The well - documented effects of aldosterone on electrolyte transport in the epithelia
of the distal nephron and colon [86, 87] can affect blood pressure and abnormal
regulation of the RAS is implicated in hypertension [19, 88] . Mineralocorticoids
also have actions in the heart [89] , vasculature and brain [90] that can infl uence
blood pressure homeostasis and cardiovascular control. Aldosterone is required
for adaptation of blood pressure to postural changes and the clinical treatment of
postural hypotension is fl udrocortisone. These rapid changes in blood pressure
occur long before any alteration in plasma volume and therefore lie outwith the
control of renal MR. Furthermore, the antihypertensive effects of MR blockade do
not correlate with any effects on renal salt balance [91] . The actions in nonepithelial
tissue are informative in that they provide insights into “ nonclassical ” activation
of MR and challenge the conventional view of receptor – ligand relationships.
Aldosterone and the Heart
Although aldosterone has both genomic and nongenomic effects on the biophysi-
cal properties of the cardiomyocyte (e.g. [92] ), a physiological role has been dis-
counted [93] on the basis that MR are antagonized by glucocorticoids under normal
circumstances (see below). In contrast a pathological role for MR activation, par-
ticularly in the setting of mineralocorticoid excess or salt loading, has been dem-
onstrated since the 1940s.
In the early 1990s a study by Brilla and Weber investigated the effects of min-
eralocorticoid excess with relation to cardiovascular function, observing that rats
exposed to high levels of both aldosterone and salt developed hypertension and
cardiac fi brosis [94] . This triggered resurgence in clinical interest with data sug-
gesting that actual mineralocorticoid excess was associated with cardiac abnor-
malities [95] . Treatment of cardiac abnormalities through MR blockade was
recommended following positive outcomes of two clinical trials: RALES and
EPHESUS [96, 97] . In the RALES study, patients with severe heart failure were
administered the MR antagonist spironolactone, alongside their continuing con-
ventional medication. This produced a 30% reduction in mortality and a 35% lower
frequency of hospitalization versus placebo - treated patients. Further verifi cation
of the benefi cial effects of MR blockade and aldosterone antagonism was provided
by the EPHESUS study in which eplerenone, an antagonist at MR more selective
than spironolactone, was administered to patients who had suffered an acute
myocardial infarction. Again, the results of MR blockade were particularly positive
in terms of patient morbidity and mortality.
These trials show MR blockade to be benefi cial in the treatment of heart disease,
but the underlying mechanisms of action were not clear. The most straightforward
explanation was that MR blockade inhibited the effects of aldosterone in the heart
and was therefore cardioprotective. Indeed, it has been shown experimentally that
increased aldosterone levels coupled with increased salt levels instigates deleteri-
ous cardiac and vascular pathologic responses [98] and, circumstantially, aldoste-
rone levels are often raised in congestive heart failure [99] . However, in neither
RALES nor EPHESUS were plasma aldosterone levels elevated [96, 97] . Similarly,
in Dahl - salt - sensitive rats fed a high salt diet, MR blockade prevented the develop-
ment of cardiac hypertrophy and the onset of chronic heart failure, despite the fact
that aldosterone was lower in this group than controls [100] . In this case, the car-
dioprotective effects of eplerenone were independent of the antihypertensive effect
of MR blockade, as has been reported elsewhere [91] . Together these data indicate
that MR activation per se , rather than excess of agonist is critical to the developing
pathology. Experiments using transgenic approaches are not so clear: mice over-
expressing human MR display only mild cardiomyopathy [101] and mice in which
MR has been knocked down via an inducible antisense transgene have severe heart
failure (Figure 1.7 ) [103] .
In contrast to classical aldosterone target tissues, occupancy of cardiac MR by
glucocorticoids is the physiological norm [104] : 11 β HSD2 is not normally expressed
in cardiomyocytes at physiologically relevant levels. This would indicate that the
benefi ts of MR blockade could be ascribed to relief from stimulation by glucocor-
ticoids. However, the mode of glucocorticoid action at cardiac MR is not clear.
Experiments designed to test this hypothesis followed the generation of a mouse
expressing 11 β HSD2 selectively in cardiomyoctes [102] . Surprisingly, these mice
developed severe cardiac hypertrophy and fi brosis, and died from accelerated heart
failure (Figure 1.7 ). Moreover, an MR antagonist rescued the cardiopathology,
whereas a GR antagonist did not. These data indicate that (i) glucocorticoids nor-
mally occupy cardiac MR, but act as an antagonist rather than agonist, and (ii) that
aldosterone activation of MR – only observed when 11 β HSD2 prevents glucocorti-
coid occupancy – is detrimental to heart function.
The data above are confusing and often confl icting, suggesting that MR blockade
is both benefi cial and damaging and that glucocorticoids can both activate and
antagonize the MR. Recent data may reconcile these observations [105] . In isolated
cardiomyocytes, aldosterone will activate the Na+K – 2Cl
cotransporter, whereas
cortisol will not [106] : coadministration of cortisol with aldosterone blocks the
activation of the cotransporter. Moreover, if the redox state is altered to mimic
production of reactive oxygen species, cortisol no longer antagonizes the actions
of aldosterone and even acts as a mineralocorticoid. Thus, the question of what
prompts the glucocorticoids to turn from tonic antagonists into pathological ago-
nists may well rest with the generation of reactive oxygen species that can occur
following cardiac trauma [89, 105] .
of the distal nephron and colon [86, 87] can affect blood pressure and abnormal
regulation of the RAS is implicated in hypertension [19, 88] . Mineralocorticoids
also have actions in the heart [89] , vasculature and brain [90] that can infl uence
blood pressure homeostasis and cardiovascular control. Aldosterone is required
for adaptation of blood pressure to postural changes and the clinical treatment of
postural hypotension is fl udrocortisone. These rapid changes in blood pressure
occur long before any alteration in plasma volume and therefore lie outwith the
control of renal MR. Furthermore, the antihypertensive effects of MR blockade do
not correlate with any effects on renal salt balance [91] . The actions in nonepithelial
tissue are informative in that they provide insights into “ nonclassical ” activation
of MR and challenge the conventional view of receptor – ligand relationships.
Aldosterone and the Heart
Although aldosterone has both genomic and nongenomic effects on the biophysi-
cal properties of the cardiomyocyte (e.g. [92] ), a physiological role has been dis-
counted [93] on the basis that MR are antagonized by glucocorticoids under normal
circumstances (see below). In contrast a pathological role for MR activation, par-
ticularly in the setting of mineralocorticoid excess or salt loading, has been dem-
onstrated since the 1940s.
In the early 1990s a study by Brilla and Weber investigated the effects of min-
eralocorticoid excess with relation to cardiovascular function, observing that rats
exposed to high levels of both aldosterone and salt developed hypertension and
cardiac fi brosis [94] . This triggered resurgence in clinical interest with data sug-
gesting that actual mineralocorticoid excess was associated with cardiac abnor-
malities [95] . Treatment of cardiac abnormalities through MR blockade was
recommended following positive outcomes of two clinical trials: RALES and
EPHESUS [96, 97] . In the RALES study, patients with severe heart failure were
administered the MR antagonist spironolactone, alongside their continuing con-
ventional medication. This produced a 30% reduction in mortality and a 35% lower
frequency of hospitalization versus placebo - treated patients. Further verifi cation
of the benefi cial effects of MR blockade and aldosterone antagonism was provided
by the EPHESUS study in which eplerenone, an antagonist at MR more selective
than spironolactone, was administered to patients who had suffered an acute
myocardial infarction. Again, the results of MR blockade were particularly positive
in terms of patient morbidity and mortality.
These trials show MR blockade to be benefi cial in the treatment of heart disease,
but the underlying mechanisms of action were not clear. The most straightforward
explanation was that MR blockade inhibited the effects of aldosterone in the heart
and was therefore cardioprotective. Indeed, it has been shown experimentally that
increased aldosterone levels coupled with increased salt levels instigates deleteri-
ous cardiac and vascular pathologic responses [98] and, circumstantially, aldoste-
rone levels are often raised in congestive heart failure [99] . However, in neither
RALES nor EPHESUS were plasma aldosterone levels elevated [96, 97] . Similarly,
in Dahl - salt - sensitive rats fed a high salt diet, MR blockade prevented the develop-
ment of cardiac hypertrophy and the onset of chronic heart failure, despite the fact
that aldosterone was lower in this group than controls [100] . In this case, the car-
dioprotective effects of eplerenone were independent of the antihypertensive effect
of MR blockade, as has been reported elsewhere [91] . Together these data indicate
that MR activation per se , rather than excess of agonist is critical to the developing
pathology. Experiments using transgenic approaches are not so clear: mice over-
expressing human MR display only mild cardiomyopathy [101] and mice in which
MR has been knocked down via an inducible antisense transgene have severe heart
failure (Figure 1.7 ) [103] .
In contrast to classical aldosterone target tissues, occupancy of cardiac MR by
glucocorticoids is the physiological norm [104] : 11 β HSD2 is not normally expressed
in cardiomyocytes at physiologically relevant levels. This would indicate that the
benefi ts of MR blockade could be ascribed to relief from stimulation by glucocor-
ticoids. However, the mode of glucocorticoid action at cardiac MR is not clear.
Experiments designed to test this hypothesis followed the generation of a mouse
expressing 11 β HSD2 selectively in cardiomyoctes [102] . Surprisingly, these mice
developed severe cardiac hypertrophy and fi brosis, and died from accelerated heart
failure (Figure 1.7 ). Moreover, an MR antagonist rescued the cardiopathology,
whereas a GR antagonist did not. These data indicate that (i) glucocorticoids nor-
mally occupy cardiac MR, but act as an antagonist rather than agonist, and (ii) that
aldosterone activation of MR – only observed when 11 β HSD2 prevents glucocorti-
coid occupancy – is detrimental to heart function.
The data above are confusing and often confl icting, suggesting that MR blockade
is both benefi cial and damaging and that glucocorticoids can both activate and
antagonize the MR. Recent data may reconcile these observations [105] . In isolated
cardiomyocytes, aldosterone will activate the Na+K – 2Cl
cotransporter, whereas
cortisol will not [106] : coadministration of cortisol with aldosterone blocks the
activation of the cotransporter. Moreover, if the redox state is altered to mimic
production of reactive oxygen species, cortisol no longer antagonizes the actions
of aldosterone and even acts as a mineralocorticoid. Thus, the question of what
prompts the glucocorticoids to turn from tonic antagonists into pathological ago-
nists may well rest with the generation of reactive oxygen species that can occur
following cardiac trauma [89, 105] .
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