these "emotionally charged" reactions, common for all mammals, have served to protect the individual and species in a merciless environment, and they certainly remain principally the same also when Homo Sapiens faces modern society. As then the ancient "defence" and "defeat" reactions, intended for quite different situations, are often activated by the many artificial stimuli and symbolic threats inherent in today's hectic and competitive life, their principal organisation and functional consequences are the main topic of this survey. They are, for example, also marginally engaged along with ordinary shifts in mood during events in daily-life but are probably in this mild form fairly harmless and actually often supportive for efficient performance. However, when intensely engaged over longer periods they can, indeed, profoundly disturb inner organ systems and metabolic events, often resulting in disorder and even in premature death, as particularly convincingly shown by Henry and co-workers in studies on rodent "micro-societies". Transferred to man's situation in modern life, these model studies have been crucial for insight into the indeed complex mechanisms involved when long-term psychosocial stress in predisposed or particularly exposed individual contributes to some of today's most important "disorders of civilisation".

Comments on "endpoints in hypertension": peripheral resistance vessels--though mainly on their involvement as "starting-points".

In SHR, and probably often in human primary hypertension as well, the structural-geometric changes in proximal resistance arteries (r(i) decrease combined with w/r(i) increase) seem to occur so early in life, and are already then so pronounced, that they must serve also as major "starting-points" for this disorder of regulation, besides contributing to late deterioration and "end-point" situations by increasingly interfering with myocardial, cerebral, renal etc. blood supplies, and hence functions. Furthermore, particularly in early phases of primary hypertension they may have some easily overlooked influences on evaluations of average vascular smooth muscle activity, and of overall haemodynamics as well, which is briefly discussed.

Hypertensive structural changes in systemic precapillary resistance vessels: how important are they for in vivo haemodynamics?

OBJECTIVE: To discuss recent findings that seem to question the importance of structural vascular changes for the raised resistance observed in hypertension. MAIN ISSUES: First, in daily life situations, the proximal resistance sections, which are the main site for vasoconstrictor fibre effects, are also the main site for structural elevation of resistance in hypertension. The most distal ones are crucially important for local flow distribution, and their unaltered design suggests that they are usually protected from pressure elevations by a raised resistance upstream. Furthermore, recent findings indicate that central neurohormonal mechanisms are much more important than myogenic ones for inducing hypertension at least in spontaneously hypertensive rats. Second, the function of structurally altered resistance vessels is often misunderstood, mainly because the haemodynamic importance of wall distensibility is disregarded. Vascular geometric design and distensibility tend to be altered to an 'ideal' extent, so that with ordinary changes in smooth muscle activity a normal flow range is maintained, despite elevations in both perfusion and transmural pressures and in resistance. Third, the rapid normalization of blood pressure on declipping of two-kidney, one clip or of one-kidney, one clip renally hypertensive rats by no means refutes the haemodynamic importance of a prevailing structural upward resetting. Declipping leads to a powerful and prolonged release of vasodilator-sympathoinhibitory medullipins, which create a subnormal smooth muscle tone. Because the structurally hyper-reactive resistance vessels now operate along a steeper resistance curve the pressure fall becomes, if anything, accentuated, which opens the way for structural regression. Fourth, the highly sophisticated and often differentiated neurohormonal control system usually explains why vasoactive agents, for example, do not regularly produce exaggerated pressure changes in vivo, even in the presence of hypertensive structural changes. In addition, counteracting effects by endothelial mechanosensitive mechanisms seem to be of great importance in these situations. CONCLUSION: The arguments and views outlined recently do not, on closer scrutiny and for the reasons given, really challenge the importance of structural vascular changes in hypertension in vivo and may, indeed, in some respects serve to support this concept.

Kidneys and primary hypertension--initiators, stabilizers or/and victim-aggravators?

As the kidneys so importantly contribute to longterm blood pressure control, and decisively to e.g. Goldblatt hypertension, it is often assumed that they are "prime movers" also in most variants of primary hypertension. The "pros and cons" of such a view are briefly discussed, and not least because strategies in therapy and preventive measures in man greatly depend on the nature, and major sites of expression, of the polygenetic predisposition. It is emphasized how the predisposing elements usually seem to exert their main influences via decidedly extra-renal parts of cardiovascular control systems in general, though soon leading to secondary "upward resetting" of the renal barostat function concerning both salt-water excretion and the renal pressure-regulating hormones. In SHR, for example, all proximal systemic resistance vessels, including the renal preglomerular ones, show an intrinsic tendency towards structural upward resetting quite early in life. Further, already early common variants of human primary hypertension, as well as SHR, exhibit an evidently "primary" central hyper-reactivity to psychosocial stimuli. Via neuro-hormonal pressor and growth-promoting effects such in principle extra-renal influences soon induce the same type of cardiovascular and renovascular structural upward resettings. Therefore the transfer of such kidneys to normotensive organisms here induces hypertension because of the prevailing preglomerular resistance increase, which easily gives the impression that these kidneys must have been the cause of hypertension in the donor organism as well.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathophysiology of hypertension: differences between young and elderly.

Pathogenesis of hypertension: Primary hypertension has a multifactorial background, consisting of three main elements, (1) polygenic predisposition, (2) excitatory environmental effects and (3) structural upward resetting of the heart and vessels. These three elements are inter-related, since excitatory environmental effects are usually needed to precipitate the functional expression of genetic predisposition (particularly in man) and structural upward resetting is sometimes genetically facilitated. As hypertension progresses, the structural upward resetting becomes the dominating element, underlying the elevation in both pressure and resistance. Progression of hypertension: In the early phases of both human and animal models of primary hypertension, interactions between the genetic predisposition and excitatory environmental effects are often expressed mainly as mildly enhanced central neurohormonal activity. Not infrequently, cardiac output is increased more than systemic resistance. The structural factor, at this point, is still mainly expressed as a fairly reversible cardiac and vascular muscle hypertrophy (or hyperplasia), and a modest degree of resistance vascular narrowing. Aging effects on hypertension: The normal aging process affects the cardiovascular system to a greater degree in hypertensives than normotensives, implying more pronounced reductions in cardiac and vascular compliance, muscle strength and contractile speed, and in renal functional capacity. With age and a prolonged positive-feedback interaction between genetic/environmental factors and structural adaptation at the systemic resistance level, the structurally based elevation in resistance becomes even more dominant, and is further complicated by increasing interstitial involvement and therefore reduced reversibility.(ABSTRACT TRUNCATED AT 250 WORDS)

Early structural changes in hypertension: pathophysiology and clinical consequences.

The structural upward resetting of heart, vessels, and barostat functions represents what may be the most important long-term cardiovascular alteration in hypertension; the altered geometric design of the systemic precapillary resistance vessels is of profound hemodynamic relevance. This is especially true in primary (essential) hypertension, for which three major etiological elements can be distinguished: polygenetic predisposition, environmental factors, and the structural factor. The physical and biological principles behind the early "structural upward resetting" of heart and vessels in hypertension are outlined and experimentally illustrated. Further, the long-term hemodynamic effects of this per se "normal" structural adaptation are discussed, particularly concerning systemic precapillary resistance, but also concerning the heart, barostat mechanisms of reflex and renal nature, and the venous capacitance vessels. With this background in mind, the primary long-term goal of therapy must be to reverse these structural changes toward normal cardiovascular design and dimensions, whereas in the future preventive measures may be actualized. Thus, treatment should serve not only to reduce the increased load on heart and vessels but also, wherever possible, to reduce the influence of trophic, growth-promoting factors of local and remote nature, as exemplified by model studies in rats.

The pathophysiology of hypertension. Differences between young and elderly patients.

While structural and functional signs of a genetic predisposition to hypertension may sometimes be detected in the juvenile cardiovascular system, the borderline phase characteristic of young hypertensive patients is often dominated by a 'hyperkinetic' circulatory state. The modest pressure elevation is then mainly due to an increase in cardiac output and accentuated responses to neurohormonal stimuli. During the development of established hypertension, cardiac output gradually returns to normal and the high pressure state is largely a result of chronically elevated systemic resistance with cardiovascular 'structural upward resetting'. Signs of increased neurohormonal influences usually become less prominent. In general, the chronic high pressure state tends to accelerate ordinary cardiovascular aging, and therefore the advanced stages of primary hypertension are characterised by considerable interstitial infiltration with consequent wall stiffening and reduced aortic 'Windkessel' function. This further enhances the end-systolic afterload for the left ventricle, while at the same time myocardial strength and coronary reserve tend to decline. Age-related reductions in barostat function, reflex efficiency, and renal excretory capacity are also accentuated, and endothelial function suffers. Thus, the cardiovascular system in elderly hypertensive patients is generally characterised by pronounced and apparently poorly reversible structural changes. Nevertheless, recent studies indicate that even late phases of hypertension in elderly patients may respond favourably to treatment. This may predominantly reflect the high risk of serious cardiovascular damage in the elderly, but also that therapeutic intervention is able to reverse the structural changes observed in the advanced stages of hypertension.