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

Regulation of Vasopressin Secretion. An increase in
plasma osmolality is the principal physiological stimulus
for vasopressin secretion by the posterior pituitary
(Bankir, 2001). Severe hypovolemia/hypotension also is
a powerful stimulus for vasopressin release. In addition,
pain, nausea, and hypoxia can stimulate vasopressin
secretion, and several endogenous hormones and pharmacological
agents can modify vasopressin release.
Hyperosmolality. The relationship between plasma osmolality and
plasma vasopressin concentration is shown in Figure 25–17A, and
the relationship between plasma vasopressin levels and urine osmolality
is illustrated in Figure 25–17B. The osmolality threshold for
secretion is ~280 mOsm/kg. Below the threshold, vasopressin is
barely detectable in plasma, and above the threshold, vasopressin
levels are a steep and relatively linear function of plasma osmolality.
A small increase in plasma osmolality leads to enhanced vasopressin
secretion. Indeed, a 2% elevation in plasma osmolality causes
a 2- to 3-fold increase in plasma vasopressin levels, which in turn
causes increased solute-free water reabsorption, with an increase in
urine osmolality. Increases in plasma osmolality above 290
mOsm/kg lead to an intense desire for water (thirst). Thus, the vasopressin
system affords the organism longer thirst-free periods and, in
the event that water is unavailable, allows the organism to survive
longer periods of water deprivation. It is important to point out, however,
that above a plasma osmolality of ~290 mOsm/kg, plasma
vasopressin levels exceed 5 pM. Since urinary concentration is maximal
(~1200 mOsm/kg) when vasopressin levels exceed 5 pM, further
defense against hypertonicity depends entirely on water intake
rather than on decreases in water loss.
Several CNS structures are involved in osmotic stimulation of
vasopressin release by the posterior pituitary; these structures are collectively
referred to as the osmoreceptive complex. Although magnocellular
neurons in SON and PVN are osmosensitive, afferent inputs
A
Plasma vasopressin
pg/ml
12
8
4
Thirst
B
from other components of the osmoreceptive complex are required
for a normal vasopressin response. The SON and PVN receive
projections from the subfornical organ (SFO) and the organum vasculosum
of the lamina terminalis (OVLT) either directly or indirectly
by means of the median preoptic nucleus (MnPO). Subgroups of neurons
in the SFO, OVLT, and MnPO are either osmoreceptors or
osmoresponders (i.e., are stimulated by osmoreceptive neurons
located at other sites). Thus, a web of interconnecting neurons contributes
to osmotically induced vasopressin secretion.
Aquaporin 4, a water-selective channel, is associated with
CNS structures involved in osmoregulation and may confer
osmosensitivity. In the CNS, aquaporin 4 resides on glial and
ependymal cells rather than on neurons, suggesting that osmotic status
may be communicated to the neuronal cell by a glial-neuron
interaction (Wells, 1998).
Hepatic Portal Osmoreceptors. An oral salt load activates hepatic
portal osmoreceptors leading to increased vasopressin release. This
mechanism augments plasma vasopressin levels even before the oral
salt load increases plasma osmolality.
Hypovolemia and Hypotension. Vasopressin secretion also is regulated
hemodynamically by changes in effective blood volume
and/or arterial blood pressure (Robertson, 1992). Regardless of
the cause (e.g., hemorrhage, Na + depletion, diuretics, heart failure,
hepatic cirrhosis with ascites, adrenal insufficiency, or
hypotensive drugs), reductions in effective blood volume and/or
arterial blood pressure may be associated with high circulating
vasopressin concentrations. However, unlike osmoregulation,
hemodynamic regulation of vasopressin secretion is exponential;
i.e., small decreases (5%) in blood volume and/or pressure have
little effect on vasopressin secretion, whereas larger decreases
(20-30%) can increase vasopressin levels to 20-30 times normal
(exceeding the vasopressin concentration required to induce maximal
antidiuresis). Vasopressin is one of the most potent vasoconstrictors
Urine osmolality
mOsm/kg
1400
1200
1000
800
600
400
703
CHAPTER 25
REGULATION OF RENAL FUNCTION AND VASCULAR VOLUME
0
270 280 290 300 310
Plasma osmolality
mOsm/kg
200
0
0 1 2 3 4 5 10 15
Plasma vasopressin
pg/ml
Figure 25–17. A. The relationship between plasma osmolality and plasma vasopressin levels. Plasma osmolality range associated with
thirst is indicated by arrow. B. The relationship between plasma vasopressin levels and urine osmolality. (From Robertson et al., 1977,
and Kovacs and Robertson, 1992, with permission. Copyright © Elsevier.)