Physiologic mechanisms that might mediate stress-induced hypertension
Since the evidence that chronic stress contributes to the development of hypertension is not yet widely accepted, it is not surprising that relatively little is known about the underlying physiological mechanisms. It can be assumed that the brain is the prime mover, but there are in principle two types of mechanism that could be involved. First, there might be a direct effect, for example via stress leading to increased activity of the sympathetic nervous system. Second, there might be an indirect effect such as a stress-induced increase in sodium intake.
Sympathetic Nervous System
For any postulated mechanism linking the brain and blood pressure, the autonomic nervous system is the primary candidate. There is increasing evidence for a subtle overactivity of the sympathetic nervous system in the early stages of essential hypertension, which raises the question, What is the origin of such overactivity? Although it may well be genetic, it is equally plausible that environmental stressors play a role. It is relatively easy to show that stress can cause a transient elevation in blood pressure. However, this is of doubtful relevance to sustained hypertension, which appears to be primarily a disorder of the tonic regulation of blood pressure rather than of its short-term variability. It is therefore appropriate to examine the time course of the effects of stress on blood pressure, and the mechanisms by which the cardiovascular effects of a stressor may outlast the stimulus.
The sympathetic nervous system is normally regarded as being primarily responsible for the short-term regulation of blood pressure, and other mechanisms such as the role of the kidney or structural changes in the resistance vessels regulate the tonic level. This poses a problem for those who believe that stress may influence the development of hypertension. How is it that transient increases of sympathetic activity can lead to a sustained increase in blood pressure? There are in fact a number of possible mechanisms.
A series of pharmacologic studies, predominantly conducted by Majewski et al., have identified a potential mechanism by which adrenaline (epinephrine) might mediate stress-linked hypertension. It has been shown by both in vitro and in vivo studies that infusion of epinephrine in low doses (equivalent to the levels seen during naturally occurring stress) can enhance norepinephrine release from sympathetic nerve terminals. This effect is thought to be mediated by prejunctional β2 receptors, because it can be blocked by β-blocking agents. Furthermore, circulating epinephrine may be taken up by the sympathetic nerve terminals, stored with norepinephrine as a cotransmitter, and released with it during sympathetic nerve stimulation. There are two crucial components to this mechanism that make it relevant to stress-induced hypertension. First, the release, reuptake, and presynaptic facilitation of norepinephrine release acts as a positive feedback loop. Second, whereas the half-life of epinephrine in the plasma is only a few minutes, for epinephrine stored in the sympathetic nerves it may be many hours, providing the potential for producing sustained effects.
Human studies have also implicated this mechanism. An acute infusion of epinephrine produces a tachycardia, with an increased systolic and slightly decreased diastolic pressure. When the infusion is terminated, the plasma epinephrine level rapidly returns to normal, although the tachycardia and increased systolic pressure persist for an hour or two, and diastolic pressure rises to above baseline levels. The most impressive demonstration of the delayed pressor effect of epineph-rine was provided in a study conducted by Blankenstijn et al., who infused epinephrine, norepinephrine, or dextrose for 6 h in normal volunteers, and monitored the effects on blood pressure over the next 26 h using intra-arterial monitoring. The infusion was given between 10:00 am and 4:00 pm, and the subjects were in bed from midnight to 8:00 am. Arterial pressure was at first reduced by the epinephrine, but by the end of the infusion was above the baseline value, and remained elevated throughout the night. Infusion of norepinephrine produced an initial elevation in pressure, but no sustained effects. The pressor effect of epinephrine was most marked during periods of increased sympathetic activity, e.g., when the subjects were active, and not when they were at rest. The increased blood pressure following epinephrine infusion was not accompanied by any changes in heart rate. However, a more direct test of the epinephrine hypothesis was recently reported by Goldstein et al., who found that local infusion of epinephrine does not enhance norepinephrine release. This casts doubt on the proposed mechanism of this phenomenon.
Another mechanism is via the renal sympathetic nerves, which promote sodium retention and renin release as well as increase renal vascular resistance. DiBona et al. have shown that air-jet stress leads to an increased activity in the renal sympathetic nerves, and that enhanced sympathetic responsiveness to air-jet stress cosegregates with arterial pressure in a back-cross experiment between the borderline hypertensive and the Wistar-Kyoto rat strains. The sympathetic nervous system may also influence the permeability of vascular smooth muscle cells to sodium, and there may also be trophic effects an cardiac and vascular muscle.
Renin-Angiotensin System
Several studies have implicated the renin-angiotensin system in the development of stress-induced hypertension, an effect that could be mediated by the influence of sympathetic nerves on renin release. Thus, in the borderline hypertensive rat, 10 d of air-jet stress can induce sustained hypertension, but this is prevented by pretreatment with captopril. Plasma catecholamines were unaffected by either the exposure to stress or treatment with captopril, suggesting that the sympathetic nervous system was not the prime mover in this model of hypertension. Plasma renin activity was increased in Henry’s mice subjected to chronic social stress, and captopril also lowered the blood pressure.
Endogenous Optoid System
There has recently been a lot of interest in the possibility that endogenous opioids may modulate the effects of stress on blood pressure, stemming from human studies using opioid antagonists such as naloxone and naltrexone. It has been shown that pretreatment with these agents can increase the blood pressure, catecholamine, and glucocorticoid response to psychologic stress. Young adults who are presumed to be at low risk for future hypertension (e.g., those who have a low casual pressure or who are physically fit) show a more developed opioid inhibition of the stress response or reactivity than those at higher risk. And a study using ambulatory monitoring to evaluate the effects of naturally occurring stress found that opioid blockade had no effect on the resting pressure, but did enhance the blood pressure response during periods of stress.
Structural Changes in the Heart and Resistance Vessels
It is well recognized that in the majority of patients with sustained hypertension, peripheral resistance is increased. That this is not wholly attributable to neurohumoral influences has been argued most forcefully by Folkow, on the basis of both anatomical and functional studies. Thus, even during maximal vasodilation such as occurs following a period of ischemia, hypertensive subjects still show an increased resistance to blood flow. These changes are largely owing to medial hypertrophy, and can be regarded as an adaptive process in the presence of increased pressure and for flow. The extent to which stress can produce such changes is unclear, but there is evidence that the growth of vascular smooth muscle can be influenced by a number of stress-related factors, including angiotensin, catecholamines, and corticosteroids.
Sodium Retention and the Kidney
The case for the dominant role of the kidneys in the long-term regulation of blood pressure has been proposed by Guyton on the basis of the phenomenon of pressure natriuresis: an increase in arterial pressure (by any mechanism) causes increased sodium and water excretion, which will tend to lower the blood volume and hence also the pressure.
Sustained hypertension occurs only when the set point of the renal-volume mechanism for pressure control is reset to a higher level of pressure. This could occur either because of sodium and volume retention or because of a change occurring in the kidney (e.g., an increase in prerenal resistance).
There is increasing evidence from animal experiments that environmental stress can cause sodium retention mediated via renal sympathetic nerve activity. The same phenomenon has also been described in humans. In addition, mental stress results in a greater increase in blood pressure in salt-sensitive than in salt-resistant subjects, which would be consistent with the observation of Anderson et al. that experimental hypertension is more readily produced when environmental stress is combined with a high salt intake.
In the borderline hypertensive rat, chronic exposure to conflict stress for 2 h a day can lead to sustained hypertension. In the early stages of this process, however, exposure to the conflict situation produces only a slight increase in blood pressure. Analysis of the hemodynamic pattern shows that there is a profound renal and mesenteric vasoconstriction that is offset by skeletal muscle vasodilation. An analogous observation by Hollenberg et al. showed that the effects of a behavioral challenge on renal blood flow lasted much longer than the effects on blood pressure.
Role of Glucocorticoids
An important physiologic component of Frankenhaeuser’s Effort-Distress model is the increase of cortisol that occurs in the “high effort-high distress” situation. Although most of the attention has been given to the sympathetic nervous system as the prime mediator of stress-induced increases in blood pressure, there is also evidence to suggest that glucocorticoids may be involved. The effects of glucocorticoids on blood pressure are complex and not well understood, although there is agreement that they tend to have a pressor effect, as reviewed recently by Whitworth. They may also increase the reactivity to adrenergic stimulation, particularly to epinephrine, although this effect is less certain in humans. Whitworth et al. gave four different synthetic steroids to normal subjects for 5 d, at doses that had similar glucocorticoid activity, but that had little or no mineralocorticoid effect. All four raised blood pressure without any accompanying sodium retention. The effects on the diurnal profile of blood pressure were not evaluated; it might be expected that the increase in blood pressure would be particularly pronounced at night.
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