| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Biological Sciences (R.M.S.), Stanford University, Stanford, California 94305; Department of Biology (L.M.R.), Tufts University, Medford, Massachusetts 02155; and Department of Physiology (A.U.M.), Dartmouth Medical School, Lebanon, New Hampshire 03756
 |
Abstract |
|---|
 Top Abstract I. The Decline and...II. Definition of Terms,...III. GC Actions in...IV. An IntegrationV. Molecular Mechanisms...VI. ConclusionsReferences |
|---|
|
I. The Decline and Modern Revision of Glucocorticoid Physiology |
|---|
|
TopAbstractI. The Decline and...II. Definition of Terms,...III. GC Actions in...IV. An IntegrationV. Molecular Mechanisms...VI. ConclusionsReferences |
|---|
Two broad explanations have been offered for the decline of GC physiology as a discipline (1):
1. Disparate and new GC actions emerged (notably the antiinflammatory actions reported in 1949) (2), which did not fit into the existing paradigm of stress physiology, namely that GCs enhanced the response to stress. Many physiologists either dismissed these effects by declaring them to be pharmacological or ignored them (3, 4) (despite the antiinflammatory effects accounting for more research and publications on GCs after 1949 than all the traditional physiological effects together).
2. Selye, one of the most prolific champions of GC physiology, turned out to be profoundly wrong about critical features of the physiology that he espoused. His claim throughout the early 1940s that GC excess could cause arthritis, allergies, and collagen-related disorders was shattered by the discovery of GC’s antiinflammatory actions. This debacle discouraged further attempts to make physiological sense of GC actions. Instead, attention moved to the dramatic new clinical applications of these hormones and, eventually, to their cellular and molecular actions.
A consequence of this withering of GC physiology was that it seemed irrelevant to ask the question that dominated earlier research—how do GCs help in surviving stressors? An earlier review (1) aimed to restore the integrative role of GC physiology by means of a new paradigm to encompass the disparate actions of GCs and remove the unconvincing physiological/pharmacological dichotomy. The authors proposed that GCs, rather than enhancing the stress response, through their suppressive actions limit its size and contribute to recovery from it. To quote (1):
"We propose that: (a) the physiological function of stress-induced increases in GC levels is to protect not against the source of stress itself, but against the normal defense reactions that are activated by stress; and (b) the GCs accomplish this function by turning off those defense reactions, thus preventing them from overshooting and themselves threatening homeostasis."
Unknown to the authors of Ref. 1 , a paper by Marius Tausk in 1951 (5) published in the periodical of a pharmaceutical firm, included the germ of this idea, which unfortunately did not enter the regular literature. Tausk illustrated his thought pithily by comparing stress to a fire and the role of GCs to that of preventing water damage rather than putting out the fire.
The permissive and suppressive effects of GCs have been suggested to complement each other, the former preparing or priming defense mechanisms for action and the latter, limiting the actions (6). The present review represents a synthesis of the classical view of Selye (that stress-induced secretion of GCs enhances and mediates the stress response), of Ingle (that basal GC levels are permissive of the stress response; 3), and of the emphasis on GCs as limiting the stress response and contributing to the recovery from it (1, 5, 6). The goals of the review are 4-fold: 1) to define the ways in which GCs influence the response to stress; 2) to propose criteria by which to discriminate between these roles in particular cases; 3) to apply those criteria to a broad spectrum of GC actions as organized by physiological systems, extending the analysis into areas not contemplated previously; 4) to attempt a synthesis of the physiological implications and evolution of these GC actions and establish why particular combinations of them make biological sense. As an important caveat, while we are reviewing a considerable body of facts (i.e., a large percentage of the literature concerning the physiology of GC actions) that are generally accepted within the endocrine community, our interpretations and emphases represent a very personal perspective.
|
II. Definition of Terms, and Criteria for Analyzing the Role of GCs in the Stress Response |
|---|
|
TopAbstractI. The Decline and...II. Definition of Terms,...III. GC Actions in...IV. An IntegrationV. Molecular Mechanisms...VI. ConclusionsReferences |
|---|
In this prototypical stressor, a herbivore, with no prior warning, is attacked by a predator. Injured, it manages to escape, but continues to be stalked and chased over the next hour, until the predator gives up. Note that this stressor includes physical injury, a demand for skeletomuscular activation, cognitive vigilance, as well as a perceived challenge to well-being that constitutes "psychological" stress. Note also that the lack of prior warning precludes any anticipatory stress.
We outline the broad features of the endocrine response to this
stressor, concentrating on hormones whose responses are most consistent
across stressors and whose actions are best understood (Fig. 1
). The first wave, occurring within seconds, involves: 1) enhanced secretion of catecholamines (epinephrine and norepinephrine) from the sympathetic nervous system; 2) hypothalamic release of CRH into the portal circulation and, perhaps 10 sec later, enhanced secretion of pituitary ACTH; 3) decreased hypothalamic release of GnRH and, shortly thereafter, decreased secretion of pituitary gonadotropins; and 4) pituitary secretion of PRL and (in primates) GH, and pancreatic secretion of glucagon. In the case of a hemorrhage, this first wave also includes massive secretion of arginine vasopressin (AVP) from the pituitary and renin from the kidney (in contrast to the moderate AVP response after other stressors); this response is bracketed, since loss of fluid volume (as in hemorrhage) will be analyzed as a separate facet of the stress response
|
A time course also exists with which the stress-induced endocrine changes in Fig. 1A are "heard" as target tissue effects (Fig. 1B). Commensurate with their rapid secretion, the hormones of the first wave exert most of their effects through rapid second messenger cascades within seconds to a few minutes. In contrast, because the bulk of steroid actions are genomic (for an exception, see Refs. 7 and 8), few GC actions are exerted until about an hour after the onset of the stressor, whereas the consequences of the decreasing reproductive steroid levels do not occur for several hours. The relatively slow effects of GCs become critical throughout this review.
These varied hormone effects bring about the major physiological changes of the stress response (Fig. 1C); the specifics of each set of changes will be considered in detail. On the scale of seconds to a few minutes, these include: 1) diversion of energy to exercising muscle (in the form of mobilization of stored energy, inhibition of subseuent energy storage, and gluconeogenesis); 2) enhanced substrate delivery to muscle via enhanced cardiovascular tone; 3) a stimulation of immune function; 4) inhibition of reproductive physiology and behavior (in the form of rapid declines in proceptive and receptive behavior in both sexes and loss of erections in males); 5) decreased feeding and appetite; 6) sharpened cognition and increased cerebral perfusion rates and local cerebral glucose utilization. In the specialized case of fluid loss due to hemorrhage, responses also include water retention through both renal and vascular mechanisms. Note that Fig. 1C only specifies the onset of these physiological responses; the duration of each will be a point of detailed analysis below. The critical point at this stage is to define the stress-induced GC target tissue effects.
B. Definitions of the classes of GC actions
We begin by analyzing what GCs do during stress with respect to
this early wave of endocrine stress responses and physiological
consequences. We distinguish between two classes of GC actions:
modulating actions, which alter an organism’s response to the
stressor; and preparative actions, which alter the organism’s response
to a subsequent stressor or aid in adapting to a chronic stressor.
Among the modulating GC actions we distinguish the following:
1. Permissive actions are exerted by GCs present before the stressor and prime the defense mechanisms by which an organism responds to stress. Their consequences are first manifested during the initial stress response and occur whether or not there is a stress-induced increase in GC concentrations.
2. Suppressive GC actions are those attributable to the stress-induced rise in GC concentrations, and thus have an onset of from about an hour or more after the onset of the stressor. These relatively delayed GC actions rein in the stress-activated defense reactions and prevent them from overshooting.
3. Stimulating GC actions are also attributable to the stress-induced rise in GC concentrations, with an onset of from about 1 h or more after the onset of the stressor. These GC actions enhance the effects of the first wave of hormonal responses to stress and thus are the reverse of the suppressive actions. Because permissive and stimulatory actions both enhance the first wave of response to the stressor, we will refer to them collectively as helping to mediate the stress response.
Finally, preparative GC actions are defined as those that do not affect the immediate response to a stressor but modulate the organism’s response to a subsequent stressor. They can be mediating or suppressive.
These actions may best be illustrated with an analogy. In response to the stressor of an invading army, an immediate response would be to shoot at the enemy; this is akin to the actions of the first wave of stress-responsive hormones (catecholamines, CRH, etc.). Among actions that would modulate this response, permissive actions would be those already in place at time of the attack, such as setting up defenses. Stimulating actions enhance the response and are undertaken after the attack, e.g., calling up active combatants from reserves. Suppressive actions, which constrain defense responses, might include calling off an attack to avoid self-destructive friendly fire (friendly fire being an example of defensive "overshoot", akin to autoimmunity). Preparative actions would be, for example, to institute rationing, an action designed not to repel the invader but to set up long-term measures for survival should the conflict continue, or enhance responsiveness to the next invasion (such as designing better systems for detection).
Permissive and suppressive actions have been recognized since the 1950s. Stimulating actions were once assumed to be responsible for the protection against stress afforded by stress-induced levels of GCs, but for which evidence has been weak (1). To our knowledge, the designation of some GC actions as preparative is new. As will be seen, it is rare that GC effects upon some physiological system consist of only one of these types of actions (i.e., permissive, suppressive, stimulatory, or preparative). In principle, all could be exerted over the whole range of GC concentrations, with dose-response curves depending on the receptors through which they are produced. In actuality, permissive actions are typically associated with basal levels of GCs, and the other three types of actions with stress-induced levels, but as we will indicate, there are instances of permissive actions being induced by higher than basal levels of GCs, so long as they precede an actual stressor.
These actions are exerted generally through GC (GR, or Type II) receptors, although in some cases, the mineralocorticoid (MR, or Type I) receptor may be involved. Such actions exhibit monotonic dose-response curves, i.e., response curves that continually either rise or fall with increasing GC concentrations in proportion to the number of GC-receptor complexes formed. The most convincing way to document that a GC effect is monotonic is to show that removal of GCs or their influence has a particular effect upon an endpoint, and that administration of physiological GC concentrations reverses the effect of removal. Monotonic dose-response curves are typical of classical GC effects used in bioassays for GC activity, such as liver glycogen deposition or thymus involution. Many GC actions are not monotonic, in that the steroid acts differently at low vs. high concentrations. This dichotomy can emerge, for example, from GCs permissively enhancing target tissue sensitivity to a cytokine, and simultaneously lowering the concentration of the cytokine, generating a bell-shaped or biphasic dose-response curve (6, 9). As will be seen, the biphasic nature is accentuated if the permissive actions are exerted through mineralocorticoid receptors (MRs) and the suppressive actions through glucocorticoid receptors (GRs), the former having more than 10 times greater affinity for natural GCs than the latter (cf. Ref. 10).
Duration and timing of hormone exposure can have major influences on responses. Excess GCs, while beneficial or harmless for a few days, can be fatal if prolonged. Just as there is diurnal and even minute-to-minute variation in GC levels, so there may be diurnal and minute-to-minute variation in responses to stress (11, 12). How soon GC effects are manifested after the hormones bind to their receptors may vary from a few minutes to days, and how long a hormone effect takes to decay after the hormones have been removed may vary from hours to days to weeks, depending on the life spans of the mRNAs and proteins that transmit the effects. Generally we have not examined the effects of long-term or chronic GC excess and deficiency, as in Cushing’s and Addison’s disease. In such conditions the primary physiological adaptations to altered GC levels that concern us here are often obscured by widespread and pathological secondary changes that are probably irrelevant to normal physiology and to evolution of the role of GCs in stress.
Finally, we will interpret with caution results obtained with synthetic GCs such as prednisolone or dexamethasone. These substances are extraordinarily useful clinically and experimentally, but may not be good substitutes for the natural GCs in physiological settings. They often do not bind to MRs, and may interact with GRs with different kinetics or affinities than the natural GCs (13).
C. Criteria for analyzing the role of GCs in the stress response
Does a particular GC action modulate the stress response through
permissive, suppressive, or stimulatory actions, or prepare the
organism for the next stressor?
To analyze systematically these actions we will apply a set of criteria for discriminating among them, using several styles of evidence. The criteria concentrate on the critical implications of the idea that GCs keep the primary defenses from overshooting (1, 5, 6), and, in the aftermath of the stress response, reduce the actions of those primary defenses to bring about recovery. While additional criteria may be valid, and each current criterion has some flaws, we have found these to be useful in judging the nature of each of a variety of GC effects upon various organs and physiological systems.
1. The criterion of conformity. Does a particular GC action
enhance or reduce the effects of the first wave of stress-responsive
hormones in Fig. 1A
(e.g., catecholamines, CRH)? If the
action reduces their effects, then by this criterion the GC action is
suppressive. If the effect is enhancement, and due to basal levels of
GCs present before that first wave, it would be viewed as permissive,
while enhancement by the subsequent stress-induced levels of GCs would
be viewed as stimulatory. Note that a GC action can be viewed as
enhancing that first wave without having to have the identical
effects—distributing guns and building aircraft carriers are both
defensive reactions.
2. The criterion of time course. Suppressive or stimulating
actions of stress-induced levels of GCs have an onset of minutes to
hours after the onset of the stressor. A particular action of
stress-induced levels of GCs can be considered to be suppressive (or
stimulating) only if it suppresses (or stimulates) the immediate stress
response (i.e., something that occurs in Fig. 1C before GCs
begin to exert their effects). Thus, for example, if stress-induced
levels of GCs stimulate appetite, this would qualify as a suppressive
action only if appetite is suppressed during the first minutes of the
stress response. In contrast, permissive effects require the presence
of GCs before the stressor and result in enhancement of the initial
stress response.
3. The criteria of hormone subtraction and replacement. What
happens to the physiological stress response (Fig. 1C) if there is no
stress-induced rise in GC activity? If some feature of Fig. 1C is
attenuated, then this supports the classical view that GCs stimulate
the stress response. In contrast, if an effect is enhanced (either in
the form of "overshooting" with a higher peak, and/or a delayed
recovery from the stress response), this supports the revisionist view
that the stress-induced rise in GCs suppresses the stress response.
Administering exogenous GCs post-stressor to replicate stress-induced
secretion should restore the stress response to that obtained with
normal endogenous GCs.
Similar outcomes should occur when GC actions are eliminated for days before a stressor, unless the stress response requires permissive GC actions. If permissive actions are required, however, then allowing previously established permissive actions to decay should attenuate or abolish the stress response, and neither stimulating nor suppressive actions would be manifested. To restore the normal stress response, exogenous GCs would have to be administered not only at stress-induced levels after the stressor as above, but at basal levels before the stressor.
The usual method for subtracting endogenous GCs is adrenalectomy. It subtracts other hormones as well and can require days of postoperative recovery. More specific subtraction is achieved with the GC antagonist RU486 (which also antagonizes progestins and sometimes displays agonist activity). It has been used in vivo and in vitro to reversibly block GC actions via GRs acutely or for extended periods. It does not block GC actions via MRs. To establish that changes in stress responses due to such manipulations result specifically from lack of GC activity, one must show that appropriate administration of exogenous GCs reverses the changes. (Note: we are not concerned here with effects of GC subtraction on endpoints in the absence of stress, which can nonetheless inform about tonic effects of GCs).
4. The criterion of homeostasis. Given the nature of the stressors experienced by most organisms and the adaptations needed to survive them by restoring homeostasis, does a particular GC action make more physiological sense as permitting, stimulating, or suppressing the stress response, or as preparing the organism for the next stressor?
Collectively, we feel that these criteria help identify GC actions that
are either permissive, stimulatory, or suppressive. Somewhat by
default, if an action fails to fit into any of these categories, we
will consider whether this constitutes preparative action, a
"bystander" effect, or if the action is simply not well understood
(Table 1).
|
|
III. GC Actions in the Context of These Criteria |
|---|
|
TopAbstractI. The Decline and...II. Definition of Terms,...III. GC Actions in...IV. An IntegrationV. Molecular Mechanisms...VI. ConclusionsReferences |
|---|
, whose latencies until actions are shown in Fig. 1B) and
their role in bringing about the relevant physiological changes (Fig. 1C). We will then review GC effects upon that particular system. With
those data in hand, we will then apply the criteria to categorize GC
actions in that realm.
A. Cardiovascular effects
In this section we consider GC actions upon blood pressure, heart
rate, and cardiac output during stress. For a number of reasons, we
separate this from the next section, which focuses on GCs effects on
the related subject of fluid volume during hemorrhage. First, we will
suggest that cardiovascular changes are a central feature of adaptation
to most physical stressors, whereas fluid volume changes are critical
to the specialized stressor of hemorrhage. Moreover, the mechanisms
underlying GC actions in the two realms appear quite different.
Finally, the conclusions regarding mediation or suppression of the
stress response are opposite in these two arenas, and we do not wish to
obscure these differences.
The cardiovascular stress response and the roles of hormones from the
first wave (Fig. 1A) are both well understood. Since the days of Walter
Cannon, who first described the fight or flight response at the
beginning of this century, rapid activation of the cardiovascular
system has been viewed as the sine qua non of surviving a
physical stressor. Such activation involves elevated arterial pressure,
heart rate, and cardiac output, accompanied by diversion of blood to
muscle via constriction of mesenteric and renal vessels and dilation of
vessels supplying skeletal muscle (14). Subtle and important qualifiers
have been introduced in recent years. For example, a different picture
emerges for stressors that demand quiet vigilance (such as an avoidance
task, or an organism remaining immobile to evade detection by a
predator). Such vigilance involves decreased heart rate and cardiac
output, and increased vascular resistance in all target tissues (15).
Despite this elaboration, stressors that produce a physical output as a coping response consistently cause rapid cardiovascular activation. The mediation of such activation by catecholamines is part of the canon of autonomic physiology. More recent work also implicates CRH. In addition to CRH regulating ACTH release, the peptide occurs diffusely in the brain and serves as a neurotransmitter that mediates sympathetic arousal, providing an important link between the adrenocortical and autonomic branches of the stress response (16). As such, intracerebroventricular administration of CRH elevates plasma catecholamine concentrations, blood pressure, and heart rate (17, 18, 19). This represents a central action of CRH, in that it occurs in hypophysectomized animals (20, 21), and is physiologically relevant, as sympathetic activation is partially attenuated with CRH antagonists (22).
The effects of GCs upon the cardiovascular stress response are also well understood. They increase blood pressure and cardiac output, as demonstrated by the positive inotropic effect of GCs (23), the hypotension and feeble cardiac function of adrenalectomized individuals, or by the hypertension of Cushings patients or individuals treated with GCs. We review these actions in the context of the criteria.
1. The criteria of conformity and of time course. Insofar as catecholamines and neurotransmitter CRH cause cardiovascular activation, GC actions are not only similar to these, but are inextricably intertwined with them. These GC actions are permissive, in that most involve "permitting" catecholamines and other vasoconstrictors to exert their full actions (24, 25). Treatment of normal rats with RU486 decreases vascular reactivity to norepinephrine and angiotensin II (26). GCs exert their permissive effects upon catecholamine action in both vascular and cardiac tissue (27, 28, 29, 30, 31, 32, 33, 34) [as well as in the lungs (35, 36)]. This is thought to arise in a number of ways. GCs induce phenylalanine-N-methyltransferase (PNMT), the rate-limiting enzyme in epinephrine synthesis (37, 38). Furthermore, GCs prolong catecholamine actions in neuromuscular junctions by inhibiting catecholamine reuptake and decreasing peripheral levels of catechol-O-methyltransferase and monoamine oxidase (39, 40). They also enhance cardiovascular sensitivity to catecholamines by increasing the binding capacity and affinity of ß-adrenergic receptors in arterial smooth muscle cells (41, 42), receptor-G protein coupling, and catecholamine-induced cAMP synthesis (43, 44, 45). In other tissues, such as nasal mucosa, GCs increase adrenergic receptor mRNA levels (46). Finally, by inhibiting PG synthesis at basal levels, GCs block their vasodilatory effects (47, 48). While the physiological relevance of this last mechanism has been questioned (24), there is evidence for it being the main route by which GCs elevate blood pressure in Cushing’s syndrome (25).
GCs can also inhibit a few features of sympathetic function (49). For example, GCs inhibit catecholamine release in response to some stressors (50, 51) and decrease cardiac norepinephrine turnover (52, 53). Nonetheless, in most cases GCs facilitate sympathetic interactions, and their overall physiological effects are to permissively augment cardiovascular activation during stress. Thus, by the criteria of conformity and of time course, GCs mediate the cardiovascular component of the stress response through their permissive actions.
2. The criteria of subtraction and replacement. These criteria support the view of GCs permitting the cardiovascular stress response. Both Addisonian and adrenalectomized individuals are characterized by basal hypotension (due in part to lack of aldosterone). Furthermore, as noted, RU486 decreases vascular reactivity to vasoconstrictors. In Addisonians, such hypotension can progress into an acute Addisonian crisis when the individual is challenged with a physiological stressor (infection, surgery, a burn). At such times, blood pressure is unresponsive to exogenous catecholamines. Thus, rather than removal of GCs causing a cardiovascular overshoot during stress, there is an undershoot.
This conclusion should be considered in the context of adrenalectomy being associated in some cases with elevated norepinephrine concentrations in response to a stressor (18, 50, 54, 55, 56), which has been interpreted by some authors as evidence for GCs constraining the cardiovascular stress response from overshooting (50). However, circulating concentrations of catecholamines, the endpoint in the studies just cited, are not equal to cardiovascular endpoints (blood pressure, heart rate, etc.). The varied GC effects upon catecholamine stability in the sympathetic synapse, upon the efficacy of catecholamines at their receptors, and upon post- receptor mechanisms apparently counteract the endpoint of circulating catecholamine concentrations (with the increased catecholamine concentrations after adrenalectomy perhaps being appropriately viewed as a partial compensation for the absence of these other GC effects). Thus, the total effect of GC underexposure is an attenuated cardiovascular stress response.
3. Criterion of homeostasis. The logic of activating the cardiovascular system during most stressors is apparent and has figured in thinking about the physiology of the stress response since Cannon’s The Wisdom of the Body (57). The complexity of regulatory factors uncovered since that time reinforces the conclusion that the mobilization of cardiovascular tone, as contributed to by GCs, represents a vital adaptation to stress.
All four criteria lead to the conclusion that GCs help mediate, rather than suppress, the cardiovascular stress response. These mediating effects involve permissive actions over the entire GC dose range (57). Whether these mediating actions include stimulatory ones as well (i.e., effects that are amplified by stress-induced elevations of GC concentrations) remains untested.
Conclusions: Varied stressors trigger cardiovascular activation; this effect is primarily mediated by the sympathetic nervous system, with GCs, over their entire dose range, enhancing these effects. Removal of GCs impairs the cardiovascular stress response, rather than causing it to overshoot. These findings, plus the logic of enhancing cardiac output in coping with a stressful physical challenge, suggest that GCs help mediate permissively the cardiovascular stress response.
B. Fluid volume and hemorrhage
As earlier, hemorrhage is a quite different and specialized
stressor than is the sprint across a savanna. Because of this and, most
importantly, the nature of GC actions, we have treated them separately.
Hemorrhage (as induced experimentally by controlled blood withdrawal)
causes the robust stress response of Fig. 1A, along with enhanced
secretion of AVP and renin, producing water retention and
vasoconstriction. GCs indirectly inhibit the release of AVP (by
restoring the actions of inotropic and vasoconstrictive hormones,
resulting in reflexive inhibition of secretion), increase glomerular
filtration rate, and increase the secretion and efficacy of atrial
natriuretic polypeptide (58, 59), all of which enhance water excretion.
These actions occur in response to both basal and stress-induced levels
of GCs, and rate of excretion of a water load has been used to test
patients for adrenal insufficiency (60). The implications of these
actions during a hemorrhage has different implications than the
cardiovascular responses to more general stressors. This view arises
from a meticulous series of studies (61, 62, 63), in which the hemorrhage
insult was a moderate one, involving withdrawal of 15 ml of blood/kg
over a 5-min period from rats.
The authors first demonstrated that adrenalectomy robustly potentiated secretion of the vasoactive hormones (including hypersecretion of AVP and norepinephrine but, because of the adrenalectomy, obviously not epinephrine) (61). In other words, GCs normally constrain the size of the vasoactive response to hemorrhage. When such a hemorrhage in adrenalectomized rats was coupled with fasting, the hemorrhage invariably proved fatal (in contrast, intact rats, whether fed or fasted, always survived a similar hemorrhage) (62).
The authors thereupon dissected the complex chain of events underlying the death (62, 63). The critical step appeared to be the AVP overshoot, resulting in a vast vasoconstriction of the hepatic and coronary circulation. This produced ischemia in these organs and also led to a profound hypoglycemia (which arose because there was minimal hepatic gluconeogenesis in the absence of perfusion through the liver). The authors suggested the following features to this cascade:
1. The cause of death was probably the ischemia due to circulatory failure, rather than the hypoglycemia. As evidence, intravenous infusion with glucose did not prevent death (63).
2. This seemed to contradict the authors’ finding that feeding prevented hemorrhage-induced death in adrenalectomized rats. However, feeding not only elevated circulating glucose concentrations, but also stimulated blood flow to the gut and liver (via gastrointestinal distention) (64), apparently enough to override the vasoconstriction induced by the AVP.
3. In the adrenalectomized rats, it was the overshoot of the AVP stress response, rather than of the norepinephrine or renin responses, which proved fatal. As evidence, a replacement regimen with GC concentrations in the low basal range, which normalized the norepinephrine and renin responses, but not the AVP response, did not prevent death (63). Protective effects were seen only when circulating GC levels were raised to the range seen during the circadian peak.
4. Hemorrhage in the fasted, adrenalectomized rats caused a decrease in vascular sensitivity to AVP (but not to norepinephrine or renin) (62). This can be viewed as a protective down-regulation in response to the vastly increased AVP signal, a compensation that was nevertheless insufficient to prevent death.
Conclusion. These data are commensurate with a picture of GCs suppressing, rather than mediating, the fluid volume response to a hemorrhage stressor. The stressor leads to a rapid burst of secretion of vasoconstrictive stress hormones, and of vasoconstriction itself, both of which are opposed by GCs. Thus, by the criteria of time course and conformity, GCs are suppressive. Moreover, adrenalectomy results in a (potentially fatal) overshoot of the secretion of AVP, satisfying the criterion of subtraction. From the point of view of homeostasis, the importance of the suppression by GCs of the response to hemorrhage is that it prevents the organism from being injured or killed by its own defense mechanisms.
These findings, when combined with those concerning GC effects upon cardiovascular physiology, generate a subtle but important insight. As reviewed, insufficient GCs can lead to enhanced catecholamine overflow during a stressor. However, such insufficiency also blunts sensitivity of cardiovascular tissues to the catecholamines. Similarly, lack of GCs leads to hypersecretion of the vasoconstrictive hormones after hemorrhage and to damped target tissue sensitivity to the critical AVP. In the former cardiovascular case, the loss of tissue sensitivity most likely reflects the numerous GC actions upon catecholamine half-life in the synapse and upon the efficacy of receptor and postreceptor mechanisms. In the case of hemorrhage, the desensitization is speculated to arise more directly from the down-regulatory effects of the excessive AVP (since GCs themselves have been reported to increase AVP receptor number (65, 66, 67). In both systems, however, adrenalectomy leads to both an enhanced signal and a decreased sensitivity to that signal.
Despite this similarity, the outcomes are the opposite. In the case of general stressors that activate the cardiovascular system, the result of those two opposing consequences of adrenalectomy is a marked hypotension during stress (i.e., the stress-response is attenuated). In the specialized case of a hemorrhage stressor, the result is ischemic vasoconstriction (i.e., the stress-response overshoots). GCs often have opposite effects upon the strength of a particular signal and the target tissue sensitivity to the signal (6), and as described later, the combination of those two trends can produce a bell-shaped curve of dose responsiveness. The GC effects upon the signal and upon the sensitivity to that signal need not mirror each other perfectly, and depending upon which predominates, GC can enhance or damp the system. GC actions upon the general cardiovascular stress response, and upon the response to a hemorrhage stressor, appear to represent difference balancings of those two opposing trends.
C. Immunity and inflammation
We now consider GC effects upon immunity and inflammation,
an area of great confusion in making a physiological whole of GC
actions. We begin by considering the immunological and inflammatory
effects of the first wave of hormones secreted as stress response (Fig. 1A). This is an arena of considerable complexity, as such hormones have
both stimulating and inhibitory effects (reviewed in Refs. 68, 69).
For example, CRH decreases T cell proliferation and natural killer (NK)
cell cytotoxicity; this is a centrally acting event, as it can be
reversed with intracerebroventricular infusion of CRH antibodies (70, 71). CRH (at extremely high doses that also cause hypotension) can also
act as an antiinflammatory and antiedemic agent, reducing inflammatory
exudate volume and cell concentration in models of injury to skin,
mucosa, brain, or muscle (72, 73, 74). In contrast, CRH can also be an
immune stimulant, enhancing B cell proliferation and the proliferative
lymphocyte response to various mitogens and increasing interleukin 2
(IL-2) receptor number (75, 76).
We next consider the rapid physiological effects of stress upon immune
function (Fig. 1C). Various infectious stressors cause rapid immune
activation that precedes adrenocortical activation. These include
exposure to endo- or exotoxins and inoculation with an infectious
microorganism or antigen (Refs. 77, 78, 79 ; also, see Ref. 80).
Surprisingly, the same can be triggered by noninfectious stressors. For
example, psychological stressors, such as placement of rats in
open-field settings or conditioned aversion stress, will trigger
cytokine release and its associated fever response before there is a
rise in GC concentrations (81, 82, 83). Thus, rapid activation of the
immune system appears to be a response to a number of generalized
stressors.
This link is made more interesting by the fact that this immune activation contributes to the subsequent GC release. First, the activated immune system can synthesize ACTH-like molecules (84). However, the bioactivity of those peptides is probably insufficient to be of much physiological relevance (85, 86).
Second, as postulated by Besedovsky and colleagues (87, 88, 89, 90),
various cytokines emanating from activated immune cells can stimulate
the adrenocortical axis. For example, IL-1 can release CRH from the
hypothalamus (91, 92, 93) and can directly release ACTH from the pituitary
(94), although this is controversial (78). Since then, other cytokines,
including IL-2, IL-6, tumor necrosis factor-
(TNF-), and
interferon-
(IFN-), have been shown to stimulate the
adrenocortical axis, although none with the potency of IL-1 (reviewed
in Ref. 79).
We now consider the GC effects in this realm. The immunosuppressive and antiinflammatory actions of GCs have been recognized for decades (6, 68, 77, 95, 96, 97, 98, 99, 100, 101) and is the rationale for their clinical use to control autoimmune diseases and inflammation and to prevent organ rejection after transplantation.
The most general effect of GCs is to inhibit synthesis, release, and/or
efficacy of cytokines and other mediators that promote immune and
inflammatory reactions, both in cell culture systems and in whole
organisms (reviewed in Refs. 21, 102). These include IL-1, IL-2,
IL-3, IL-4 [inhibited in human but stimulated in murine cells (103)],
IL-5, IL-6, IL-12, granulocyte monocyte colony-stimulating factor
(GM-CSF), IFN-, TNF-, chemokines like IL-8 (62, 81), R ANTES
(regulated on activation normal T cell expressed and secreted) (104),
and macrophage inflammatory protein-1 (105), and inflammatory
mediators and enzymes such as histamine, bradykinin,
eicosanoids, nitric oxide (106, 107, 108), collagenas
e, elastase, and
plasminogen activator. GCs reduce eicosanoid synthesis by inhibiting
expression of the inducible form of cyclooxygenase, cyclooxygenase 2
(COX-2) (109, 110, 111, 112, 113). They inhibit
12-O-tetradecanoylphorbol-13-acetate and TNF- induction
of intercellular adhesion molecule 1 (ICAM-1) (114). GCs can inhibit
antigen presentation and expression of major histocompatibility complex
(MHC) class II proteins, reduce activation and proliferation of T and B
cells (memory cells being much less sensitive than naïve
cells), and shift responses from Th1 cells (which predominantly secrete
IL-2 and IFN-) to Th2 cells (which secrete IL-10 among other
antiinflammatory cytokines) (115, 116). They increase activity of
transforming growth factor-ß (TGF-ß), an antiproliferative cytokine
that inhibits activation of T cells and macrophages (117, 118) and may
induce expression of lipocortin-1 (119), which can regulate immune
reactions (120).
Trafficking and function of peripheral cells are altered transiently by GCs, which rapidly lower circulating levels of lymphocytes (T more than B cells, and CD4 helper cells more than CD8 cytotoxic cells and NK cells), eosinophils, basophils, macrophages, and monocytes, but increase levels of neutrophils. This redistribution of cells is probably due largely to alterations in cell adhesion molecules (121, 122). Lymphocyte, monocyte, and granulocyte chemotaxis are suppressed, with reduced accumulation of phagocytic cells at inflammatory sites. GCs also atrophy the thymus and, to a lesser extent, other lymphoid tissues, triggering apoptotic death in immature T and B cell precursors and mature T cells. The lymphocytolytic actions of GCs are central in treatment of lymphocytic leukemias and lymphomas. During prolonged exposure to GC therapy, they may contribute to immunosuppression. Physiologically, their role may be to facilitate both negative and positive selection of the T cell repertoire (95, 123, 124) and to remove potentially toxic activated cells (125).
Despite evidence of the suppressive actions of GC stretching back decades, enhancement of immune functions by GCs has been reported, and some recent results are striking. Jefferies (126, 127) argues for the importance of enhancing effects—which he ascribes to permissive actions—and laments their neglect in clinical practice. He cites instances where physiological doses of GCs improve the condition of patients or experimental animals, e.g., by enhancing resistance to infection. Which immune functions are enhanced in such cases is unclear. As Jefferies notes, one that has been observed fairly consistently in vitro is the stimulation of immunoglobulin synthesis by cultured B cells (128, 129, 130, 131, 132, 133). For such stimulation, GCs generally are required early in a culture, consistent with them being permissive. Some of these effects could be secondary to GC modulation of cytokine production or activity, such as the shift from T helper 1 and 2 cells (Th1 to Th2 cells) already mentioned, or the induction of cytokine receptors described below (134). However, inhibition of immunoglobulin production in culture has also been reported occasionally (135), and GCs inhibit some of the steps preceding B cell differentiation to antigen-secreting state (132) and suppress immunoglobulin production in whole organisms (97). Thus, the physiological role of these influences on B cell functions is difficult to evaluate.
While most reports indicate that GCs suppress T cell function,
enhancement has been observed in humans and rats. Barber et
al. (136) demonstrated suppression of TNF- and IL-6 responses
to endotoxin in humans by cortisol administered within 6 h of
endotoxin. They gave cortisol (as hemisuccinate) in 6-h intravenous
infusions that raised plasma cortisol levels to the micromolar range,
corresponding to high stress-induced levels. By contrast, they also
showed that if cortisol is given 12, 36, 72, or 144 h before
endotoxin, TNF- and IL-6 secretion are markedly enhanced, suggesting
that permissive actions can be induced by high GC
concentrations.
GCs can also enhance T cell responses in rats in vivo and
vitro (102, 137, 138, 139). The response to the mitogen
concanavalin A by peripheral T cells from rats adrenalectomized for 1
week was reduced 65% compared with cells from sham-operated rats. It
was restored by administering low physiological plasma levels of
corticosterone (
17 nM, maintained with
subcutaneous pellets) and almost totally suppressed by high levels
(170 nM). Corticosterone in vitro
at all concentrations suppressed the mitogenic response of cultured
cells from either adrenalectomized or sham-operated rats, an effect
blocked by RU486 at 500 nM. However, RU486 at 50
nM changed the suppression by 10
nM corticosterone to stimulation (137). Similar
observations were obtained with splenic lymphocytes, stimulated with
either concanavalin A (138, 139) or with the more specific stimulus of
anti-T cell antigen receptor (139). In the experiments with anti-T cell
antigen receptor, corticosterone had to be added within the first hour
of stimulus to enhance; enhancement seemed to be due to increased
expression of IL-2 receptors on T cells. In other experiments, even
brief preexposure to corticosterone or aldosterone (with subsequent
washing out of the steroid) enhanced the response to concanavalin A
several days later (138). From these and other results, Wiegers
et al. (139) propose that, as previously inferred from GC
effects on hippocampal slices, corticosterone at low concentrations
enhances T cell responses through MRs, and at high concentrations
suppresses those responses through GRs (137, 138, 139).
GCs also play permissive and suppressive roles in the acute-phase
response, a general systemic response to immune and inflammatory
reactions triggered by injury and infection (140, 141). Cytokines and
other mediators such as IL-1 and TNF- are released into the
circulation and stimulate hepatic synthesis of acute-phase proteins
such as serum amyloid A, C-reactive protein, and complement components.
GCs enhance the hepatic acute-phase response by increasing sensitivity
to mediators, while suppressing the overall response by inhibiting
mediator production (140).
A final example of GC-induced immune enhancement comes from an unexpected reinterpretation of classic data. Even relatively minor increases in GC concentrations can deplete circulating leukocytes. This has typically been interpreted as a decline in immune competence, as most evidence suggested that such leukocytes were being sequestered, inactive, in immune tissues. However, such depletion might instead involve diversion of circulating leukocytes to local areas of need (such as in inflamed skin) (101, 142, 143, 144, 145, 146). In an example of immune activation, delayed-type hypersensitivity (DTH), acute stress experienced immediately before the administration of an antigen to the skin significantly enhances a cell-mediated immune response directed against the antigen (147) [while, in contrast, chronic stress over a period of weeks suppresses the DTH response (148)]. Thus, rather than being immunosuppressive, this would represent, in the apt words of the authors, GC-induced migration of leukocytes to "battle stations."
We now consider these GC actions in the context of the criteria. The criterion of conformity—do GCs have effects on the immune system that are similar to, opposite to, or different from the more rapid stress-responsive hormones?—offers little information because, as noted, there is no consensus as to the effects of that first wave of hormones.
As discussed, the first wave of immune responses to various stressors
is one of activation. Thus, the criterion of time course suggests that
the inhibitory effects of GCs upon immunity and inflammation should be
viewed as suppressive, whereas the more recently appreciated enhancing
effects are permissive. For example, as noted, exposure of humans to
cortisol for up to a week before a challenge with endotoxin enhances
TNF- and IL-6 levels, whereas cortisol at the time of or after
endotoxin suppresses the cytokine response (136); in rats, preexposure
to corticosterone in vivo or in vitro enhances
mitogenesis (137, 138, 139). Furthermore, the fact that the enhancing
effects of GCs in rats are seen with low levels of the hormone and can
be mediated by the MR supports the permissive scenario of such
enhancement occurring under basal conditions in place at the onset of a
stressor. In contrast, the requirement for higher concentrations of GCs
and GR involvement for the emergence of the inhibitory effects supports
the picture of suppressive actions occurring as GC concentrations rise
into the stress-induced range.
The criteria of subtraction and replacement—is there an overshoot of
immunity or inflammation in circumstances of diminished adrenocortical
activity, and can the overshoot be counteracted with GCs?—strongly
support the view that GCs suppress immunological and inflammatory
stress responses. The earliest such report came in 1922, with the
observation by Kepinov (discussed in Ref. 119) that adrenalectomy
sensitizes guinea pigs to bronchial anaphylaxis. Adrenalectomy has also
long been known to cause the thymus and other lymphoid organs to
hypertrophy. Flower et al. (149), in a direct test of the
hypothesis that endogenous GCs suppress inflammatory responses, found
that adrenalectomy markedly enhanced the response to carrageenin.
Moreover, the response of normal rats is enhanced by administration of
RU486 (150). Bacterial endotoxin-induced sepsis in rats causes GC
secretion secondary to the actions of cytokines upon the adrenocortical
axis (151, 152), adrenalectomy significantly increases fever and
mortality induced by the sepsis, and GCs reverse these effects
(81, 153, 154). Doses of IL-1 or TNF- that are readily survived by
intact rats prove fatal in adrenalectomized animals (155); this effect
also is reversed with GC supplementation. Circulating levels of
TNF-, IL-6, and epinephrine stimulated by endotoxin in humans were
diminished by cortisol administered within 6 h of endotoxin (136, 156). Adrenalectomized rats, and intact rats treated with RU486,
developed substantially higher levels of plasma IL-6 than control rats
after injection of endotoxin, an effect attenuated by administration of
GCs (81, 157). In some circumstances, basal GC concentrations do not
prevent immune or inflammatory overshoot; stress concentrations of GCs
must be attained (81, 158). Miller et al. (159), however,
found a linear correlation over the entire dose range between the
extent of binding of GCs to splenic GRs and the extent of inhibition of
mitogen-induced T cell proliferation, showing that GCs can suppress
immunity over their entire concentration range.
A striking example of inflammatory overshoot is the Lewis rat, in which cytokines such as IL-1 fail to stimulate CRH synthesis or secretion so that an inflammatory stressor does not stimulate GC secretion. Lewis rats are exceptionally susceptible to experimental arthritis induced with streptococcal cell wall polysaccharide when compared with Fischer rats, and can be protected by treatment with GCs (160, 161). Similarly, Fischer rats, normally resistant to experimental arthritis, become susceptible when GC actions are blocked with RU486 (160, 161) or adrenalectomy (78, 162). Lewis rats are also very sensitive to carrageenin-induced inflammation (72) and to induction of experimental allergic encephalomyelitis (EAE), a model of multiple sclerosis (163). In normal rats the stressor of induction of EAE triggers substantial GC secretion, most probably via the stimulating actions of cytokines, and adrenalectomy significantly increases EAE-induced mortality; this increased mortality is prevented by administration of GCs that produce circulating concentrations in the stress range, but not in the basal range (158, 163, 164). Immune overshoot also occurs in obese strain chickens that spontaneously develop autoimmune thyroiditis (99, 165, 166). Their hypothalamic-pituitary-adrenal (HPA) axes are resistant to cytokine activation (79); furthermore, the biological potency of any secreted GCs is greatly decreased because of a doubling of circulating transcortin concentrations (167).
Clinical reports show parallels to these findings. Individuals with Addison’s disease are prone to bronchial asthma, various allergies, and autoimmune adrenalitis (168, 169, 170). Moreover, unilateral adrenalectomy to remove an adrenocortical adenoma can cause a flare-up of autoimmune thyroid disease (171); whether the adrenalitis or thyroid disease in these two cases is more readily triggered in circumstances of stress is not known. Furthermore, individuals with inflammatory arthritis (i.e., rheumatoid), but not those with degenerative arthritis (i.e., osteoarthritic), have significantly impaired GC stress responses (69, 172).
The criterion of homeostasis—do GC effects in this realm during stress make sense?—has long presented a challenge, because of the classical inhibitory actions of GCs. As noted, one response of many GC physiologists has been to relegate them to pharmacology. Other attempts at incorporating them into physiology now appear quite unsatisfactory, such as the speculation that immunity is suppressed to spare energy during the prototypical physical stressor (173) or that GC-induced lymphocytolysis provides substrate for gluconeogenesis and tissue repair (174).
More recent work has helped clarify the homeostatic logic of the immunosuppressive effects of GCs, as well as their predominance at higher concentrations and only after the first wave of the stress response. Immunosuppression is logically viewed as suppressing the stress response to an infectious stressor to decrease the likelihood of autoimmune overshoot. Antigenic challenges to the immune system trigger polyclonal responses, raising the risk of autoimmunity where epitopes recognized by some of the clones overlap with those of normal body constituents. It has been suggested that under physiological conditions GCs are selective, "sculpting" the immune response so that superfluous or autoimmune-prone components are selectively inhibited (175). This is due to the preferential targeting by GCs of lymphocytes that are less active or that produce antibodies with lower affinities for the antigen (176, 177). Consistent with this role of GCs, after an infectious stressor, GC concentrations peak when the antiantigen response peaks (80, 178), which may be days later. A similar synchrony of ACTH, corticosterone, and IL-6 responses follows an inflammatory stressor (179). Another argument for the homeostatic value of GC suppression is that many cytokines induced by stressors can be toxic in excess, independent of their stimulation of immune and inflammatory reactions, and thus their levels need to be controlled (180, 181).
Thus, the criterion of homeostasis suggests that the enhancing effects of GCs be viewed as permissive, while the delayed inhibiting effects of GCs be viewed as permissive, while the delayed inhibiting effects are suppressive.
Why were enhancing, permissive effects of GCs so rarely observed in earlier studies? Surprisingly, the results of Barber et al. (136) were obtained with large doses of GCs administered to subjects with normal GCs. Classical permissive effects, such as those on gluconeogenesis or cardiovascular functions, have generally been elicited with basal levels of GCs in subjects with subnormal or no GCs. This illustrates the earlier point that permissive effects probably have dose-response relations similar to other GC effects, but whose effects at high doses of GCs are usually obliterated by suppressive effects. In the experiments of Barber et al., permissive and suppressive effects were separated by timing of GC administration. Wiegers et al. (139), in trying to account for the differences between their results and those of others with rats, mention that the density of cells in culture may be a critical variable for the responses of T cells. They also suggest that in the other studies, high and prolonged GC exposure may have suppressed enhancing effects. One of their tools for uncovering permissive effects was the GR antagonist RU486, which does not block MRs. Thus, if permissive effects on T cell functions are generally mediated by MRs, a reinterpretation may be necessary of experiments in which administration of RU486 exacerbates immune or inflammatory responses. Exacerbation has usually been interpreted as being caused simply by blocking of suppressive GC actions, but could also be due partly to RU486 uncovering permissive enhancement by GCs through MRs. Synthetic GC agonists like dexamethasone, which are often used for immunosuppression both experimentally and clinically, would be unlikely to reveal permissive effects through MRs since they are effective immunosuppressants at much lower concentrations than corticosterone or cortisol and would activate MRs much less than the natural GCs. Finally, another reason for the dearth of earlier reports of permissive effects of GCs on T cell functions may be that not all T cell-mediated responses require permissive enhancement.
Enhancement by GCs via up-regulation of hormone, cytokine, and growth
factor receptors has been proposed to underlie permissive activation of
several physiological systems (134, 139, 182, 183). Among such
receptors are those for IL-2 (139), IL-6, IFN-, GM-CSF, and CSF-1
(6, 100). For example, GC up-regulation of GM-CSF can explain GC
synergism with GM-CSF to increase MHC class II expression (184). Such
effects could also account for the generally beneficial influences of
GCs in culture media (182). GC inhibition of production of mediators
that act through many of these receptors is initially paradoxical.
However, a simple mathematical model shows that combined stimulating
and inhibitory effects, even with identical dose-response curves,
generate a bell-shaped dose-response curve according to which GCs
activate homeostatic mechanisms permissively at basal levels reached
during normal diurnal variation and suppress them at stress-induced
levels (Fig. 2). The bell-shaped curve generated via GC receptors extends GC influences over a wide concentration range, which is even further extended at low concentrations if permissive GC actions are mediated via MRs, as just described for T cell mitogenesis. Although there is no time axis in the figure, permissive actions should be thought of as preceding, and suppressive actions as following, a stressor.
|
D. Metabolism
The early phases and endocrine mediators of the metabolic
stress response have been understood for decades (Fig. 1, A and C).
Blood glucose levels are elevated rapidly, in part by mobilization from
existing stores, and by inhibition of further storage through a rapid
insulin resistance (185); thus, energy is diverted from storage sites
to exercise muscle. These changes are brought about by catecholamines,
glucagon, and GH.
The preeminent effect of GCs upon metabolism is their ability to increase circulating glucose concentrations. This is accomplished through a number of mechanisms. One, discussed later, is via stimulation of appetite by low levels of GCs (186). In addition, when GCs are present for hours before the stressor, there is 1) the stimulation of glycogenolysis and gluconeogenesis by glucagon and catecholamines that constitute the immediate stress response; 2) stimulation of hepatic gluconeogenesis and glycogen deposition; and 3) inhibition of peripheral glucose transport and utilization (reviewed in Refs. 187, 188, 189, 190, 191, 192, 193). In addition, GCs mobilize lipids through lipolysis in fat cells, and amino acids through inhibition of protein synthesis and stimulation of proteolysis in various muscle types.
The criteria yield a clear interpretation of these GC actions. By the criterion of conformity, GCs help to mediate permissively the metabolic stress response, synergizing with catecholamines, GH, and glucagon to stimulate lipolysis and to elevate circulating glucose concentrations by stimulating glycogenolysis and gluconeogenesis (cf. Refs. 189, 192, 193). Epinephrine and glucagon act quickly, whereas GCs act slowly to enhance and prolong for several hours the increase in blood glucose due to epinephrine or glucagon (189).
A similar conclusion is reached by applying the criteria of time course and subtraction: during a physical stressor, Addisonian and adrenalectomized individuals are impaired in mobilizing the necessary energy substrates, a defect corrected with maintenance doses of GCs. As early an investigator as Selye (194) showed that this impaired capacity to mobilize substrates becomes fatal during stress when the organism is already food deprived. Furthermore, from the standpoint of homeostasis, it makes abundant sense for the metabolic stress response to be one of mobilization of substrate stores and their diversion to the subset of tissues that need them.
With regard to the slower stimulation of gluconeogenesis and inhibition of peripheral glucose utilization by stress-induced GCs, they clearly supplement the permissive actions and may be responsible for extending and prolonging the stress response. They can therefore be categorized as stimulatory. Stimulation of liver glycogen deposition, however, which similarly takes a few hours, can have little influence on the stress response, but by restoring glycogen levels prepares for the next one. It thus is best classified as preparative.
Conclusions. All four criteria suggest that during a prototypical stressor, GCs help mediate the metabolic response through both permissive and stimulating actions and also have preparative actions. These actions appear to arise from a mixture of monotonic and biphasic effects over the GC dose range. For example, GC inhibition of glucose uptake is monotonic (195). Fat depletion is stimulated by GCs over their entire dose range (188). In contrast, the muscle-wasting effects of GCs appear to occur only in the stress range (196). These mediating GC actions should be viewed as both permissive and stimulatory. The preparative GC stimulation of hepatic glycogen deposition gives a classic monotonic dose-response curve.
These interpretations of the roles of GCs in metabolic stress responses differ from those in Ref. 1 , where GC actions were viewed as "counterregulatory" to those of insulin, and therefore suppressive (202). This shift in interpretation can be understood by distinguishing between the effects of GCs upon metabolism, and those of GC-induced insulin secretion. During the normal daily fluctuations of fasting and feeding, of repose and activity, each with their associated metabolic demands, and after injury or during disease states, the metabolic actions of GCs are intertwined with those of insulin and certain other hormones. In these interactions a central physiological variable is the level of blood glucose, which must be kept from falling below some threshold for normal brain function and may have to be raised acutely to satisfy a sudden need for energy. GC actions generally oppose but sometimes synergize with those of insulin. For example, GCs and insulin have opposite actions on blood glucose levels, as well as on appetite, gluconeogenesis, glucose transport, protein synthesis, muscle wastage, lipolysis, lipogenesis, and fat deposition in adipose tissue (197); they synergize in stimulating hepatic glycogen deposition and lipogenesis (188, 198, 199). Elevated GCs raise insulin concentrations; whether this is due to direct GC stimulation of secretion or is secondary to the metabolic actions of GCs is unclear (188, 200). Sustained GC secretion causes sustained insulin secretion after a delay of a few hours. Chronically elevated GCs, as in Cushing’s syndrome, cause pronounced muscle wastage, fat accumulation and redistribution, and are diabetogenic. Thus, in analyzing the actions of GCs, the concurrent effects of insulin must be taken into account. True GC effects are most readily demonstrated in the absence of insulin secretion (e.g., in streptozotocin diabetic rats), in which GC’s lipolytic, proteolytic, and gluconeogenic effects are dramatic (188, 198, 199, 201).
Catecholamines, glucagon, GH, and GCs are known as "counterregulatory" hormones, reflecting their ability to counteract the hypoglycemic activity of insulin by raising blood glucose levels (203, 204). This term is often used to describe how the secretion of these hormones, stimulated by the postprandial elevation of insulin levels (188, 205) or by insulin administration in the diabetic patient, protects against hypoglycemia. However, in a mammal sprinting across the savanna, it is the secretion of the "counterregulatory" hormones that comes first, mobilizing energy substrates. Only with the abatement of the stressor do insulin’s opposing actions emerge, reversing the metabolic actions of these other hormones.
Insulin administration to a laboratory animal or normal human has long been used to stimulate an endocrine stress response or simulate the rise in insulin levels that follow a meal. This reflects not only the convenience of the method, but the importance that the understanding and management of diabetes has in clinical endocrinology. Within that framework, GCs are "suppressive" as they prevent insulin-induced hypoglycemia from overshooting (1). However, an insulin surge and a sprint across the savanna are different stressors. The latter, we believe, is the more logical setting to understand the evolution and physiological relevance of GC secretion during stress, although the former, which utilizes the same hormonal actions and metabolic pathways, also carries survival value.
If stress physiology had a tradition of drawing upon ethologists rather than diabetologists, insulin would perhaps be termed a "counterregulatory" hormone. However, under basal, nonstressed circumstances, GCs, catecholamines, GH, and glucagon interact with insulin in complex ways that justify the view that each class of hormones counterregulates the other at some point.
E. Neurobiological effects
The neurobiological actions of GCs were only briefly touched on in
Ref. 1 . Since then, numerous studies have reported electrophysiological
and neurochemical effects of GCs (cf. Ref. 206). Unfortunately, most of
these findings are too reductive to be interpreted physiologically. For
example, consider that GCs modulate the effects of a neurotransmitter
upon turnover of a second messenger in a particular brain region (207),
or that GCs modulate the levels of mRNAs for a particular subtype of
the N-methyl-D-aspartate receptor
(208). It is unlikely that information exists as to the time course and
dose responsiveness of effects such as these, the effect of the rapid
stress-responsive hormones on these endpoints, and the preparative
value of any such actions.
For this reason, we have chosen three topics among the neurobiological and behavioral effects of GCs. They are interpretable in the context of adapting to stress, and there is information as to the effects of the early wave of stress-responsive hormones on these endpoints, plus dose-response information regarding GC actions.
1. Cerebral glucose transport and utilization. Stress increases local cerebral glucose utilization within seconds (209), an effect mediated by sympathetic activation. It is probably not due to catecholamines directly acting upon glucose transport mechanisms in neurons or glia, since catecholamines do not readily pass the blood-brain barrier. Instead, sympathetic arousal stimulates cardiovascular tone and increases cerebral blood flow.
GCs are well known for inhibiting glucose transport in various peripheral tissues (210). This phenomenon appears to extend to the brain. In vivo, GCs inhibit local cerebral glucose utilization throughout the brain (211, 212, 213, 214) and inhibit glucose transport in neurons, glia, and possibly endothelial cells in vitro (215, 216). The effect requires stress levels of GCs (a minimum of 100 nM) and is GR-mediated. The mechanisms underlying the inhibition are understood. Over the course of minutes to hours, GCs cause the translocation of glucose transporters from the cell surface to inactive intracellular storage sites (217, 218, 219). In addition, over the course of hours to days, GCs also decrease the level of mRNA for the glucose transporter (220).
These findings yield a consistent categorization when the criteria are applied. Insofar as GCs do the opposite of catecholamines, by the criterion of conformity GC actions are suppressive. GCs are also suppressive by the criterion of time course in that they reverse the stimulation of glucose utilization occurring in the early seconds of the stress response. Adrenalectomy increases glucose utilization throughout the brain (211), suggesting a suppressive action by the subtraction criterion.
2. Appetite and feeding.Stress suppresses feeding in less than 1 h, even in food-deprived animals (221). This effect is probably mediated by CRH; the peptide is a potent anorexic agent, and CRH antagonists block the anorexic effects of stress (222). These CRH actions reflect a neurotransmitter role, as the effect occurs in hypophysectomized animals, or after intracerebroventricular injection of CRH (223).
In contrast, GCs stimulate appetite over days in rats. Adrenalectomy decreases feeding and food-seeking behavior (224), which is reversed by GC administration. Appetite normally peaks at the time of the circadian cycle when GC concentrations peak, and this peak can be shifted with GC treatment (188). These GC actions appear to center in the paraventricular nucleus of the hypothalamus, where crystalline implants of GCs also stimulate feeding (225, 226).
GCs stimulate appetite monotonically over the entire dose range in various species, including humans. There are two complications in reaching this conclusion. First, while basal concentrations of GCs stimulate appetite (188), stress concentrations decrease appetite, a finding that changes the interpretation of this section (227, 228). This inhibition was subsequently shown to be due to the high concentrations of GCs stimulating a burst of insulin secretion. The inhibitory effects of insulin upon appetite (229) more than offset the stimulating GC effects; in the absence of GC-induced insulin secretion (in streptozotocin diabetic rats), GCs stimulate appetite over the entire dose range (188).
Second, aldosterone, or GCs at concentrations that only occupy the MR, stimulate consumption of both carbohydrates and fats, whereas GR-specific agonists stimulate only carbohydrate consumption (226). However, despite low and high concentrations of GCs stimulating appetite in different ways, GCs nonetheless stimulate feeding in a monotonic manner over their entire dose range.
Thus, by the criteria of conformity and of time course, GC actions suppress these facets of the stress response. The criterion of subtraction leads to this categorization as well as the adrenalectomy data just noted.
In considering the criterion of homeostasis, we can perceive no way in which the relatively slow stimulation of appetite (by GCs) could help during a stressor such as a sprint across a savanna. In contrast, the earlier responses, which are then inhibited by GCs, are readily viewed in that manner. Feeding, a costly process that provides energy relatively slowly, is obviously expendable during a stressful crisis. Thus, this criterion suggests that GC actions suppress and aid the recovery from the anorectic facet of the stress response. In addition, to the extent that GCs stimulate appetite to the point that metabolic stores are ultimately greater than before the onset of the stressor [a pattern often seen (188)], there are preparative features to this GC effect, equipping the organism for the metabolic costs of a subsequent stressor.
Thus, by stimulating appetite and feeding, GC effects are mostly suppressive, with some preparative features as well. The fact that GCs have these effects over their entire dose range, plus the seeming involvement of both MRs and GRs, suggest that basal and stress levels of GCs tend to suppress this facet of the stress response. Moreover, insofar as feeding is preparatory for the energy expenditure of the next sprint across a savanna, there are preparative elements to these GC actions as well.
3. Memory formation. Acute stressors enhance memory formation, a phenomenon familiar to many in the form of vividly remembering where they were when some tragic historical news was announced (230). As a more controlled demonstration of this phenomenon, volunteers were read one of two storie
