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

inhibits renin secretion). Simultaneous activation of the G i
pathway
by Ca 2+ reduces cAMP synthesis and lowers the activity of PKA,
also a negative signal for PTH secretion. Conversely, reduced occupancy
of CaSR by Ca 2+ reduces signaling through G i
and G q
, lessening
inhibition of adenylyl cyclase and lowering activation of the G q
pathway, thereby promoting PTH secretion. Thus, the extracellular
concentration of Ca 2+ is controlled by a classical negative-feedback
system, the afferent limb of which is sensitive to the ambient activity
of Ca 2+ and the efferent limb of which releases PTH. Acting via
the CaSR, hypercalcemia reduces intracellular cyclic AMP content
and activates PKC, whereas hypocalcemia does the reverse. The precise
links between these changes and alterations in PTH secretion
remain to be defined. Other agents that increase parathyroid cell
cyclic AMP levels, such as β adrenergic receptor agonists and
dopamine, also increase PTH secretion, but the magnitude of
response is far less than that seen with hypocalcemia. The active
vitamin D metabolite, 1,25-dihydroxyvitamin D (calcitriol), directly
suppresses PTH gene expression. There appears to be no relation
between physiological concentrations of extracellular phosphate and
PTH secretion, except insofar as changes in phosphate concentration
alter circulating Ca 2+ . Severe hypermagnesemia or hypomagnesemia
can inhibit PTH secretion.
Effects on Bone. PTH exerts both catabolic and anabolic effects on
bone. Normally, these processes are tightly coupled. Chronically elevated
PTH enhances bone resorption and thereby increases Ca 2+
delivery to the extracellular fluid, whereas intermittent exposure to
PTH promotes anabolic actions. The primary skeletal target cell for
PTH is the osteoblast, although evidence points to the presence of
functional PTH receptors on osteocytes (O’Brien et al., 2008). PTH
also recruits osteoclast precursor cells to form new bone remodeling
units. Sustained increases in circulating PTH cause characteristic histological
changes in bone that include an increase in the prevalence
of osteoclastic resorption sites and in the proportion of bone surface
that is covered with unmineralized matrix (Martin and Ng, 1994).
Direct effects of PTH on osteoblasts in vitro generally are
inhibitory and include reduced formation of type I collagen, alkaline
phosphatase, and osteocalcin. However, the response to PTH in
vivo reflects not only hormone action on individual cells but also the
increased total number of active osteoblasts, owing to initiation of
new remodeling units. Thus, plasma levels of osteocalcin and alkaline
phosphatase activity actually may be increased. No simple
model can fully explain the molecular basis of PTH effects on bone.
PTH stimulates cyclic AMP production in osteoblasts, but there also
is evidence that intracellular Ca 2+ mediates some PTH actions.
Effects on Kidney. In the kidney, PTH enhances the efficiency of Ca 2+
reabsorption, inhibits tubular reabsorption of phosphate, and stimulates
conversion of vitamin D to its biologically active form, calcitriol
(Figure 44–3). As a result, filtered Ca 2+ is avidly retained, and
its concentration increases in plasma, whereas phosphate is excreted,
and its plasma concentration falls. Newly synthesized calcitriol interacts
with specific high-affinity receptors in the intestine to increase
the efficiency of intestinal Ca 2+ absorption, thereby contributing to
the increase in plasma (Ca 2+ ).
Calcium. PTH increases tubular reabsorption of Ca 2+ with concomitant
decreases in urinary Ca 2+ excretion. The effect occurs at
distal nephron sites. This action, along with mobilization of calcium
from bone and increased absorption from the intestine, increases the
concentration of Ca 2+ in plasma. Eventually, the increased glomerular
filtration of Ca 2+ overwhelms the stimulatory effect of PTH on
tubular reabsorption, and hypercalciuria ensues. Conversely, reduction
of serum PTH depresses tubular reabsorption of Ca 2+ and
thereby increases urinary Ca 2+ excretion. When the plasma Ca 2+ concentration
falls below 7 mg/dL (1.75 mM), Ca 2+ excretion decreases
as the filtered load of Ca 2+ reaches the point where the cation is
almost completely reabsorbed despite reduced tubular capacity.
Phosphate. PTH increases renal excretion of inorganic phosphate
by decreasing its reabsorption by proximal tubules. This action is
mediated by retrieval of the luminal membrane Na–P i
cotransport
protein, NPT2a, rather than an effect on its activity. Patients with
primary hyperparathyroidism therefore typically have low tubular
phosphate reabsorption.
Cyclic AMP apparently mediates the renal effects of PTH on
proximal tubular phosphate reabsorption. PTH-sensitive adenylyl
cyclase is located in the renal cortex, and cyclic AMP synthesized in
response to the hormone affects tubular transport mechanisms. A
portion of the cyclic AMP synthesized at this site, so-called
nephrogenous cyclic AMP, escapes into the urine. Measurement of
urinary cyclic AMP is used as a surrogate for parathyroid activity
and renal responsiveness.
Other Ions. PTH reduces renal Mg 2+ excretion. This effect
reflects the net result of enhanced renal Mg 2+ reabsorption and
increased mobilization of the ion from bone (Quamme, 2010). PTH
increases excretion of water, amino acids, citrate, K + , bicarbonate,
Na + , Cl – , and SO 4
2–
, whereas it decreases the excretion of H + . These
effects are minor and generally can be seen only under tightly controlled
circumstances.
Calcitriol Synthesis. The final step in the activation of vitamin D
to calcitriol occurs in kidney proximal tubule cells. Three primary
regulators govern the enzymatic activity of the 25-hydroxyvitamin
D 3
-1α-hydroxylase that catalyzes this step: P i
, PTH, and Ca 2+ (see
later for further discussion). Reduced circulating or tissue phosphate
content rapidly increases calcitriol production, whereas hyperphosphatemia
or hypercalcemia suppresses it. PTH powerfully stimulates
calcitriol synthesis. Thus, when hypocalcemia causes a rise in PTH
concentration, both the PTH-dependent lowering of circulating P i
and a more direct effect of the hormone on the 1α-hydroxylase lead
to increased circulating concentrations of calcitriol.
Integrated Regulation of Extracellular Ca 2+ Concentration by PTH.
Even modest reductions of serum Ca 2+ stimulate PTH secretion. For
minute-to-minute regulation of Ca 2+ , adjustments in renal Ca 2+ handling
more than suffice to maintain plasma calcium homeostasis.
With more prolonged hypocalcemia, the renal 1α-hydroxylase is
induced, enhancing the synthesis and release of calcitriol that
directly stimulates intestinal calcium absorption (Figure 44–3). In
addition, delivery of calcium from bone into the extracellular fluid
is augmented. In the face of prolonged and severe hypocalcemia,
new bone remodeling units are activated to restore circulating Ca 2+
concentrations, albeit at the expense of skeletal integrity.
When plasma Ca 2+ activity rises, PTH secretion is suppressed,
and tubular Ca 2+ reabsorption decreases. The reduction in circulating
PTH promotes renal phosphate conservation, and both the decreased
PTH and the increased phosphate depress calcitriol production and
thereby decrease intestinal Ca 2+ absorption. Finally, bone remodeling
is suppressed. These integrated physiological events ensure a coherent
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CHAPTER 44
AGENTS AFFECTING MINERAL ION HOMEOSTASIS AND BONE TURNOVER