DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1220 effect of other agents, such as growth hormone and β
adrenergic receptor agonists, resulting in an increase in
free fatty acids after glucocorticoid administration.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
One hypothesis for the redistribution of body fat is that
peripheral and truncal adipocytes differ in their relative sensitivities
to insulin and to glucocorticoid-facilitated lipolytic effects. Truncal
adipocytes respond predominantly to elevated levels of insulin resulting
from glucocorticoid-induced hyperglycemia, whereas peripheral
adipocytes are less sensitive to insulin and respond mostly to the glucocorticoid-facilitated
effects of other lipolytic hormones. This differential
sensitivity may reflect differences in the expression of
11βHSD1 that converts inactive cortisone into active cortisol in target
tissues (Figure 42–6). Consistent with this idea, overexpression
of 11βHSD1 in adipocytes causes obesity in a transgenic mouse
model. The potential role of this enzyme in adipocyte function has
prompted speculation that 11βHSD1 inhibitors may have a role in
the treatment of obesity.
Electrolyte and Water Balance. Aldosterone is by far the
most potent endogenous corticosteroid with respect to
fluid and electrolyte balance. Thus, electrolyte balance is
relatively normal in patients with adrenal insufficiency due
to pituitary disease, despite the loss of glucocorticoid production
by the inner cortical zones. Mineralocorticoids act
on the distal tubules and collecting ducts of the kidney to
enhance reabsorption of Na + from the tubular fluid; they
also increase the urinary excretion of K + and H + .
Conceptually, it is useful to think of aldosterone as stimulating
a renal exchange between Na + and K + or H + ,
although this does not involve a simple 1:1 exchange of
cations in the renal tubule.
These actions on electrolyte transport, in the kidney
and in other tissues (e.g., colon, salivary glands, and
sweat glands), appear to account for the physiological
and pharmacological activities that are characteristic of
mineralocorticoids. Thus, the primary features of hyperaldosteronism
are positive Na + balance with consequent
expansion of extracellular fluid volume, normal or slight
increases in plasma Na + concentration, normal or low
plasma K + , and alkalosis. Mineralocorticoid deficiency,
in contrast, leads to Na + wasting and contraction of the
extracellular fluid volume, hyponatremia, hyperkalemia,
and acidosis. Indeed, mineralocorticoid-deficient
patients are especially predisposed to Na + loss and volume
depletion through excessive sweating in hot environments.
Chronically, hyperaldosteronism causes hypertension,
whereas aldosterone deficiency can lead to
hypotension and vascular collapse.
Further insights into the roles of aldosterone target genes in
fluid and electrolyte balance have emerged from analyses of patients
with rare genetic disorders of mineralocorticoid action, such as
pseudohypoaldosteronism and pseudoaldosteronism. Despite elevated
levels of mineralocorticoids, patients with classical pseudohypoaldosteronism
(i.e., type 1 disease) present with clinical manifestations
suggestive of deficient mineralocorticoid action (i.e., volume
depletion, hypotension, hyperkalemia, and metabolic acidosis).
Molecular analyses have defined discrete subpopulations of patients
with this disorder. One form of the disease is caused by autosomal
dominant mutations in the MR that impair its activity. A second,
autosomal recessive form results from loss-of-function mutations in
genes encoding subunits of the amiloride-sensitive epithelial Na +
channel. A nonclassical pseudohypoaldosteronism (type 2, also
known as Gordon’s syndrome) presents with hyperkalemia, mild
metabolic acidosis, and familial hypertension. In some of these
patients, the disease is caused by autosomal dominant mutations in
the protein kinase genes WNK1 and WNK4 that inhibit the sodium
chloride cotransporter. Pseudoaldosteronism, also termed Liddle’s
syndrome, is an autosomal dominant disease that results from mutations
in subunits of the amiloride-sensitive Na + channel that interfere
with its downregulation. The constitutive activity of this channel
leads to hypertension, hypokalemia, and metabolic alkalosis, despite
low levels of plasma renin and aldosterone.
Glucocorticoids also exert effects on fluid and electrolyte balance,
largely due to permissive effects on tubular function and
actions that maintain glomerular filtration rate. Glucocorticoids play
a permissive role in the renal excretion of free water. In part, the
inability of patients with glucocorticoid deficiency to excrete free
water results from the increased secretion of AVP, which stimulates
water reabsorption in the kidney.
In addition to their effects on monovalent cations and water,
glucocorticoids also exert multiple effects on Ca 2+ metabolism.
Steroids lower Ca 2+ uptake from the gut and increase Ca 2+ excretion
by the kidney. These effects collectively lead to decreased total body
Ca 2+ stores.
Cardiovascular System. The most striking effects of corticosteroids
on the cardiovascular system result from
mineralocorticoid-induced changes in renal Na + , as is
evident in primary aldosteronism. Studies have shown
direct effects of MR activation on the heart and vessel
wall; aldosterone induces hypertension and interstitial
cardiac fibrosis in animal models. The increased cardiac
fibrosis is proposed to result from direct mineralocorticoid
actions in the heart rather than from the effect
of hypertension because treatment with spironolactone,
a MR antagonist, blocks the development of fibrosis
without altering blood pressure. Indeed, in age-, sex-,
and blood pressure-matched hypertensive patients,
those with primary aldosteronism have a higher prevalence
of atrial fibrillation, stroke, and myocardial
infarction, indicating direct effects of increased aldosterone
on the cardiovascular system. Similar cardiac
effects of MR activation in human beings may explain
the beneficial effects of spironolactone in patients with
congestive heart failure (Chapter 28).
The second major action of corticosteroids on the
cardiovascular system is to enhance vascular reactivity